On the importance of intermolecular interactions of 3-(2,3-dihydroxy-isopentyl)-4-hydroxyacetophenone: Crystal structure, spectroscopic and hirshfeld surface analysis

Article abstract of DOI:10.1016/j.molstruc.2020.128393

The compound 3-(2,3-dihydroxy-isopentyl)-4-hydroxyacetophenone has been synthesized and characterized by ¹H Nuclear Magnetic Resonance (NMR), Infrared (IR) and Raman spectroscopies and its crystal structure was solved by single crystal X-ray diffraction. The molecular geometry of the compound was investigated theoretically by performing density functional theory (DFT) calculations to access reliable results to the experimental data. The substance crystallizes in the triclinic P1ˉcrystal system with Z = 2 molecules per unit cell. The crystal structure of the compound shows the two methyl groups attached to the C11 atom are in a gauche conformation in relation to the C9 methylene group which in turn is antiperiplanar with respect to the C11 hydroxyl group. A similar disposition was observed for the C13 methyl group in relation to the C10 hydroxyl group. The most stable conformer obtained by conformational analysis shows the O3–H3 and O4–H4 hydroxyl groups in an anti-conformation. The differences observed between experimental and calculated results were interpreted in terms of intermolecular interactions in the crystal packing. The structure reveals that the crystal packing is governed by O–H?O hydrogen bonding and weak C–H?O and C–H···π non-covalent interactions. A detailed analysis of Hirshfeld surfaces and their associated 2D fingerprint plots allowed quantifying the interactions within the crystal structures.

Full text of DOI:10.1016/j.molstruc.2020.128393

Journal of Molecular Structure 1217 (2020) 128393
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
On the importance of intermolecular interactions of 3-(2,3-dihydroxy-
isopentyl)-4-hydroxyacetophenone: Crystal structure, spectroscopic
and hirshfeld surface analysis
,
*
,
,
Diego M. Gil a 1, Emilio Lizarraga b c, Gustavo A. Echeverría d, Oscar E. Piro d,
e
ꢀ
ꢀ
Cesar A.N. Catalan
a
ꢀ
ꢀ
INBIOFAL (CONICET e UNT), Instituto de Química Organica. Facultad de Bioquímica, Química y Farmacia. Universidad Nacional de Tucuman. Ayacucho
ꢀ
471, T4000INI, San Miguel de Tucuman. Argentina
b
ꢀ
ꢀ
Fundacion Miguel Lillo, Instituto de Fisiología Animal, Miguel Lillo 251, T4000JFE, San Miguel de Tucuman, Argentina
c
ꢀ
ꢀ
Facultad de Ciencias Naturales e Instituto Miguel Lillo, Universidad Nacional de Tucuman, Miguel Lillo 205, T4000JFE, San Miguel de Tucuman, Argentina
d Departamento de Física, Facultad de Ciencias Exactas, Universidad Nacional de La Plata and Institute IFLP (CONICET, CCT-La Plata), C. C. 67, 1900, La Plata,
Argentina
e
ꢀ
ꢀ
Instituto de Química Organica. Facultad de Bioquímica, Química y Farmacia. Universidad Nacional de Tucuman, Ayacucho 471, T4000INI, San Miguel de
ꢀ
Tucuman, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
The compound 3-(2,3-dihydroxy-isopentyl)-4-hydroxyacetophenone has been synthesized and charac-
terized by 1H Nuclear Magnetic Resonance (NMR), Infrared (IR) and Raman spectroscopies and its crystal
structure was solved by single crystal X-ray diffraction. The molecular geometry of the compound was
investigated theoretically by performing density functional theory (DFT) calculations to access reliable
results to the experimental data. The substance crystallizes in the triclinic P1crystal system with Z ¼ 2
molecules per unit cell. The crystal structure of the compound shows the two methyl groups attached to
the C11 atom are in a gauche conformation in relation to the C9 methylene group which in turn is
antiperiplanar with respect to the C11 hydroxyl group. A similar disposition was observed for the C13
methyl group in relation to the C10 hydroxyl group. The most stable conformer obtained by confor-
mational analysis shows the O3eH3 and O4eH4 hydroxyl groups in an anti-conformation. The differ-
ences observed between experimental and calculated results were interpreted in terms of intermolecular
interactions in the crystal packing. The structure reveals that the crystal packing is governed by OeH/O
Received 14 February 2020
Received in revised form
24 April 2020
Accepted 5 May 2020
Available online 10 May 2020
Keywords:
Hydrogen bonds
Non-covalent interactions
Hirshfeld surfaces
DFT
NBO analysis
hydrogen bonding and weak CeH/O and CeH$$$
p non-covalent interactions. A detailed analysis of
Hirshfeld surfaces and their associated 2D fingerprint plots allowed quantifying the interactions within
the crystal structures.
