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. 2018 Aug 30;3(8):10250–10254. doi: 10.1021/acsomega.8b01455

Revisiting the Case of an Intramolecular Hydrogen Bond Network Forming Four- and Five-Membered Rings in d-Glucose

Francisco A Martins 1, Matheus P Freitas 1,*
PMCID: PMC6645413  PMID: 31459154

Abstract

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The conformational behavior of cyclic monosaccharides has been widely studied over the past years, but there is no general agreement about which effects are in fact responsible for the observed conformational preferences. A recent microwave spectroscopy study determined the conformational equilibrium of d-glucose in the gas phase with a preference for a counterclockwise arrangement of the hydroxyl groups. Nevertheless, the effects that control this orientation are still uncertain because the role of intramolecular hydrogen bonds (IHBs), electrostatic and steric repulsions is not clear. This work reports a density functional theory approach based on the conformational energies of d-glucose and of some derivatives in which the anomeric hydroxyl is replaced with hydrogen (H, small and not prone to participate in proton transfer), fluorine (F, small, electronegative, and as capable as OH of forming hydrogen bonds as a proton acceptor), and chlorine (Cl, big and not anticipated to be involved in effective hydrogen bond formation) to obtain insights into the effects of the substituent at the anomeric carbon on the arrangement of the hydroxyl groups in d-glucose. The nature of the substituents at this position is crucial to determine the orientation of the remaining hydroxyl groups. Natural bond orbital (NBO) and quantum theory of atoms in molecules (QTAIM) analyses, in addition to NMR chemical shift calculations, have been provided to support the conformational energy outcomes. Overall, the results agree with the lack of IHBs forming four- and five-membered rings in d-glucose and emphasize that steric and electrostatic repulsions involving the hydroxyl groups in the clockwise orientation are driving forces of the conformational behavior.

1. Introduction

Organic compounds play a fundamental role in biological chemistry because of their numerous biological properties determined along the years.1−3 However, the properties of biomolecules, such as amino acids, lipids, and carbohydrates, are not limited to biological functions. Carbohydrates, for example, have specific applications in materials science in addition to their well-known biological role.4−6 In fact, a huge number of studies have been reported with focus on the carbohydrate chemistry, and one of the most important topics highlights the conformational behavior of these molecules.7−10

The importance of the complete understanding of the conformational behavior of organic molecules is remarkable because the stereochemical arrangement of atoms in a molecule can deeply affect its macroscopic features.11,12 In this sense and still regarding carbohydrates, a number of conformational effects are relevant to account for this class of compounds. The most remarkable interaction affecting the stereochemistry of this class of compounds is the anomeric effect, according to which the α-anomer of a pyranoside ring is surprisingly stable if only traditional steric effects are taken into consideration.13,14 The gauche effect is also important for the conformational preferences in cyclic sugars because these systems bear vicinal electronegative groups that tend to be arranged in a gauche orientation because of hyperconjugative interactions.15 Nevertheless, another interesting and controversial conformational finding in d-glucose is the counterclockwise (cc) preference for the orientation of the hydroxyl groups.

The complete conformational assignment of d-glucose in the gas phase has been recently carried out through a microwave spectroscopy experiment;16 only one out of the seven conformers found for d-glucose adopts a clockwise (cl) arrangement of hydroxyl groups. In addition, the authors addressed the conformational preference for the cc orientation in d-glucose to a cooperative network of intramolecular hydrogen bonds (IHBs), despite the well-known statement that IHBs forming small rings are weak or even absent.17−19 Since then, some studies have focused on clarifying the actual origin of this preference. Silla et al.,20 using a joint analysis of noncovalent interactions (NCI), quantum theory of atoms in molecules (QTAIM), and natural bond orbital (NBO) theoretical approaches, described that the cc orientation of the hydroxyl groups in d-glucose is caused by electron lone pair repulsion involving the endocyclic oxygen and the anomeric hydroxyl group in the cl conformer. Both arguments based on IHBs and repulsion in the cl conformation have been refuted by Lomas and Joubert,21 who established a complexation model of d-glucose with pyridine (a proton acceptor) and NMR chemical shift calculations to conclude that cooperativity of IHBs is not full nor absent and that the interaction with an electron-accepting solvent enhances the IHB strength.

