Organic Letters
Letter
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
(ΔGr°) are entirely in accordance with ratios determined by
1H NMR. Moreover, all of these values (ΔG⧧ and ΔG°r )
correlate reasonably with the computed data also presented in
Table 1 as well as the quantified OH/π strength of ∼10 kJ/mol
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
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Experimental details, characterization, NMR spectra,
VT-NMR experiments, X-ray data (3a), and computa-
Accession Codes
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
CCDC 1939031 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
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Corresponding Author
ORCID
Notes
The authors declare no competing financial interest.
Figure 6. 1H NMR spectra at 500 MHz with ratios of 3a−c
conformers at 298 K (the C3−H region is expanded).
ACKNOWLEDGMENTS
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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 crystallo-
graphic 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
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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