© 2020 Elsevier B.V. All rights reserved.
1. Introduction
assembly in organic compounds and also play vital roles in various
fields from medicinal chemistry to material science [3,4]. These
Crystal engineering and supra-molecular chemistry are at the
forefront of current structural chemistry research interest with a
variety of applications related to the structure of different com-
pounds [1,2]. Various non-covalent interactions, such as hydrogen
interactions are individually weaker and geometrically less well-
defined; however, their combined effect can be as important as
strong interactions [5]. A proper understanding of these weak in-
teractions is crucial to extrapolate structure-reactivity/property
relationships [6]. Recently, we have reported the synthesis, spec-
troscopic characterization and a complete structural analysis of two
Schiff bases, obtained from 4-aminoacetophenone, and their supra-
molecular arrangement were studied by Hirshfeld surface analysis
[7,8]. In addition, we have evaluated the role of the hydrogen bonds,
bonding, halogen bonding, CeH$$$p interactions, p-stacking and
other weak forces, can be decisive in controlling the molecular
* Corresponding author.
halogen interactions and CeH$$$p and p-stacking interactions that
E-mail address: dmgil@fbqf.unt.edu.ar (D.M. Gil).
Member of the Research Career of CONICET.
1
stabilize the crystal packing of a new perfluoromethylaminoenone
https://doi.org/10.1016/j.molstruc.2020.128393
0022-2860/© 2020 Elsevier B.V. All rights reserved.

2
D.M. Gil et al. / Journal of Molecular Structure 1217 (2020) 128393
derivative [9].
2.2. Instrumentation
p-Hydroxyacetophenone and its derivatives are phenolic me-
tabolites frequently found in both angiosperms and gymnosperms,
where they have been considered to act as defense metabolites,
mainly as antifungal agents [10e13]. On the other hand, prenylated
p-hydroxyacetophenone derivatives have been proposed as bioge-
netic precursors of benzofurans and chromanes which are charac-
teristic bioactive metabolites of certain tribes of the Asteraceae
family [13e16]. In this sense, we recently described [17] a bio-
mimetic synthesis of the natural benzofuran (4) and natural chro-
mane (3) starting from the antifungal 4-hydroxy-3-(3-methyl-2-
butenyl)-acetophenone (4-HMBA) (1) [10], the main secondary
metabolite of Senecio nutans [18], Xenophyllum poposum [19], and
Xenophyllum incisum [20]. These compounds were characterized by
different spectroscopic techniques such as IR, Raman and UVeVis
and their crystal structures were solved by single-crystal XRD
methods. Thus, treatment of (1) with m-chloroperbenzoic acid
yielded a mixture of epoxide (2), along with the chromane 2,2-
dimethyl-3-hydroxy-6-acetylchromane (3) and the benzofuran
10,11-dihydro-10-hydroxytremetone (4). Hydrolysis of epoxide (2)
1H NMR spectra were recorded in CDCl3 solvent on a Bruker AC
(200 MHz) spectrometer. Tetramethylsilane (TMS) was used as in-
ternal standard. Chemical shifts were recorded in
d (ppm) values
relative to TMS and J values were expressed in Hertz. Infrared ab-
sorption spectra were recorded in the range of 4000e400 cmꢁ1 on
a PerkinElmer GX1 Fourier Transform infrared spectrometer with
2 cmꢁ1 of spectral resolution. The solid state Raman spectrum was
measured at room temperature in the spectral range from 3500 to
50 cmꢁ1 using a Thermoscientific DXR Raman microscope. Raman
data have been recorded using a diode-pump, solid state laser of
532 nm with a resolution of 5 cmꢁ1. The UVeVisible measurements
were recorded using quartz cells (10 mm optical path length) in a
Specord S-600 diode array spectrophotometer. For this purpose, a
solution of 12.33 mg/L of compounds in ethanol was prepared. Each
spectrum was recorder between 205 and 700 nm region.
2.3. X-ray diffraction data
produced
the
phenol-diol
3-(2,3-dihydroxysopentyl)-4-
The X-ray measurements were performed on an Oxford Gemini,
hydroxyacetophenone (5), a metabolite isolated from the medici-
nal plant Werneria ciliolata [21]. This phenol-glycol was isolated as
an oil by preparative HPLC which crystallized after several weeks in
the refrigerator producing single crystals suitable for structural
studies. The results are presented and discussed here.
In this work, the synthesis and characterization of 3-(2,3-
dihydroxy-isopentyl)-4-hydroxyacetophenone (5) is reported. The
solid was characterized by IR, Raman and 1H NMR spectroscopy.