Therefore, a theoretical approach based primarily on an analysis of the structure and conformational energies of d-glucose and some derivatives, where the OH group at C1 was replaced with H, F, and Cl, rather than on topological electron density and NMR chemical shift analyses was carried out to find out the reason for the cc preference in d-glucose (Figure 1). In this way, an evaluation independent of NCI methods (which have been demonstrated to be conflicting in some instances22−24) is provided because only the choice of an accurate method for geometry optimization and energy calculation is required to obtain reliable insights into the effects governing the orientation of hydroxyl groups in d-glucose. The derivative with a H atom at C1 rather than OH allows evaluation of the absence of both steric repulsion and a proton transfer group at C1 on the orientation of the remaining hydroxyl groups in the ring; the fluorinated derivative nearly resembles the d-glucose molecule in terms of proton acceptance because of the similar size and electronegativity of fluorine compared to oxygen; and the chlorine substituent in the chlorinated model provides high steric hindrance, and it is a weak hydrogen-bond acceptor.25−28 Moreover, an explicit water molecule was attached to the endocyclic oxygen in order to evaluate the ability of the latter (O5) in modulating IHBs as a proton acceptor upon the influence of the former (explicit water).

Figure 1.

Figure 1

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cc and cl conformers of d-glucose (X = OH) and the respective derivatives studied herein (X = H, F, and Cl).

2. Results and Discussion

The conformational energies and populations obtained for d-glucose at the B3LYP/aug-cc-pVDZ level in the gas phase (Table 1) are in agreement with Fourier transform microwave spectroscopy results16 as well as with other theoretical levels reported elsewhere,20 thus validating our density functional theory calculations for further studies with d-glucose derivatives. For d-glucose, the α-anomer is the major stereoisomer as a result of the well-known anomeric effect, while the hydroxyl groups are mainly oriented in a cc arrangement, with only a single minor conformer (α_G-g+/cl/g−) exhibiting a cl orientation for these groups. The controversy lies in the nature of this preferential orientation, since a chain of cooperative IHBs and electron lone pair repulsion between O5 and the anomeric OH as the starting point have been invoked to explain such a behavior. Because of the difficulty in dissecting the contributions from steric and dipolar repulsions, the general term repulsion will be often used herein. A comparison of d-glucose with derivatives bearing anomeric substituents with different properties relative to the OH group, such as size, electron-withdrawing character, and proton-donating/proton-accepting ability, is expected to outline the reasons for the observed pattern.

Table 1. Relative Conformational Energies (kcal mol–1) and Boltzmann Conformer Populations (%, in Parentheses) for d-Glucose (X = OH) and Its Derivatives (X = H, F, and Cl).

conformer X = OH X = H X = F X = Cl X = OH + explicit water
β_G+g–/cc/t 0.7 (9) 0.7 (16) 2.4 (1) 2.9 (0) 1.7 (3)
β_G–g+/cc/t 0.7 (9) 0.7 (16) 2.4 (1) 2.9 (0) 1.2 (7)
β_Tg+/cc/t 1.1 (4) 1.2 (6) 3.1 (0) 3.7 (0) 2.7 (1)
α_G+g–/cc/t 0.1 (25) 1.2 (6) 0.3 (29) 0.2 (35) 0.9 (11)
α_G–g+/cc/t 0.0 (30) 1.3 (5) 0.0 (48) 0.0 (49) 1.4 (4)
α_G–g+/cl/g– 0.8 (8) 0.0 (49) 1.5 (4) 2.2 (1) 0.5 (22)
α_Tg+/cc/t 0.4 (15) 1.8 (2) 0.6 (17) 0.7 (15) 0.0 (52)
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Replacement of the anomeric OH in d-glucose with a H atom significantly changes the conformational preferences of the resulting compound, which exhibits a cl orientation of the hydroxyl groups at C2, C3, and C4 as the most stable conformer (Table 1). Therefore, the absence of significant steric hindrance at C1 and the lack of a proton donor/acceptor at this position lead to a shift toward the α_G–g+/cl/g– conformation, but the question on the origin of the cc orientation in d-glucose still remains unanswered. However, an α-F substituent suppresses the proton donor ability observed for the OH group at C1, whereas it retains the steric, electrostatic, and proton acceptor features of the oxygen atom. As a result of considering the fluorinated derivative, tiny conformational changes are observed when compared to d-glucose itself, thus indicating that the effect ruling the significant changes in the H-derivative relates to atomic size (steric hindrance) and electronegativity (dipolar repulsion) rather than to IHBs. To better support this finding, the chlorinated derivative was considered to account for a steric increase relative to OH. The replacement of OH in d-glucose with Cl reduces the population of the cl conformation to almost zero, confirming the hypothesis that lone pair repulsion between O5 and X in the cl conformation is responsible for the preferred cc orientation in d-glucose.

