5,7-Dihydroxy-2-(4-hydroxyphenyl)chroman-4-one (naringenin): X-ray diffraction structures of the naringenin enantiomers and DFT evaluation of the preferred ground-state structures and thermodynamics for racemization

Article abstract of DOI:10.1016/j.molstruc.2016.10.068

The R- and S-enantiomers of naringenin were separated by chiral supercritical fluid (SCF) and the absolute configuration of each enantiomer was established by X-ray crystallography. The solid-state data is in agreement with the reported circular dichroism spectra. Both enantiomers crystallize in the monoclinic crystal system in the space group P2₁ with two independent molecules in the asymmetric unit. In all molecules, the pyrone ring adopts a flattened chair-like conformation in which the C1 atom deviates from the plane drawn through the remaining five atoms of this heterocycle. The 4-hydroxyphenyl substituent located at C1 of the pyrone ring occupies an equatorial position and lies in a plane that is almost perpendicular to the aromatic platform associated with the heterocyclic portion of the molecule. Strong intramolecular O-H?O hydrogen bonding exists between the carbonyl moiety and the aryl hydroxyl group at C5. In both enantiomers, a favorable mutual orientation of two independent molecules promotes the formation of intermolecular O-H?O hydrogen bonds that link them into dimers. There are additional long-range intermolecular O-H?O hydrogen bonds and weak C-H?O contacts within the unit cell of each enantiomer that connect dimers in an extended network. DFT calculations have been performed and the thermodynamics for naringenin racemization via an acyclic chalcone have been computed. Eight energetically accessible conformations have been verified for S-naringenin.

Full text of DOI:10.1016/j.molstruc.2016.10.068

Accepted Manuscript
5,7-Dihydroxy-2-(4-hydroxyphenyl)chroman-4-one (naringenin): X-ray diffraction
structures of the naringenin enantiomers and DFT evaluation of the preferred ground-
state structures and thermodynamics for racemization
Volodymyr V. Nesterov, Lev N. Zakharov, Vladimir N. Nesterov, Jose G. Calderon,
Antonella Longo, Khadiza Zaman, Feroza Kaneez Choudhury, William Farrell,
Vladimir Shulaev, Michael G. Richmond
PII:
S0022-2860(16)31125-5
10.1016/j.molstruc.2016.10.068
MOLSTR 23069
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 18 July 2016
Revised Date: 18 October 2016
Accepted Date: 20 October 2016
Please cite this article as: V.V. Nesterov, L.N. Zakharov, V.N. Nesterov, J.G. Calderon, A.
Longo, K. Zaman, F.K. Choudhury, W. Farrell, V. Shulaev, M.G. Richmond, 5,7-Dihydroxy-2-(4-
hydroxyphenyl)chroman-4-one (naringenin): X-ray diffraction structures of the naringenin enantiomers
and DFT evaluation of the preferred ground-state structures and thermodynamics for racemization,
Journal of Molecular Structure (2016), doi: 10.1016/j.molstruc.2016.10.068.
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ACCEPTED MANUSCRIPT
5
,7-Dihydroxy-2-(4-hydroxyphenyl)chroman-4-one (naringenin):
X-ray diffraction structures of the naringenin enantiomers and DFT
evaluation of the preferred ground-state structures and thermodynamics for
racemization
a
b
a,*
a
Volodymyr V. Nesterov, Lev N. Zakharov, Vladimir N. Nesterov, Jose G. Calderon,
c
c
c
d
Antonella Longo, Khadiza Zaman, Feroza Kaneez Choudhury, William Farrell, Vladimir
c
a
Shulaev, and Michael G. Richmond
a
Department of Chemistry, University of North Texas, Denton, TX 76203, USA
b
CAMCOR Center for Advanced Materials Characterization in Oregon, University of Oregon,
Eugene, Oregon 97403, USA
c
Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA
d
Pfizer Global R&D, San Diego, CA 92121, USA
Keywords: Naringenin, chiral HPLC, circular dichroism, crystal structure, DFT calculations.
Highlights
•
•
•
The R- and S-enantiomers of naringenin were separated by chiral HPLC and their
absolute configuration was established by X-ray crystallography
Each enantiomer exhibits strong intermolecular O-H···O hydrogen bonds that link two
independent molecules in the unit cell
DFT calculations on the eight energetically accessible conformers for the (S)-enantiomer
are reported
Correspondence e-mail: vladimir.nesterov@unt.edu
1