The crystal structure of the compound was solved by X-ray
diffraction (XRD) methods along with the DFT calculations to study
the molecular geometry. The role of weak hydrogen bonds and
other intermolecular interactions in building possible supra-
molecular assemblies was evaluated by Hirshfeld surface analysis.
Eos CCD diffractometer with graphite-monochromated CuK
¼ 1.54184 Å) radiation. X-ray diffraction intensities were
collected ( scans with w and -offsets), integrated and scaled with
a
(l
u
k
CrysAlisPro suite of programs [22]. The unit cell parameters were
obtained by least-squares refinement (based on the angular set-
tings for all collected reflections with intensities larger than seven
times the standard deviation of measurement errors) using Cry-
sAlisPro. Data were corrected empirically for absorption employing
the multi-scan method implemented in CrysAlisPro. The structure
was solved by intrinsic phasing with SHELXT of the SHELX suit of
programs [23] and refined with SHELXL of the same package. All
hydrogen atoms were located in a difference Fourier map phased
on the heavier atoms and refined at their found positions with
isotropic displacement parameters.
Crystal data and data collection procedure are summarized in
Table 1. Crystallographic structural data have been deposited at the
Cambridge Crystallographic Data Centre (CCDC). Enquiries for data
can be direct to: Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, UK, CB2 1EZ or (e-mail) deposit@ccdc.cam.ac.uk
or (fax) þ44 (0) 1223 336033. Any request to the Cambridge
Crystallographic Data Centre for this material should quote the full
literature citation and the reference number CCDC 1958399.
2. Experimental
2.1. Synthesis of 3-(2,3-dihydroxy-isopentyl)-4-
hydroxyacetophenone (racemic)
The compound was synthesized by treating of 4-hydroxy-3-(3-
methyl-3-butenyl)-acetophenone (4-HMBA) with m-chlor-
operbenzoic acid as reported earlier [17]. During the formation of
epoxide (2), an intramolecular nucleophilic attack by the phenolic
hydroxyl at the epoxide carbons produces chromane (3) and
benzofuran (4), while dissolution in aqueous solutions yields the
corresponding solvolysis product, i.e. phenol-diol (5). After sepa-
ration and purification by preparative HPLC phenol-diol (5) was
obtained as colorless needles, m.p. 139e140 ꢀC (from methanol).
Single-crystals adequate for XRD measurements were obtained
from slow evaporation of a methanolic solution of the compound at
room temperature.
2.4. Hirshfeld surface analysis
The Hirshfeld surface (HS) analysis and their decomposed two-
dimensional fingerprint (FP) plots were used to quantify the
contribution of intermolecular interactions that stabilize the crystal
packing and to understand the nature of intermolecular in-
teractions [24e27]. The HS and their 2D fingerprint plots were
generated by using the CrystalExplorer17.5 program using the
crystallographic information files (CIF) obtained from the X-ray
crystal structure determination [28]. The function dnorm is given by
the formula involving the ratio encompassing the distances of any
surface point to the nearest interior (di) and exterior (de) atom and
the van der Waals radii (rvdW) of the atoms [24].
EIMS: m/z (rel. int. %) [M]þ 238 (4), 220 (5), 205 (2), 187 (2), 180
(18), 165 (6), 163 (7), 150 (25), 149 (29), 137 (52), 119 (12), 107 (21),
91 (11), 77 (16), 71 (17), 59 (39), 43 (100). 1H NMR (200 MHz,
di ꢁ rivdW
de ꢁ revdW
CDCl3): d 7.79 d (1H, 2.1 Hz, H-6), 7.70 dd (1H, 8.3 and 2.1 Hz, H-4),
dnorm
¼
þ
(1)
6.88 d (1H, 8.3 Hz, H-3), 3.90 br (3H, OH; this signal disappears by
exchange with D2O), 3.60 dd (1H, 10.3 and 1.4 Hz, H-10), 2.91 dd
(1H, 14 and 1.4 Hz, H-9A), 2.66 dd (1H, 14 and 10.3 Hz, He9B), 2.52 s
(3H, H-8), 1.25 s and 1.23 s (3H each, H-12 and H-13) (for 1H NMR in
CD3OD see Refs. [17]). The 1H NMR spectrum in CDCl3 is shown in
Fig. S1 (Supplementary Information).
rivdW
revdW
The red regions in the dnorm plots indicate that the sum of de and
di is shorter than the sum of van der Waals (vdW) radii and
therefore considered to be a close contact. The white colour denotes
intermolecular interactions with distances close to vdW contacts

D.M. Gil et al. / Journal of Molecular Structure 1217 (2020) 128393
3
Table 1
Crystal data and structure refinement for 3-(2,3-dihydroxy-isopentyl)-4-hydroxyacetophenone.
