O H-Bond-Dependent

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Intramolecular OH/π versus C−H/O H‑Bond-Dependent Conformational Control about Aryl−C(sp3) Bonds in Cannabidiol Derivatives Clément Denhez,†,‡ Pedro Lameiras,† and Hatice Berber*,† †

Université de Reims Champagne Ardenne, CNRS, ICMR UMR 7312, 51097 Reims, France Université de Reims Champagne Ardenne, MaSCA, P3M, 51097 Reims, France

‡

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S Supporting Information *

ABSTRACT: Conformational control in cannabidiol derivatives has been studied by NMR, XRD, and DFT. The stabilization of their axial M and P conformations about the aryl−C(sp3) bond is an effect of competing intramolecular OH/π and CH/O H-bonds. In a nonpolar solvent and in the solid state, the OH/π bond is a determinant of the M conformation. In polar solvents, the CH/O H-bond shifts the equilibrium toward the P conformer because of the breaking of the OH/π bond. synthetic CBD derivatives have been only sparsely explored.2 Among the CBD derivatives, its (+)-CBD enantiomer and Abn-CBD regioisomer as well as O-1602 (Figure 1A) also showed biological activities.3 Some structural aspects around the CBD scaffold should be considered in future therapeutic development. In particular, the slow rotation about the bond connecting the two rings of CBD, studied in the 1980s,4 is an interesting case of aryl−C(sp3) bond hindered rotation en route to atropisomerism. Thus, it is necessary to take into account the implication of a possible atropisomerism for the discovery of new CBD analogues insofar as atropisomers with long half-lives and better drug/target specificity are more prone to development.5 In our previous work, we have shown by theoretical calculations that conformational control in CBD derivatives [1b and 1c (Figure 1B)] arises from stabilizing stereoelectronic effects through orbital donor−acceptor interactions.6 Weak attractive forces are important in deciding the conformation and, consequently, the reactivity of organic compounds and in governing the stability of biological macromolecules, and among them, hydrogen bonds are one of the most important. The current definition of a hydrogen bond could be extended to X−H···Y−Z interactions in which the electronegativity of elements X and Y is moderate to weak.7 Typical of these nonconventional hydrogen bonds are the C−H···Y (Y = O or N) and X−H···π (X = O, N, or C) interactions.8 Here, we provide direct NMR evidence of solvent-dependent intramolecular OH···π and CH···O nonconventional hydrogen bonds, which are responsible for the conformational preference in CBD derivatives 1a and 3a (Figure 1C). These

(−)-Cannabidiol [(−)-CBD (Figure 1A)] is attracting considerable interest as a single drug due to its beneficial neuroprotective, anxiolytic, anti-inflammatory, and antitumor properties, among others.1 The molecular targets involved in the diverse therapeutic properties produced by CBD are still not very well understood. Therefore, the CBD scaffold is becoming more interesting to medicinal chemists, while

Figure 1. Previous works and outline of our current study of cannabidiol derivatives. © XXXX American Chemical Society

Received: July 17, 2019

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DOI: 10.1021/acs.orglett.9b02484 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

Figure 2. Conformational analysis of 1a and 3a in (A) CDCl3 and (B) THF-d8 based on the two-dimensional EXSY/NOESY NMR spectra at 500 MHz (the C3−H region is expanded).