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Abstract
The R- and S-enantiomers of naringenin were separated by chiral HPLC and the absolute
configuration of each enantiomer was established by X-ray crystallography. The solid-state data
is in agreement with the reported circular dichroism spectra. Both enantiomers crystallize in the
monoclinic crystal system in the space group P2 with two independent molecules in the
1
asymmetric unit. In all molecules, the pyrone ring adopts a flattened chair-like conformation in
which the C1 atom deviates from the plane drawn through the remaining five atoms of this
heterocycle. The 4-hydroxyphenyl substituent located at C1 of the pyrone ring occupies an
equatorial position and lies in a plane that is almost perpendicular to the aromatic platform
associated with the heterocyclic portion of the molecule. Strong intramolecular O-H···O
hydrogen bonding exists between the carbonyl moiety and the aryl hydroxyl group at C5. In both
enantiomers, a favorable mutual orientation of two independent molecules promotes the
formation of intermolecular O-H···O hydrogen bonds that link them into dimers. There are
additional long-range intermolecular O-H···O hydrogen bonds and weak C-H···O contacts
within the unit cell of each enantiomer that connect dimers in an extended network. DFT
calculations have been performed and the thermodynamics for naringenin racemization via an
acyclic chalcone have been computed. Eight energetically accessible conformations have been
verified for S-naringenin.
1
. Introduction
Naringenin (4',5,7-trihydroxyflavanone) is a natural flavanone mainly found in citrus
fruits. It has been experimentally documented to possess numerous biological properties with
anti-oxidant, anti-inflammatory, and anti-apoptotic activities, as well as a cancer chemo-
preventive/therapeutic agent and as a radioprotective agent (Bharti et al., 2014; Mir & Tiku,
1
,2
2
015; Kumar & Tiku, 2016). Naringenin consists of two aromatic rings joined by a three-
carbon link with one chiral carbon atom and can be found in two enantiomeric forms. Most
studies are carried out with racemic naringenin and utilize achiral analysis. Therefore, very
limited attention has been dedicated to understand the role the two stereoisomers may have in
human health and in stereospecific pharmacokinetics. When the stereospecific distribution of
naringenin in natural sources was studied, the S-enantiomer was predominant in most of the
3
juices examined (orange, grapefruit, lemonade, lime, apple and tomato juice) (Yáñez et al.).
2

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Since stereo-configurations of compounds are important for their interaction with enzymes, some
limited studies have been carried out on the differences in the two enantiomers. In one example,
naringenin has the ability to inhibit the activity of cytochrome P450. When the separate
enantiomers were used, it was shown that (S)-naringenin was 2-fold more potent as inhibitor of
CYP19 and CYP2C19 than (R)-naringenin, while (R)-naringenin was 2-fold more potent as
4
5
inhibitor of CYP2C9 and CYP3A (Lu et al., 2011). Gaggeri et al. evaluated the relevance of
chirality in the anti-inflammatory effect exerted by naringenin and showed that (R)-naringenin
exerts a higher effect than the (S)-enantiomer. These studies prove the importance of the
configuration at the C-2 chiral center when the enantiomeric forms are observed.
Several reports exist on the separation of racemic naringenin into its respective
enantiomers by chiral HPLC, but the identity of the naringenin enantiomers rests on non-
empirical inferences drawn from circular dichroism (CD) and DFT calculations of the optical
D
rotation properties (CD spectrum and [α] ). While two reports on the solid-state structure for
6
,7
racemic naringenin exist, unequivocal determination of the R- and S-forms of naringenin are
required if the CD spectra are to be corroborated. With this need in mind, we have determined
the molecular structure of the HPLC-separated enantiomers and the CD spectra of the naringenin
enantiomers have been analyzed in solution and their chirality confirmed. DFT calculations on
the different conformational and rotational isomers for S-naringenin are also reported.
2
. Experimental
2
.1. General
All solvents were purchased from Fisher Scientific (Waltham, MA, USA) and used as
received. Racemic naringenin standards for separation were purchased from Sigma-Aldrich (St.
Louis, MO, USA).
2
.2. Instrumentation
Purity analysis was performed using an Agilent 1260 Infinity Series SFC/MS system
consisting of a binary pump, SFC control module, UV/DAD detector, and column compartment
with an internal 2-position, 6-port valve, and 6120 MSD with an APCI source (Agilent, Inc.,
Santa Clara, CA, USA), and CTC HTS PAL autosampler (Leap Technologies, Carrboro, NC,
3