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
C13 H18 O4
238.27
297(2) K
1.54184
Triclinic
P1
Unit cell dimensions
a ¼ 6.9478(5) Å
b ¼ 9.922(1) Å
a
b
g
¼ 108.464(10)
¼ 102.477(8)
¼ 102.324(7)
c ¼ 10.928(1) Å
664.5(1) Å3
Volume
Z, density (calculated)
Absorption coefficient
F(000)
Crystal size
w-range for data collection
Index ranges
2, 1.191 Mg/m3
0.721mmꢁ1
256
0.2020.354 mm3
4.481e72.390ꢀ.
ꢁ8 ꢂ h ꢂ 6, ꢁ12ꢂ k ꢂ 11, ꢁ13 ꢂ l ꢂ 13
4270
Reflections collected
Independent reflections
Observed reflections [I > 2
2576 [R(int) ¼ 0.0207]
s(I)]
1925
Completeness to w ¼ 67.684ꢀ
99.8%
Refinement method
Full-matrix least-squares on F2
2576/0/169
Data/restraints/parameters
Goodness-of-fit on F2
1042
Final R indicesa [I > 2
s(I)]
R1 ¼ 0.0491, wR2 ¼ 0.1354
R1 ¼ 0.0648, wR2 ¼ 0.1515
0.187and ꢁ0.183 e.Åꢁ3
R indices (all data)
Largest diff. peak and hole
a
R1 ¼ S||Fo|-|Fc||/S|Fo|, wR2 ¼ [Sw(|Fo|2-|Fc|2)2/Sw(|Fo|2)2]1/2
.
with dnorm equal to zero. The blue surfaces are assigned to contacts
longer than the sum of vdW radii with positive dnorm values. The 3D
dnorm surfaces were mapped over a fixed colour scale of ꢁ0.315 au
(red) to 0.460 au (blue). The 2D fingerprint plot is the combination
of di and de providing quantitative pictures of the intermolecular
contacts, including the relative percentage of each type of inter-
action in the crystal. The FP plots were displayed by using a
translated 0.6e2.6 Å range, and included reciprocal contacts.
Molecular electrostatic potential (ESPs) mapped over electron
density distribution on 0.005 e Åꢁ3 isosurfaces are calculated at
B3LYP/cc-pVDZ approximation by using the TONTO program inte-
grated into CrystalExplorer17.5.
C9eC10eC11eO4 dihedral angle because the conformation ob-
tained in solid state is related with the mentioned angle (see
below). The results of these calculations showed the existence of
three conformers and the energies of CI and CIII conformers are
significantly lower than CII conformer. The optimized molecular
structures computed at B3LYP/6e311þþG(d,p) level of the three
conformers are depicted in Fig. 1b. Table S1 (Supplementary In-
formation) shows the relative total energies and free energies of the
three conformers calculated at the same level of theory. The fre-
quencies calculated for the three structures were all positive con-
firming that they corresponds to minima in the potential energy
curve.
In the most stable conformer for the compound (CI), the
dihydroxi-isopentyl group adopts an anti-conformation, while in
CII and CII conformers, the O3eH2 and O4eH4 hydroxyl groups are
present in a gauche conformation. In accordance with the results
showed in Fig. 1b, CI is the most stable conformer, but it is not the
conformer present in the crystal structure of the title compound
(CII conformer). In the solid, the gauche conformation in mainly
stabilized by intermolecular hydrogen bonding interactions (see
below) that are absent in gas phase. The experimental and calcu-
lated geometrical parameters for the three possible conformers of
3-(2,3-dihydroxy-isopentyl)-4-hydroxyacetophenone are listed in
Table 2.
2.5. Computational details
The quantum chemical calculations were performed using
Gaussian 03 program package [29]. For structural optimization, the
crystal structure geometry was used as a starting model. The mo-
lecular structure was fully optimized using B3LYP/6e311þþG(d,p)
level of theory. The vibration frequencies were calculated for the
optimized structure in gas phase to ascertain the global minima on
the potential energy surface and were found to have no imaginary
frequencies. The assignment of the vibration modes and the po-
tential energy distribution were calculated using the VEDA 4 pro-
gram [30,31]. The UVeVisible electronic transitions have been
calculated by using Time-dependent DFT (TD-DFT) approach [32] at
B3LYP/6e311þþG(d,p) level taking into account the solvent effect
(ethanol) using the conductor-like polarizable continuum model
(CPCM) [33].
3.2. Crystal structure
An ORTEP [34] diagram of the asymmetric unit content of the
compound along with the atoms numbering scheme is shown in
Fig. 2. The main experimental geometrical parameters are listed in
Table 2, where the corresponding values obtained from quantum
chemical calculations are also reported for comparison. There is a
good agreement between both sets of structural data.