results were supported by X-ray diffraction and DFT calculations using IEFPCM/M06-2X/6-31G(d,p) methodology. The synthesis of naphthyl derivatives 3a−c is described in detail in the Supporting Information from the same procedure employed for 1a−c.6 The solvent-dependent conformational behavior of phenol 1a and naphthol 3a highlighted the competitive intramolecular OH/π bond in CDCl3 versus the CH/O bond in THF-d8, by using NMR spectroscopy. Figure 2 shows the 1H−1H EXSY/ NOESY spectra of both 1a and 3a at two different temperatures in each solvent in the region containing C3−H protons (see also the full spectra in Figures S1−S8). As one can see on the first spectra, in-phase cross peaks (black) indicate the presence of two rotamers presenting chemical exchange between C3−H protons. On the second spectra recorded at lower temperatures, antiphase cross peaks (blue) corresponding to NOE enhancement effects show a major rotamer in which the C3−H proton is close to the CH3 group in (M)-1a in CDCl3 and the OH group in (P)-1a in THF-d8. Likewise, the C3−H proton correlates with the C8′−H proton in (M)-3a and the OH group in (P)-3a. The minor rotamer NOE peaks are not visible due to the low concentration of this species with respect to the major one. Thereby, according to the NOESY spectra in CDCl3 (Figure 2A), interconversion between the (M) and (P) conformers led to ratios of 97:3 and 95:5 for 1a and 3a at 218 and 223 K, respectively. The predominant (M) conformers exhibit stabilizing intramolecular OH/π interaction in this nonpolar solvent, which seems stronger than CH/O interaction (Figure 3A). The strength of these intramolecular interactions is well demonstrated by comparing the 1H NMR deshielding of the O−H and C3−H protons between both conformers. The remarkable downfield shifts in chemical shifts for O−H protons between conformers in 1a and 3a (ΔδO−H = 1.3 and 1.6 ppm, respectively) are well above those of C3−H protons (ΔδC3−H = 0.5 and 0.1 ppm, respectively). Crystals suitable for X-ray analysis by recrystallization from heptane were obtained for 3a, thus confirming its solid-state M conformation (Figure 4A). The DFT structure of 3a in CHCl3 also corroborates this conformation (Figure 4B). The geometrical parameters determined in the solid state are quite similar to those computed for the isolated molecule; in particular, the average

Figure 3. Solvent-dependent conformational preferences of 1a and 3a in (A) CDCl3 and (B) THF-d8 with 1H NMR chemical shifts (parts per million) of protons in O−H/O, O−H/π, and C−H/O interactions.

O···π distance has a very similar value (3.06 Å vs 3.07 Å). To gain greater insight into the origins of this noncovalent interaction, we carried out a natural bond orbital (NBO) analysis and used NCIPLOT to visualize the attractive and repulsive nonbonding interactions (Figure 5A; see also Table S8 and Figure S33). The NBO interaction leading to the strongest stabilizing effect is a πC1C2 → σ*OH interaction, which corresponds to an OH/π hydrogen bond. Likewise, the attractive interaction located in this area as a blue surface was detected by the NCI approach. On the other hand, in THF-d8, ratios of 80:20 and 93:7 at 213 K between P and M conformers were obtained in 1a and 3a from the NOESY spectra (Figure 2B), respectively. The conformational equilibrium is shifted toward the P conformer in which the OH/π interaction is broken in favor of the formation of solute−solvent interactions such as OH/O Hbonds (Figure 3B). The lack of this intramolecular interaction in polar solvents also causes stabilizing intramolecular CH/O interaction in (P)-1a and (P)-3a. It is worth noting that the B


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Organic Letters

Figure 4. Comparison of single-crystal X-ray diffraction and DFT minima of 3a calculated at the IEFPCM/M06-2X/6-31G(d,p) level of theory.