An additional model to evaluate the role of steric effects and IHBs in the arrangement of the hydroxyl groups in d-glucose is to consider an explicit water molecule interacting with O5 to inhibit intramolecular interactions (either attractive or repulsive) involving this atom (see the best positions in Figure 2). Despite the increase in the population of the cl arrangement, there is an interchange of stability between cc conformers from α_G–g+/cc/t to α_Tg+/cc/t (Table 1). Thus, it follows that the effect of a water molecule on the conformational energies is more related to its preferential mode of interaction with O5 and neighboring atoms through intermolecular hydrogen bonds than with an attenuation of intramolecular interactions in d-glucose.

Figure 2.

Figure 2

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Stable conformers of d-glucose optimized at the B3LYP/aug-cc-pVDZ level in the gas phase (upper) and with an explicit water molecule (lower).

In hyperconjugation-based terms, IHBs in d-glucose would be described by nO → σO–H* interactions. A second-order perturbation analysis of donor–acceptor interactions in the NBOs shows that, in general, only IHBs forming six-membered rings (O6H6···O4) are importantly stabilized (Supporting Information). The picture changes for the α-anomer of the chlorinated derivative, which exhibits nCl → σO–H electron delocalization energies of more than 2 kcal mol–1. An analysis based on the QTAIM supports these findings because a bond path (a region with high electron density between interacting atoms) is not observed to form four- and five-membered rings through OH···O IHBs, but it appears when the formation of a six-membered ring is possible and it is weaker (but present) for a OH···Cl interaction in the chlorinated derivative (Figure 3).

Figure 3.

Figure 3

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QTAIM plots for some system instances to show (a) a weak OH···Cl IHB forming a five-membered ring in the G+g–/cc/t conformer of the chlorinated derivative of α-d-glucose; (b) a OH···O IHB forming a six-membered ring in the Tg+/cc/t conformer of the chlorinated derivative of β-d-glucose; and (c) strong intermolecular hydrogen bonds between the explicit water molecule and O5 and H6 of β-d-glucose, forming a seven-membered ring IHB in the G+g–/cc/t conformer. Included are some geometrical and QTAIM data used to characterize hydrogen bonds: r in angstroms, ellipticity (the larger the less stable), q(H) is the atomic charge (in a.u.) on the hydrogen engaged in the hydrogen bond, and the electron density ρ between the interacting atoms.

Noteworthy is the exo-anomeric effect in d-glucose (Inline graphic), which is active when the anomeric hydroxyl group is cc but is disabled for the cl conformation because of lack of antiperiplanar symmetry between the electron donor orbital (nO1) and the acceptor antibonding orbital (Table 2). Therefore, it is anticipated that the cl conformer should be less stabilized than cc α-anomers by hyperconjugative interactions. This is similar to the case of some α-substituted tetrahydropyrans and piperidines.14 In order to investigate the role of overall electron delocalization in the conformational stabilities, an energy-partitioning scheme named NEDA (natural energy decomposition analysis) was carried out and the contributions from hyperconjugation and Lewis-type (steric and electrostatic) interactions to the overall conformational energies through the NBO framework are given in Table 3. Accordingly, the G–g+/cl/g– conformer of α-d-glucose is less stabilized by non-Lewis-type interactions than the remaining α-anomers, but it is more destabilized because of Lewis-type interactions than the cc β-anomers. The contributions from steric and electrostatic effects are more important than stabilization due to hyperconjugation for the cl conformer (with an explicit water, this difference is reduced), while these Lewis and non-Lewis contributions for the other conformers are more competitive. This finding reinforces the hypothesis that repulsion in the cl conformer explains the preference for the cc conformation rather than a cooperative chain of IHBs in the latter.