3. Results and discussion
3.1. Conformational analysis and structural results
As expected from an extended
hydroxyacetophenone ring is
p
-bonding structure, the 4-
The potential energy curve for internal rotation around the
C10eC11 bond calculated at B3LYP/6e311þþG(d,p) approximation
is shown in Fig. 1a. In this study we have selected the
essentially planar with
C8eC7eC5eC4 and C8eC7eC5eC6 dihedral angles of 176.4(2)ꢀ
and ꢁ2.7(3)ꢀ, respectively. The overall molecular conformation can

4
D.M. Gil et al. / Journal of Molecular Structure 1217 (2020) 128393
Fig. 1. (a) Potential energy curve around the C10eC11 bond computed at B3LYP/6e311þþG(d,p) approximation; (b) Optimized molecular structures of the three possible con-
formations of 3-(2,3-dihydroxy-isopentyl)-4-hydroxyacetophenone.
be described by the relative orientation of the hydroxyl groups in
the alkyl chain, which facilitate intermolecular hydrogen bonding.
The torsion angle C1eC9eC10eC11 of ꢁ160.56(14)ꢀ shows an anti-
conformation of the molecule about the C9eC10 bond. The hy-
droxyl bounded at C10 adopts a gauge conformation, with a torsion
angle C1eC9eC10eO3 of 76.67(17)ꢀ. The optimized molecular
structure of CII conformer (Fig. 1b) corroborates the anti-confor-
mation of the dihydroxy-isopentyl chain with respect to the ace-
tophenone core indicating that the calculations agree well with
corresponding data from the X-ray structural studies. Observed
bond lengths and angles agree with Organic Chemistry rules and
with data reported for similar compounds [17,18]. The CeC bond
lengths of the phenyl ring are in the range of 1.376(3)-1.400(3) Å, as
expected for a resonant-bond structure. The carbonyl C]O bond
length is equal to 1.221(3) Å, in agreement with the computed value
(1.219 Å). The C(sp2)-O bond length is 1.350(2) Å, shorter than the
other C(sp3-O) bond lengths [1.425(2) and 1.435(2) Å]. The
dihydroxy-isopentyl moiety exhibits the expected tetrahedral
bonding structure with C12eC11eC13 and C12eC11eO4 angles of
111.71(17)ꢀ and 108.37(16)ꢀ, respectively which is consistent with
the sp3 hybrid character of C11 atom. A Newman projection of the
C11eC10 bond shows that the two methyl groups attached to the
C11 atom are in a gauche conformation in relation to the C9
methylene group which in turn is antiperiplanar with respect to the
C11 hydroxyl group. A similar disposition was observed for the C13
methyl group in relation to the C10 hydroxyl group (see dihedral
angles in Table 2). The small differences between the experimental
and computed geometrical parameters can be attributed to the fact
that theoretical calculations have been carried out with isolated
molecules in gas phase whereas the experimental values corre-
spond to the crystalline state, where intermolecular interactions
play an important role.
The crystal packing in the title compound is stabilized mainly by
OeH/O hydrogen bonding interactions (See Table 3, Fig. 3). In the
structure, each molecule participates in four hydrogen bonds and
these interactions dominate the crystal packing of the compound.
As shown in Fig. 2a, neighbouring molecules are linked to each
other through intermolecular O2eH2/O3 bonds. The polymeric

D.M. Gil et al. / Journal of Molecular Structure 1217 (2020) 128393
5
Table 2
edge-fused to generate a two-dimensional molecular assembly as
shown in Fig. 3a. In addition, to molecules are also linked via non-
classical C13eH13C/O1 hydrogen bonds [d(O1/H13C) ¼ 2.793 Å].
In the crystal packing of the title compound, the oxygen atom O3
from the hydroxyl group participates in intermolecular
O3eH3/O4 hydrogen bonding interactions forming inversion di-
mers with R22ð10Þ graph-set ring motif, as shown in Fig. 3b. Two
molecules are also linked through the H12C hydrogen of the methyl
group in the dihydroxy-isopentyl moiety and hydroxyl oxygen
atom O2 to form C12eH12/O2 intermolecular interactions
[d(CeH/O) ¼ 2.62 Å, <(CeH/O) ¼ 160.8ꢀ]. The supra-molecular
arrangement of the title compound is further controlled by
Experimental and calculated bond lengths, angles and dihedral angles for the three
possible conformations of 3-(2,3-dihydroxy-isopentyl)-4-hydroxyacetophenone.