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USA) equipped with a 10 ꢀL syringe and a 5 ꢀL fixed loop with a control method to vent CO
2
from the loop before sample introduction. The effluent of the SFC was split to the MSD using a
-way tee (Valco, Houston, TX, USA) and a 50 cm long, 50 ꢀm i.d. PEEKsil capillary tubing
Upchurch Scientific, Oak Harbor, WA, USA). All data was acquired using Agilent 64-bit
3
(
ChemStation (version C.01.05).
Purification was performed using an SFC-PICLab Hybrid 10-100 SFC system (PIC
Solutions, Avignon, FRA) consisting of 3 dual-head reciprocating pumps, UV detector, column
compartment, collector assembly and SFC PICLab software (version 1.6.9.0, PLC version 0029).
The sample was introduced using the syringe pump assembly at 1500 ꢀL per injection. For post-
purification workup, the solvent was removed with a Buchi R-205 rotary evaporator (Buchi,
New Castle, DE, USA) and the crude sample was further lyophilized using a Labconco Freezone
2
5+ (Labconco, Kansas City, MO, USA).
2
.3. Analysis Conditions
The analysis was performed using a 4.6 mm x 100 mm Chiralpak AD-H column (Chiral
Technologies, West Chester, PA, USA) with 3 ꢀ particle and 1000 Å pore sizes. The flow rate
was 4.0 mL/min with the outlet back pressure set to 120 bars. The sample was dissolved in
methanol at a concentration of 1 mg/1 mL, and the injection volume was 2 ꢀL. The composition
of the mobile phase consisted of carbon dioxide and methanol with a gradient profile of 10-60 %
methanol in 3.7 minutes. The column temperature was ambient room temperature. The MSD
positive scan range was 100-800 amu with source temperature at 450 °C vaporization and 325 °C
drying gas at a flow rate of 7 L/min. The capillary voltage was 2500 V with a corona current of 5
ꢀA. Purification was performed using a 21.1 mm x 250 mm Chiralpak AD-H column (Chiral
Technologies, West Chester, PA, USA) with 5 ꢀ particle and 1000 Å pore sizes. The flow rate
was 70 mL/min with the outlet back pressure set to 150 bars. The sample was dissolved in
methanol at a concentration of 65 mg/mL, and the injection volume was 1.5 mL, stacked in 3.25-
minute intervals. The mobile phase consisted of carbon dioxide and methanol at 50 % (v/v), and
the column temperature was set to 40 °C.
2
.4. Circular dichroism data
4