Table 2. NBO Anomeric (First Entries) and Exo-Anomeric (Second Entries) Interactions (kcal mol–1) for d-Glucose and Its Respective F and Cl Derivatives.

 
graphic file with name ao-2018-01455z_m002.jpg
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conformer
graphic file with name ao-2018-01455z_m005.jpg
graphic file with name ao-2018-01455z_m006.jpg
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β_G+g–/cc/t 3.5 5.1 2.5
  14.9 11.6 7.2
β_G–g+/cc/t 3.7 5.3 2.7
  14.7 11.6 7.1
β_Tg+/cc/t 3.7 5.3 2.6
  14.4 11.7 7.2
α_G+g–/cc/t 14.3 21.7 24.3
  14.3 10.6 5.8
α_G–g+/cc/t 14.8 21.9 24.7
  14.4 10.5 5.7
α_G–g+/cl/g– 13.1 18.2 19.7
  3.5 11.7 7.0
α_Tg+/cc/t 14.7 22.0 24.8
  14.2 10.5 5.7
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Table 3. Lewis/Non-Lewis Contributions (kcal mol–1) to the Overall System Energy Obtained from NEDA.

conformer X = OH X = H X = F X = Cl X = OH + explicit water
β_G+g–/cc/t 0.6/0.0 0.4/0.0 2.2/0.0 2.3/0.0 6.9/–5.2
β_G–g+/cc/t 2.6/–1.9 2.6/–1.9 4.0/–1.7 4.2/–1.7 16.1/–14.6
β_Tg+/cc/t 3.0/–2.1 3.0/–2.0 4.7/–1.8 4.2/–1.2 3.9/0.0
α_G+g–/cc/t 6.1/–6.1 5.6/–4.5 9.5/–9.4 18.5/–18.4 20.4/–19.5
α_G–g+/cc/t 8.2/–8.1 7.9/–6.5 10.8/–10.8 19.9/–19.9 22.8/–21.4
α_G–g+/cl/g– 4.4/–3.4 1.1/–1.1 7.2/–5.7 11.8/–9.5 19.5/–19.0
α_Tg+/cc/t 8.8/–8.7 8.2/–6.6 11.6/–11.2 20.7/–20.4 11.3/–11.3
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Lomas and Joubert21 examined the effect of the presence of a proton acceptor, pyridine, on the calculated NMR 1H chemical shifts of d-glucose to probe the role of IHBs in the orientation of the hydroxyl groups. Surprisingly, the higher calculated 1H chemical shifts for (O)H1 and (O)H2 in the cl conformer (not in the cc conformers, whose stabilization has been claimed to be governed by IHBs) relative to the other conformers (Table 4) suggest that these hydrogens are engaged in IHBs. To better understand this behavior, the explicit water in our study is anticipated to reduce the ability of O5 to form an IHB with O1H1 due to the establishment of a strong intermolecular hydrogen bond O5···H2O. Consequently, considering the existence of IHBs in free d-glucose, a shielding effect on the 1H chemical shifts of d-glucose would appear upon the presence of an explicit water attached to O5. However, δH2, δH3, and δH4 practically do not vary by moving d-glucose from the free molecule to a complex with water, whereas δH1 and δH5, in general, increase because of the proximity with the explicit water, then participating in intermolecular hydrogen bonds (Table 4). Therefore, the hypothesis of IHBs forming four- and five-membered rings as driving interactions of the preferential cc arrangement of hydroxyls in d-glucose cannot be asserted by our NMR-based model as well.