Parametersa
Calculatedb
CI
Experimentalc
CII
CIII
Bond lengths (Å)
C1eC9
C2eO2
C9eC10
C10eO3
C10eC11
C11eO4
C11eC12
C11eC13
C5eC7
C7eO1
C7eC8
Bond angles (ꢀ)
C5eC7eC8
C1eC9eC10
C9eC10eC11
C10eC11eO4
C10eC11eC12
C10eC11eC13
C9eC10eO3
Dihedral angles (ꢀ)
C1eC9eC10eC11
C1eC9eC10eO3
C9eC10eC11eO4
C9eC10eC11eC12
C9eC10eC11eC13
1.512
1.363
1.544
1.426
1.548
1.436
1.535
1.535
1.494
1.223
1.521
1.511
1.369
1.535
1.425
1.552
1.451
1.531
1.532
1.494
1.219
1.519
1.511
1.365
1.547
1.424
1.548
1.435
1.535
1.538
1.494
1.220
1.520
1.510(2)
1.350(2)
1.527(2)
1.425(2)
1.538(2)
1.435(2)
1.516(3)
1.518(3)
1.477(3)
1.221(2)
1.488(3)
CeH$$$p interactions (Fig. 4) involving the H9 hydrogen of the
methylene group and the C1eC6 benzene ring [centroid Cg1;
symmetry 1-x, 1-y, 1-z].
118.9
112.0
113.9
104.1
112.3
109.5
111.4
118.9
112.7
114.8
102.0
112.8
111.6
106.9
118.9
112.3
113.1
106.2
110.2
110.7
110.5
120.41(18)
111.08(13)
113.80(13)
104.43(12)
112.79(15)
110.11(15)
107.49(13)
3.3. Hirshfed surface analysis
The intermolecular interactions affecting the packing modes of
the title compound are more easily understood using Hirshfeld
surface, with the results further highlighting the power of this
technique in mapping out interactions. It is well-known that the
Hirshfeld surface analysis is a useful visualization tool for the
analysis of intermolecular interactions in the crystal packing and
the fingerprint plots is also used to quantify the contribution of
various intermolecular contacts present in the crystal structures.
The HS are illustrated in Fig. 5 showing surfaces that have been
mapped with dnorm property. The 2D fingerprint plot provides a
quantitative description of all the intermolecular interactions in the
crystal (Fig. 6). The FP plots can be decomposed to highlight
particular atoms pair close contacts. This decomposition enables
separation of the contributions from different interactions, which
overlap in the full FP plot. In general, the intermolecular in-
teractions play a crucial role in the crystal structures of the studied
compound. A close examination of the FP plots generated for the
title compound indicates that the non-directional H/H in-
teractions are predominant (see Fig. 6) and comprise 60.9% of the
total HS area of the molecule, having minimun value of (de þ di) of
2.40 Å. These interactions play a major role in the strength of the
crystal lattice and simply represent regions which are dominated
by dispersion interactions [35]. The proportion of H/H contacts
can be used as reference for the effectiveness and stability of the
crystal packing and the relevance of another contacts can be
referred to this standard [35]. H/H contacts are weaker than other
interactions, and it is not clear if they are attractive or repulsive in
nature even though H/H bond paths are commonly found [36].
The dominant interactions between the hydroxyl O4eH4 and the
O1 atom from the carbonyl group are observed in the HS as the
bright red areas marked as 1 in Fig. 5. The red spots labelled as 2 are
assigned to O2eH2/O3 hydrogen bonding interactions. These in-
ꢁ179.4
59.99
56.40
ꢁ168.6
68.65
ꢁ175.0
ꢁ57.73
68.92
178.8
57.17
ꢁ50.74
ꢁ169.7
68.08
ꢁ160.56(14)
76.67(17)
ꢁ174.44(14)
ꢁ57.0(2)
ꢁ62.98
173.7
68.5(2)
a
See Fig. 2 for atoms numbering scheme.
b
c
Calculated values at B3LYP/6e311þþG(d,p) level of theory.
Experimental values obtained from single crystal XRD data.
Fig. 2. ORTEP diagram of the asymmetric unit of 3-(2,3-dihydroxy-isopentyl)-4-
hydroxyacetophenone, showing the labelling of the non-hydrogen atoms. Ellipsoids
are drawn at the 30% probability level.
teractions are the major contributor of the R44ð30Þ supramolecular
synthon. The visible spots around the hydroxyl O4eH4 (labelled as
3) are attributed to O3eH3/O4 contacts. The O/H/H/O contacts
appear as distinct sharp spikes on the FP plots, with a minimum
value (de þ di) of 1.65 Å coming from the strongest O3eH2/O3 and
O3eH3/O4 contacts, in accordance with the geometrical param-
eters reported in Table 3. The light red spots, labelled as 4 in the
back view of HS showing in Fig. 5, are due to non-classical CeH/O
hydrogen bonds involving as acceptor the O2 from the hydroxyl
group of one molecule and as donor the methyl group of the iso-
pentyl moiety of another molecule. The weak C13eH13C/O1 in-
teractions are not visible in the Hirshfeld surfaces because the
distances are longer than the sum of vdW radii. In the FP plot, they
appear as a thickening of the sharp spikes around (de þ di) of 2.6 Å,
Table 3
ꢀ
Hydrogen bonds parameters (Å,
hydroxyacetophenone.