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The circular dichroism (CD) spectra of the pure R- and S- enantiomers of naringenin
were recorded using a JASCO J815 CD spectrometer. All samples were carefully diluted to tenth
millimolar concentrations in HPLC grade acetonitrile, and the chiral chromophore absorption
was measured at room temperature (20 °C) in a 1.0 cm path length cell under 40 mL per minute
constant flow of dry 99.99 % pure nitrogen.
2
.5. X-ray Crystallographic data
Single crystals of R- and S-enantiomers suitable for X-ray analysis were obtained by
slow isothermal evaporation from the ethanol solution during several days. The molecular
structure of each enantiomer was determined using a Bruker SMART APEX2 CCD-based X-ray
diffractometer equipped with a low-temperature device and Cu-target X-ray tube (wavelength =
1
.54178 Å). Measurements were taken at 150(2) K for R-enantiomer and at 200(2) K for S-
enantiomer. The data collection, indexing, and initial cell refinements were carried out using
8
9
APEX2. The frame integration and final cell refinements were done using program SAINT,
1
0
and an absorption correction was applied using the program SADABS. All non-hydrogen
atoms were refined anisotropically, and all O-H hydrogen atoms were located from the
difference Fourier map and were refined isotropically. The remaining H-atoms in both
enantiomers were placed in idealized positions and refined as riding atoms. The structures were
examined using the Addsym subroutine of PLATON, in order to ensure that no additional
1
1
symmetry could be applied to the finalized model. Structure solution, refinement, graphics and
1
2
generation of publication materials were performed using SHELXTL software. Refinement
details and structural parameters for both enantiomers are summarized in Table 1. Least-squares
planes and deviations of atoms from those planes for both enantiomers, as well as selected bond
lengths and angles, are given in Tables 2 and 3, respectively.
2
.6. Computational methodology and modeling details
All calculations were performed with the hybrid DFT functional B3LYP, as implemented
1
3
by the Gaussian 09 program package. This functional utilizes the Becke three-parameter
1
4
exchange functional (B3), combined with the correlation functional of Lee, Yang, and Parr
1
5
(
LYP). The atoms were described by a 6-31Gǂ basis set, and the reported geometries
correspond to fully optimized ground-state structures based on positive eigenvalues obtained
5

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from the analytical Hessian. Unscaled vibrational frequencies were used to make zero-point and
thermal corrections to the electronic energies. Standard state corrections were applied to all
1
6
species to convert concentrations from 1 atm to 1 M according to the treatise of Cramer. The
reported free energies, which were computed at 298 K in the gas phase, are quoted in kcal/mol
relative to the specified standard. The presented geometry-optimized structures have been drawn
1
7
with the JIMP2 molecular visualization and manipulation program.
. Results and Discussion
The enantiomers of naringenin were separated by HPLC using the commercially
3
available Chiralpak column. Figure 1 shows a trace of a developed chromatogram, with the
optimized HPLC conditions affording the S-enantiomer as the initially eluted species, followed
by the R-enantiomer. The elution order of the naringenin enantiomers depends on the nature of
the chiral stationary phase, and the separation efficiency as a function of the chiral HPLC
stationary phase and mobile phase, along with the physical characterization of the enantiomers
1
8-20
by circular dichroism (CD) spectroscopy, has been discussed by several groups.
Fig. 1. HPLC chromatograms of the S- (peak 1) and R- (peak 2) enantiomers of naringenin.
6

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The structural formulas of the separated R- and S-enantiomers of naringenin are depicted
in Scheme 1. The CD spectrum of each enantiomer was recorded and the CD spectra, which are
mirror images of each other, are shown in Figure 2. The R-enantiomer exhibits a negative Cotton
effect while the S-enantiomer displays a positive Cotton effect. The recorded CD data are in
excellent agreement with the earlier work where the enantiomer assignments were based on their
1
8-20
exciton chirality properties and DFT-computed properties.
Scheme 1. 2R- (left) and 2S- (right) enantiomers of naringenin.
Fig. 2. Circular dichroism spectra for pure R- (black) and S- (red) enantiomers of naringenin.
In order to unequivocally establish the absolute structures of both naringenin
enantiomers, single crystals of the isolated enantiomers were grown and their absolute
configurations were determined by X-ray crystallography. Fig. 3 shows the diffraction structures
for the pair of enantiomers side by side and confirms the identity of the HPLC-separated species.
Fig. 3. General view of thermal ellipsoid plots of the R-enantiomer (left) and the S-enantiomer
(right) of naringenin at the 30% probability level.
7