Moreover, VT-NMR studies were conducted on 1a and 3a to estimate and compare barriers to rotation about the aryl− C(sp3) bond in polar and nonpolar solvents (Table 1; see also Tables S2−S4).The highest bond rotation barriers from major to minor rotamers were obtained in CDCl3 for phenol 1a (ΔG⧧C = 70.2 ± 1.2 kJ/mol) and naphthol 3a (ΔG⧧298 K = 75.6 ± 0.1 kJ/mol). The ΔG⧧ values are ∼15 and ∼9 kJ/mol higher than those obtained in THF-d8 for 1a and 3a, respectively. The polarity of the solvent seems to have a deep impact on ΔG⧧ values through OH/O, OH/π, CH/O, and CH/π interactions, even if steric effects are evidently a significant driving force behind these energies and the stabilization of conformers in 1a and 3a cannot be solely attributed to a bonding interaction. Notably, these high values in CDCl3 show that the intramolecular OH/π H-bond influences the pivot bond rotation in favor of M conformers (Figure 3A). The difference in barriers is higher in 1a (∼15 kJ/mol) than in 3a (∼9 kJ/mol). This could be explained by the presence of an additional CH/π interaction (πC1C2 → σ*C8′−H) in favor of (P)-3a, which is more stabilized than (P)-1a. Analysis of the relative Gibbs free energies (ΔG r° ) in both solvents demonstrates well the contribution of each intramolecular Hbond in 1a and 3a conformers (Table 1). In conformers of 1a, (M)-1a is the major conformer in CDCl3 with a ΔG°r of 9 kJ/ mol, which should correspond to the difference in energy between the OH/π and CH/O bonds, while in THF-d8, (P)1a predominates due to only a CH/O bond with a ΔGr° of 3.2 kJ/mol. From these values, the strength of the CH/O H-bond could be close to 3.2 kJ/mol and that of the OH/π bond should be the sum of both of these relative Gibbs free energies (12.2 kJ/mol). In a similar manner, for conformers of 3a, a ΔGr° of 7.1 kJ/mol should correspond to OH/π versus CH/O

Figure 5. Combined NCI plot and NBO analysis of 3a DFT minima in (A) CHCl3 and (B) THF calculated at the IEFPCM/M06-2X/631G(d,p) level of theory.

deshielding effect on C3−H protons in 1a and 3a is slightly higher in THF-d8 (ΔδC3−H = 0.7 and 0.3 ppm, respectively). Also, the O−H protons are highly deshielded in both conformers of 1a and 3a, which is indicative of strong OH/ O hydrogen bonding. The P conformer structure was also confirmed by the DFT minimum calculated for 3a in THF (Figure 4C). The short C···O distance of 2.77 Å (much shorter than the van der Waals distance of 3.22 Å) and H···O distance of 2.20 Å (much shorter than the van der Waals distance of 2.72 Å) as well as the C−H···O bond angle of 110° suggest the possibility of an intramolecular CH···O H-bond in (P)-3a. In addition, the NBO analysis reveals the charge transfer from the O lone pair to the C3−H σ* orbital, which is a fingerprint of such H-bonds (Figure 5B, Table S8, and Figure S33). Note that a significant contribution from the πC1C2 → σ*C8′−H NBO interaction corresponding to CH/π interaction also helps to stabilize this conformer. NCI plot surfaces also support these interactions.

Table 1. Experimental and Calculated Bond Rotation Barriers and Relative Gibbs Free Energies (kilojoules per mole) of the Conformers of Alkenes 1a−c and 3a−c compound 1a 1b 1c 3a

3b 3c

solvent CDCl3 THF-d8 CDCl36a THF-d86a CDCl3 THF-d86b CDCl3 THF-d8 DMSO-d6 CDCl3 THF-d8 CDCl3 THF-d8

M:P ratio

ΔG⧧Maj→Min exp

ΔG°r (M → P) exp

ΔG⧧Maj→Min calcdd

ΔG°r (M → P) calcd

97:3 (218 K) 20:80 (213 K) 25:75 (298 K) 20:80 (233 K) 82:18 (223 K) 80:20 (233 K) 95:5 (223 K) 7:93 (243 K) 11:89 (298 K) 12:88 (283 K) 6:94 (233 K) 50:50 (283 K) 50:50 (273 K)