Table 4. Calculated 1H NMR Chemical Shifts (ppm, Relative to TMS) for the Hydroxyl Hydrogens of d-Glucose in the Gas Phase and in the Presence of an Explicit Water (in Parentheses).

conformer δH1 δH2 δH3 δH4 δH6
β_G+g–/cc/t 2.0 (2.3) 1.6 (1.6) 2.0 (2.0) 1.8 (1.8) 1.1 (3.7)
β_G–g+/cc/t 2.0 (2.2) 1.6 (1.6) 2.0 (2.0) 1.8 (1.8) 0.9 (4.1)
β_Tg+/cc/t 2.0 (2.1) 1.6 (1.5) 2.0 (1.9) 2.2 (2.1) 2.2 (2.2)
α_G+g–/cc/t 1.4 (1.7) 1.1 (1.0) 2.0 (2.0) 1.8 (1.9) 1.1 (4.0)
α_G–g+/cc/t 1.4 (1.4) 1.0 (0.9) 2.0 (2.0) 1.8 (1.8) 0.7 (3.7)
α_G–g+/cl/g– 2.5 (2.7) 2.2 (2.2) 2.2 (2.3) 1.1 (1.6) 0.8 (4.4)
α_Tg+/cc/t 1.4 (4.8) 1.1 (1.2) 2.0 (2.0) 2.1 (2.2) 2.1 (2.2)
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3. Conclusions

Comparison of the conformational energies for different d-glucose derivatives provided an unequivocal assessment of the effects ruling the arrangement of hydroxyl groups in d-glucose. Our findings support the explanation of Silla et al. that the cc conformation of d-glucose starts with an O1···O5 repulsive interaction rather than by a network of cooperative IHBs. In addition, it is worth mentioning that the cl conformation disables the exo-anomeric effect in d-glucose, yielding a minimal hyperconjugative stabilization for this conformer compared to others. In summary, all of these outcomes are instructive because they suggest that modulation of the structure of d-glucose derivatives can be carried out by the replacement of hydroxyl with other groups looking at steric and dipolar hindrance rather than hydrogen bonds.

4. Computational Methods

d-Glucose is known to appear experimentally as seven stable conformers.16 Therefore, the geometries for each conformer were fully optimized at the B3LYP/aug-cc-pVDZ level,29−31 and an explicit water molecule was further placed neighboring O5 in order to establish an intermolecular hydrogen bond and then attenuate intramolecular interactions (steric/electrostatic repulsion, IHBs, and hyperconjugative interactions) with the endocyclic oxygen (Figure 2). Frequencies were checked to guarantee the absence of transition states. The conformers were named based on the O5–C5–C6–O6, C5–C6–O6–H6 and C2–C1–O1–H1 dihedral angles, according to the atom numbering provided elsewhere (Figure 1).16 The anomeric hydroxyl group of d-glucose was replaced with H, F, and Cl, and the same procedure described above was carried out for these derivatives. NBO32 and QTAIM33 analyses were additionally performed to check the consistency with the outcomes from optimization and conformational energy calculations. Whereas the QTAIM analysis provided topological parameters related to the electron density along the pathway of interacting atoms, the NBO method allowed for obtaining hyperconjugative energies and the contribution from Lewis (repulsive) and non-Lewis-type (electron delocalization) interactions to the overall electronic energy of the system (Efull = ELewis + Enon-Lewis and ELewis = Esteric + Eelectrostatic). In addition, nuclear magnetic shielding tensors were computed using the gauge-including atomic orbital method to investigate the influence of possible IHBs on 1H NMR chemical shifts.

Acknowledgments

The authors are grateful to FAPEMIG (APQ-00383/15 and PPM-00344/17) for the financial support of this research as well as to Capes for the studentship (to F.A.M.) and CNPq for the fellowship (to M.P.F.).

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b01455.

  • Standard coordinates for the optimized geometries and tables of calculated NBO and NMR data (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao8b01455_si_001.pdf (515.1KB, pdf)

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