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The crystal structure of racemic naringenin has been determined by independent
6
,7
groups, and it was found to crystallize in a monoclinic crystal system in the space group P2 /c
1
with one molecule in the asymmetric unit. The atom C1 and the 4-hydroxyphenyl substituent in
the racemate were disordered over two positions in these crystal structure determinations. The
solid-state structures of the pure naringenin enantiomers were unknown prior to our study. While
the R- and S-enantiomers crystallize in the monoclinic crystal system, they do so in a chiral
space group P2 with two independent molecules having slightly different geometries in the
1
asymmetric unit (Table 2). The pyrone ring adopts a chair-type conformation in which C1 atom
deviates from the plane drawn through the remaining five atoms of this heterocycle in each
enantiomer (Table 2). The 4-hydroxyphenyl substituent associated with the pyrone ring occupies
an equatorial position and lies in a plane that is almost perpendicular to the flattened portion of
the heterocyclic ring (Table 2). As shown in Figs. 4 and 5, the atoms of carbonyl and hydroxyl
groups form six-membered rings via strong intramolecular O-H···O hydrogen bonds (Tables 4
and 5).
In both enantiomers of naringenin favorable mutual orientation of the two independent
molecules leads to the formation of strong intermolecular O-H···O hydrogen bonds that link
them into dimers (Figs. 4 and 5). These same intermolecular O-H···O hydrogen bonds are an
important feature that helps to preserve the dimeric motif even in the gas phase as confirmed by
the DFT studies (vide infra).
Fig. 4. General view of two independent molecules of the R-enantiomer of naringenin linked by
O-H···O hydrogen bonds.
8

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Fig. 5. X-ray diffraction (left) and DFT-optimized structures for the two independent molecules
of the S-enantiomer of naringenin linked by O-H···O hydrogen bonds.
Examination of the crystal packing diagrams of both enantiomers reveals the existence of
relatively strong intra- and intermolecular hydrogen-bonding interactions between selected
oxygen atoms and O-H groups (Tables 4 and 5). In both structures, there are several weak C-
H···O intermolecular contacts (O···H distances between 2.38 and 2.43 Å) that are coupled with
the remaining O-H···O H-bonds, serving to orient the molecules into defined networks of
stacked dimer units (Figs. 6 and 7).
Fig. 6. Crystal packing of the R-naringenin with dashed lines illustrating the O-H···O hydrogen
bonds and weak C-H···O contacts.
9

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Fig. 7. Crystal packing of the S-naringenin with dashed lines illustrating the O-H···O hydrogen
bonds and weak C-H···O contacts.
While the X-ray diffraction structures of the naringenin enantiomers are straightforward
in nature, we wished to explore the relationship of the conformation displayed by the monomeric
unit of naringenin present in the solid-state structures relative to other energetically accessible
conformations using electronic structure calculations. As a prelude to the monomer studies, we
first examined the X-ray diffraction structures of the hydrogen-bonded dimers of both
enantiomers by performing single-point energy calculations using DFT. The dimer entities
displayed in Figs. 4 and 5 exhibited identical energies as required for a true mixture of
enantiomers. The intermolecular hydrogen bonding between the two monomeric units in the
solid-state structure of the naringenin enantiomers is strong, and this was verified by a
subsequent geometry optimization of the dimeric structure of S-naringenin without any
constraints. The DFT-optimized structure (Fig. 5, right side) closely mirrors the X-ray diffraction
structure and confirms the intact dimer as a ground-state minimum. The computed structure for
the dimer reveals an average hydrogen-bonding distance of 1.901 Å for the intermolecular
O-H···O interactions between the two monomers, and this distance is only 0.167 Å longer than
the mean intramolecular O-H···O bond length of 1.734 Å.
The geometry optimization of the monomeric structure of S-naringenin present in the
dimer afforded species E2, whose overall geometry and orientation of atoms is unchanged
2
1
relative to the solid-state structure (Fig. 8). Three additional conformers (E1, E3, and E4)
having an equatorial 4-hydroxyphenyl group were also computed as ground-state minima.
Structures E1-E4 differ only in the rotation of the hydroxyl groups at the C7 and C13 atoms. E4
represents the most stable form of monomeric S-naringenin, but it is only marginally more stable
1
0