a

70.2 ± 1.2 55.6 ± 1.2a

−9.0 3.2

± ± ± ± ± ± ± ± ± ±

1.2a 1.2a 1.2a 0.1b 0.1c 1.3a 1.1a 1.2a 0.3b 1.1a

3.4 3.5 3.2 −7.1 5.7 5.5 5.2 7.1 0.0 0.0

70.3 63.6 65.0 67.4 66.3 68.6 78.2 71.1 70.3 75.5 72.7 73.4 73.4

−7.8 1.1 3.2 5.7 11.1 8.5 −6.7 6.2 5.1 6.3 6.9 4.3 4.9

63.0 65.4 64.1 75.6 66.7 67.6 70.9 72.9 70.3 71.4

ΔG⧧C determined at Tc. bΔG⧧ determined at 298 K by VT-2D-EXSY. cΔG⧧ determined at 298 K by line shape analysis. dΔG⧧ calculated at 298 K.

a

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plus CH/π bonds in CDCl3 and 5.7 kJ/mol to CH/O plus CH/π bonds in THF-d8. Therefore, the strength of the OH/π H-bond fits well (7.1 kJ/mol + 5.7 kJ/mol = 12.8 kJ/mol), and that of the CH/π bond should be 2.5 kJ/mol (5.7 kJ/mol− 3.2 kJ/mol). These energetic differences between conformers (ΔG°r ) are entirely in accordance with ratios determined by 1 H NMR. Moreover, all of these values (ΔG⧧ and ΔGr°) correlate reasonably with the computed data also presented in Table 1 as well as the quantified OH/π strength of ∼10 kJ/mol described in detail in the Supporting Information. Obviously, the solvent effect does not occur when phenol 1a and naphthol 3a are converted into methyl ethers (1b and 3b, respectively) and benzoates (1c and 3c, respectively) insofar as the OH/π bond is broken (Table 1 and Figure 6). Similar

Letter

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02484. Experimental details, characterization, NMR spectra, VT-NMR experiments, X-ray data (3a), and computational results (PDF) Accession Codes

CCDC 1939031 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Pedro Lameiras: 0000-0001-8416-750X Hatice Berber: 0000-0002-9160-7734 Notes

The authors declare no competing financial interest.

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Figure 6. H NMR spectra at 500 MHz with ratios of 3a−c conformers at 298 K (the C3−H region is expanded).

ACKNOWLEDGMENTS The authors thank the URCA and the CNRS for financial support. This work was supported by the PlAneT platform for high-field NMR spectroscopy, HRMS, and XRD. The authors also thank C. Machado and C. Kowandy for X-ray crystallographic assistance.

ratios (at ≤298 K) and rotational barriers were obtained in both solvents. In ethers 1b and 3b, ratios are in favor of P conformers as for phenol 1a and naphthol 3a in THF-d8. The stabilization of (P)-3b is therefore essentially due to both intramolecular CH/O and CH/π bonds as in (P)-3a, while in (P)-1b, only a stabilized CH/O bond exists as in (P)-1a (Tables S6 and S8 and Figures S25 and S33). In the case of benzoates 1c and 3c, P conformers are no longer predominant because of the stabilization of M conformers via intramolecular π−π interactions, competing with the CH/O bond. Note that C3−H chemical shifts for 3c P and M conformers are inverted (ΔδC3−H = −0.3 ppm) showing as well the weakness of the CH/O bond due to the decreased electron density on the acceptor oxygen atom (Figure 6). In conclusion, we report consistent conformational M and P extremities about the aryl−C(sp3) bond in cannabidiol derivatives 1a and 3a depending on the polarity of the solvent, which gives rise to an opportunistic action of inter- and/or intramolecular H-bonds. While the M conformation is driven by the intramolecular OH/π bond in CDCl3 and in the solid state, intermolecular solute−solvent OH/O and intramolecular CH/O bonds dictate the molecules to adopt the P conformation in polar solvents. Our results also highlight the ability to differentiate the involvement of an interaction over another in determining the molecular conformation, and this is among a myriad of competing noncovalent interactions. Further studies of the implication of axial diastereomerism on the biological activity of these rotationally restricted CBD derivatives are ongoing, in particular for their antitumor properties.

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REFERENCES

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