)
for 3-(2,3-dihydroxy-isopentyl)-4-
D-H$$$A
D-H
H$$$A
D$$$A
< D-H$$$A Label in Fig. 5
C12eH12C/O2#1 0.96
2.62
3.539(3) 160.8
4
2
3
1
O2eH2/O3#2
O3eH3/O4#3
O4eH4/O1#4
0.89(3) 1.77(3) 2.654(2) 169(3)
0.86(3) 1.79(3) 2.642(2) 171(2)
0.86(3) 1.92(3) 2.768(2) 171(3)
Symmetry transformations used to generate equivalent atoms: (#1) x-1,y,z; (#2)
xþ1,y,z; (#3) ex,-y,-zþ1; (#4) x-1,y-1,z-1.
chains are further linked via intermolecular O4eH4/O1(keto)
hydrogen bonds, thus forming a R44ð30Þ synthon. The rings are

6
D.M. Gil et al. / Journal of Molecular Structure 1217 (2020) 128393
Fig. 3. Molecular packing of 3-(2,3-dihydroxy-isopentyl)-4-hydroxyacetophenone showing the formation of two-dimensional supra-molecular assemblies.
Fig. 4. View of the crystal packing of 3-(2,3-dihydroxy-isopentyl)-4-
hydroxyacetophenone showing CeH$$$ interactions.
p
Fig. 5. Front and back views of the Hirshfeld surfaces mapped with dnorm property.
Labels are discussed in the text and in Table 3.
in accordance with the values reported in Table 3. The proportion of
the O/H/H/O interactions, calculated from the decomposition of
the FP plot, is 23.3% of the total Hirshfeld surfaces of the molecule.
Besides, the decomposition of the FP plot shows that C/H/H/C
contacts comprise 14.6% of the total HS area of the molecule. They
hydroxyl group (ꢁ0.080 a.u.). Therefore, from an electrostatic point
of view, the interaction between both groups is favoured forming
O3eH3/O4 hydrogen bonds. Finally, the ESP values at the O1 and
H4 atoms are the smallest (ꢁ0.0542 and þ 0.1692 au, respectively).
These results indicate that the interaction O4eH4/O1 is weaker, in
accordance with the results reported in Table 3. The lowest ESP
value at the O2 atom showed in Figs. 7 (ꢁ0.0195 a.u.) is an indicator
of the weak C12eH12C/O2 hydrogen bond (Table 3, Fig. 4).
correspond to all the CeH$$$p interactions, which appear in the FP
plot in a characteristic manner.
We have computed the molecular electrostatic potential (ESP)
mapped on electron density isosurface in order to study the
attractive character of intermolecular hydrogen bonds which sta-
bilize the crystal packing of the title compound. The Hirshfeld
surface mapped over the electrostatic potential for 3-(2,3-
dihydroxy-isopentyl)-4-hydroxyacetophenone is shown in Fig. 7.
The blue and red colours are attributed to positive and negative
regions, respectively. The ESP shows the highest electropositive
value of þ0.2503 a.u. near the H2 atom attached to strong O2 donor,
and a strong electronegative region (ꢁ0.0896 a.u.) is found around
the O3 atom. This favours the formation of the strongest
O2eH2/O3 hydrogen bonds, as described in Table 3. In addition,
we have observed a positive region located around the H3 atom
(þ0.2149 a.u.) and a negative part located at the O4 atom of the
3.4. Vibrational results
Fig. 8 depicts the experimental FTIR and Raman spectra of 3-
(2,3-dihydroxy-isopentyl)-4-hydroxyacetophenone in solid state.
The frequencies obtained theoretically corresponds to CII
conformer which is the structure present in solid state. The
observed and computed vibration frequencies, together with the
corresponding assignment of bands, are listed in Table 4. A tentative
assignment of the observed bands has been performed by

D.M. Gil et al. / Journal of Molecular Structure 1217 (2020) 128393
7
Fig. 8. IR and Raman spectra of 3-(2,3-dihydroxy-isopentyl)-4-hydroxyacetophenone
in solid state.
Fig. 6. Fingerprint plots of the title compound: full and resolved into H/H, O/H/
H/O and C/H/H/C contacts showing the percentages of contacts contributing to the
total HS area.
stretching modes appear as broad bands between 3370 and
3200 cmꢁ1 hence indicating that all hydroxyl groups are involved in
intermolecular hydrogen bonds as was deduced from the crystal
structure, in accordance with related compounds [39,40].