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in comparison to three other conformations with an equatorial aryl group. An earlier study found
species E4 as their preferred ground-state structure but did not report the structures of other
1
9a
equatorial substituted conformers. Low rotational barriers facilitate the interconversion of
these minima on the potential energy surface and guarantee a complex mixture of minima of
naringenin both in the gas phase and solution. The energies for species E1-E4 are reported in
Table 6.
Fig. 8. Geometry-optimized structures of the S-naringenin conformers containing an equatorial
4
-hydroxyphenyl group.
The equatorial-to-axial conversion of the 4-hydroxyphenyl substituent in S-naringenin
was next investigated. Four distinct axial conformers (A1-A4) were found, all of which are
predictably less stable (>2.6 kcal/mol) than their equatorial counterparts. The optimized
structures of A1-A4 are depicted in Fig. 9 and their energies, relative to E4, are reported in Table
6
. Of the eight conformations (E1-E4 and A1-A4) of S-naringenin found, only those with an
equatorial 4-hydrophenyl group make significant contributions to the ground-state composition
of S-naringenin. The reported Boltzmann populations of these conformers (Table 6) reveal that
the species E1-E4 account for slightly over 98% of the structures energetically accessible at
room temperature.
1
1

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Fig. 9. Geometry-optimized structures of the S-naringenin conformers containing an axial 4-
hydroxyphenyl group.
The relative strength of the intramolecular hydrogen bond that exists between the C-5
hydroxyl group and the pyrone carbonyl oxygen atom in E2 was next investigated. Analysis of
the potential energy profile for the internal rotation of the O-H bond about the fixed C-O vector
of the carbonyl moiety confirmed species B (Fig. 10) as the non-hydrogen bonded minimum.
The energetic penalty associated with the disruption of the intramolecular hydrogen bond is high,
and species B is computed to be 12.6 kcal/mol less stable than E2. While not explicitly
examined, the intramolecular hydrogen bond strength in the three other equatorial conformers is
assumed to be similar in nature.
Fig. 10. Geometry-optimized structures of species B (top) and C (bottom).
1
2

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Optically pure naringenin has been reported to undergo racemization at elevated
1
8
temperature presumably via an acyclic chalcone intermediate. Scheme 2 depicts the
equilibrium for the isomerization of E4 to the anticipated chalcone C. The optimized structure of
-13
C is shown in Fig. 10 and the free energy for the reaction is 17.5 kcal/mol (Keq ca. 10 ). The
unfavorable thermodynamics for the racemization are in keeping with the fact that once
separated by chiral HPLC, enantiomerically pure naringenin may be employed by researchers as
2
2
a substrate in stereospecific pharmacokinetic studies.
H
H
O
O
O
O
O
H
H
H
O
O
O
H
H
H
E4
C
O
O
Scheme 2. Racemization equilibrium for naringenin (E4) to the corresponding chalcone (C).
Conclusions
The R- and S-enantiomers of naringenin were separated, and their structures and absolute
configurations were determined by X-ray diffraction analysis. Both enantiomers crystallize in the
monoclinic crystal system in the chiral space group P2 with two independent molecules having
1
slightly different geometry in the asymmetric unit. In all molecules, the pyrone ring adopts a
chair-type conformation in which C1 atom deviates from the plane drawn through the remaining
five atoms of this heterocycle. The 4-hydroxyphenyl substituent connected to the pyrone ring
occupies an equatorial position and lies in a plane which is almost perpendicular to the flat part
of this heterocycle. The atoms of carbonyl and hydroxyl groups form six-membered rings via
strong intramolecular O-H···O hydrogen bonds. In both enantiomers, the favorable mutual
orientation of the two independent molecules leads to the formation of intermolecular O-H···O
hydrogen bonds that link them into dimers. The remaining O-H···O hydrogen bonds and several
weak C-H···O intermolecular contacts combine dimers into networks.
Acknowledgments
We thank the Robert A. Welch Foundation (grant B-1093) for financial support and also
acknowledge computational resources through Center for Advanced Scientific Computing and
1
3

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Modeling (CASCaM) and UNT's High-Performance Computing Services. We also thank Prof.
Michael B. Hall (TAMU) for providing us a copy of his JIMP2 program.
1
4

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Table 1. Structure determination summary for the R- and S-enantiomers of naringenin
R-enantiomer
1493288
S-enantiomer
1493026
CCDC entry No.
Empirical formula
Formula weight
Temperature, K
Radiation type
Crystal system
Space group; Z
a, Å
C H O
C H O5
15 12
1
5
12
5
272.25
150
272.25
200
Cu K
Monoclinic
P2 , 4
α
Cu K
Monoclinic
P2 , 4
α
1
1
4.8961 (3)
15.3695 (10)
16.5583 (10)
90
4.9005 (5)
15.3775 (14)
16.5419 (15)
90
b, Å
c, Å
α
, deg
, deg
β
91.763 (4)
90
91.796 (5)
90
γ, deg
3
Volume, Å
1245.4 (1)
1.452
1245.9 (2)
1.451
3
Density (Mg/m )
Crystal size (mm)
θ scan range (°)
F(000)
0.12 × 0.08 × 0.02
2.67 - 68.30
568
0.12 × 0.07 × 0.02
2.67 - 66.59
568
Crystal color, shape
colorless, plate
0.924
colorless, plate
0.923
-1
Absorption coeff. (mm )
Absorption correction
R(int)
Multi-scan, SADABS
0.075
Multi-scan, SADABS
0.045
Indep. refls.
4507
4395
Obs. refls. [Fo > 4sig(Fo)]
3523
4052
Final R
1
0.047
0.031
Final wR2
0.127
0.086
Goodness of Fit
1.02
1.03
−
3
ꢁ
ρ
max
,
ꢁρmin (e Å )
0.21, -0.17
0.17, -0.13
Absolute structure
Flack H D (1983), Acta
Cryst. A39, 876-881
0.1 (2)
Flack H D (1983), Acta
Cryst. A39, 876-881
0.05 (14)
Absolute structure parameter
1
5

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Table 2. Least-squares planes (x,y,z in crystal coordinates) and deviations from those planes in
the R- and S-enantiomers of naringenin
Least-squares planes
Rms deviation of fitted
Angle to previous plane
two independent
(* indicates atom out of plane for two atoms in two independent (with approximate esd) in
independent molecules)
molecules, Å
o
molecules,
R-enantiomer (peak 2)
C4A,C5A,C6A,C7A,C8A,C9A
C4B,C5B,C6B,C7B,C8B,C9B
O1A,C2A,C3A,C4A,C9A
0.008(2)
0.012(2)
0.015(3)
3.3(2)
5.4(2)
*
C1A 0.646(4) Å
O1B,C2B,C3B,C4B,C9B
C1B 0.604(5) Å
0.023(2)
*
C10A,C11A,C12A,C13A,C14A,C15A 0.002(3)
C10B,C11B,C12B,C13B,C14B,C15B 0.001(3)
S-enantiomer (peak 1)
86.84(9)
88.11(9)
C4A,C5A,C6A,C7A,C8A,C9A
C4B,C5B,C6B,C7B,C8B,C9B
O1A,C2A,C3A,C4A,C9A
0.006(1)
0.012(1)
0.017(2)
3.3(1)
5.4(1)
*
C1A -0.648(3) Å
O1B,C2B,C3B,C4B,C9B
C1B -0.618(3) Å
0.024(2)
*
C10A,C11A,C12A,C13A,C14A,C15A 0.002(2)
C10B,C11B,C12B,C13B,C14B,C15B 0.001(2)
86.80 (5)
88.02(5)
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Table 3. Selected bond lengths and angles for the R- and S-enantiomers of naringenin
Bond length (Å) and
angle (°)
R-enantiomer
S-enantiomer
Two independent molecules
Two independent molecules
A
B
A
B
O1-C1
1.459(4)
1.375(4)
1.508(4)
1.502(4)
1.503(4)
1.244(4)
1.350(4)
1.358(4)
1.381(4)
114.7(2)
107.9(2)
109.5(3)
114.8(3)
1.454(4)
1.367(4)
1.509(5)
1.501(4)
1.490(5)
1.254(4)
1.346(4)
1.369(4)
1.378(4)
115.7(2)
108.6(2)
110.5(3)
113.4(3)
1.455(2)
1.367(2)
1.515(3)
1.504(3)
1.504(3)
1.244(2)
1.344(3)
1.352(2)
1.375(2)
114.82(14)
108.24(14)
109.71(15)
114.23(15)
1.461(2)
1.366(2)
1.517(3)
1.501(3)
1.493(3)
1.247(2)
1.344(2)
1.362(2)
1.376(2)
115.77(13)
108.53(14)
109.86(16)
112.98(15)
O1-C9
C1-C2
C1-C10
C2-C3
O2-C3
O3- C5
O4-C7
O5- C13
C9-O1-C1
O1-C1-C10
O1-C1-C2
C10-C1-C2
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Table 4. Hydrogen bonds O-H···O for the R-enantiomer of naringenin [Å and °]
_
_________________________________________________________________
D-H···
A
d(D-H)
d(H···A)
d(D···A)
<(DHA)
_
_________________________________________________________________
O(3A)-H(3A)···O(2A)#1 0.92(5)
O(3B)-H(3B)···O(2B)#1 1.00(6)
O(4A)-H(4A)···O(5B)#1 1.01(5)
O(4B)-H(4B)···O(5A)#1 0.91(4)
O(5A)-H(5A)···O(2B)#2 0.88(6)
O(5B)-H(5B)···O(2A)#3 1.05(5)
1.85(5)
1.75(6)
1.77(5)
1.93(4)
1.88(6)
1.63(5)
2.617(4)
2.638(4)
2.739(4)
2.794(4)
2.744(4)
2.673(4)
139(4)
145(5)
160(4)
159(3)
166(5)
171(4)
_
_________________________________________________________________
Symmetry transformations used to generate equivalent atoms:
1 x,y,z #2 -x+2,y+1/2,-z+1 #3 -x+1,y-1/2,-z+2
#
Table 5. Hydrogen bonds O-H···O for the S-enantiomer naringenin [Å and °]
_________________________________________________________________
_
D-H···
A
d(D-H)
d(H···A)
d(D···A)
<(DHA)
_
_________________________________________________________________
O(3A)-H(3A)···O(2A)#1 0.87(4)
O(3B)-H(3B)···O(2B)#1 0.93(3)
O(4A)-H(4A)···O(5B)#1 0.94(3)
O(4B)-H(4B)···O(5A)#1 0.89(2)
O(5A)-H(5A)···O(2B)#2 0.93(4)
O(5B)-H(5B)···O(2A)#3 0.92(3)
1.85(4)
1.80(3)
1.84(3)
1.94(3)
1.84(4)
1.76(3)
2.624(2)
2.637(2)
2.741(2)
2.789(2)
2.750(2)
2.672(2)
147(3)
148(3)
160(3)
160(2)
167(3)
170(2)
_
________________________________________________________________
Symmetry transformations used to generate equivalent atoms:
1 x,y,z #2 -x+1,y-1/2,-z #3 -x,y+1/2,-z+1
#
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Table 6. Relative energies (∆G) and Boltzmann’s population (%) calculated in the gas phase for
a
S-naringenin monomers
compound
E1
∆G
0.3
0.1
0.3
0.0
2.6
2.6
2.6
3.0
% Population
18.4
E2
29.4
E3
18.4
E4
32.2
A1
0.4
A2
0.4
A3
0.4
A4
0.4
a
Free energy differences are relative to species E4 and are in kcal/mol. The theoretical
population is calculated by using the Boltzmann equation at room temperature (298 K).
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Here the E and A designations employed for the naringenin conformers distinguish the orientation of
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22
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2
1