The bands located at 1364, 1302, 1198 and 1116 cmꢁ1 in the IR
spectrum (1357, 1296 and 1195 cmꢁ1 in Raman) are assigned to
CeOeH bending modes. These values are in agreement with the
computed wavenumbers (see Table 4). The torsion OH modes are
assigned to the bands at 365 and 221 cmꢁ1 in the Raman spectrum.
comparison with theoretical mode frequencies. In this work, a scale
factor 0.9679 was used to counterbalance the systematic errors
caused by basis set incompleteness, neglect of electron correlation
and vibrational anharmonicity [37,38]. Very good agreement be-
tween the experimental and computed vibrational data supported
the proposed assignment. A comparison between the experimental
and theoretical IR and Raman spectra calculated at B3LYP/
6e311þþG(d,p) approximation is shown Figs. S2 and S3 (Supple-
mentary Information).
3.4.2. CH3 and CH2 group vibrations
The methyl groups generate bands at 2986 and 2971 cmꢁ1 in the
IR spectrum (2985 and 2969 cmꢁ1 in Raman) which are assigned to
CH3 antisymmetric stretching mode. The bands corresponding to
the CH3 symmetric stretching mode appear at 2933 cmꢁ1 in IR with
counterparts in Raman at 2928 and 2920 cmꢁ1. The bands located
at 1476 and 1453 cmꢁ1 (1468 and 1442 cmꢁ1 in Raman) are
assigned to the antisymmetric CH3 bending mode of the methyl
groups from the isopentyl moiety. The Raman band at 1426 cmꢁ1 is
3.4.1. OH vibrations
The vibrations of hydroxyl group show variation according to
the molecular environment. Generally, free hydroxyl groups
without hydrogen bonding interactions show IR absorption bands
between 3700 and 3500 cmꢁ1. For the title compound, the OeH
Fig. 7. Hirshfeld surface mapped over the calculated electrostatic potential in the range ꢁ0.0910 (red) to þ0.2524 (blue) atomic units for 3-(2,3-dihydroxy-isopentyl)-4-
hydroxyacetophenone.

8
D.M. Gil et al. / Journal of Molecular Structure 1217 (2020) 128393
Table 4
Selected experimental and theoretical vibration frequencies (cmꢁ1) and their tentative assignments for CII conformer of 3-(2,3-dihydroxy-isopentyl)-4-hydroxyacetophenone.
IR (solid)
Raman (solid)
Calculated
Unscaleda
Assignment of modes (PED ꢃ 10%)c
Scaledb
3370
3200
3085
3056
2986
2971
2965
2933
e
3832
3793
3195
3147
3091
3084
3057
3034
3023
3709
3671
3092
3046
2992
2985
2959
2936
2926
y
y
y
y
OeH (100)
OeH (100)
CeH (99)
CeH (84)
e
3077
e
2985
2969
2962
2928
2920
ya CH3CO (99)
ya CH3-IP (73)
ys CH2 (100)
ys CH3CO (100)
ys CH3-IP (91)
e
2911
1655
1602
1592
1511
1476
1453
2907
1643
1598
1588
1510
1468
e
2997
1735
1644
1627
1533
1511
1501
1490
2901
1679
1591
1575
1484
1462
1452
1442
y
y
y
y
d
C10eH (93)
C]O (87)
CC-R (64)
CC-R (50)
CCH-R (44) þ
d CCC-R (16)
daCH3-IP (79)
daCH3-IP (82)
daCH3-IP (62)
1442
e
1434
1434
1426
1478
1472
1431
1425
d
CH2 (67)
da CH3CO (94)
e
1386
1364
1343
1387
1357
1346
1324
1451
1426
1386
1368
1404
1380
1342
1324
y
y
CC-R (47) þ
d
CCH (10)
C10eOH (19) þ
C9eC10 (36) þ
d
d CCH (12)
ds CH3CO (86)
y
CC-R (20) þ
d CeO2eH (11)
e
1302
1289
1296
1284
1242
1310
1291
1278
1267
1250
1237
d
y
y
C9eC10eH (12) þ
d C10eOH (12)
C2eO2 (49)
C5eC7 (22)
e
1215
1198
1183
1148
1116
1078
1064
1035
1209
1195
1167
1143
e
1227
1207
1180
1169
1130
1098
1077
1042
1033
1188
1168
1142
1131
1094
1063
1042
1009
999
d
d
d
r
d
y
y
r
r
CCH-R (23)
CeO2eH (21) þ tu CH2 (11)
CCH-R (44) þ
d
CeO2eH (14)
CH3 (12)
CCH-R (16)
CH3 (29)
CeO4eH (41) þ
r
1074
1062
e
C10eO3 (26)
C10eO3 (26) þ
d
CH3 (70) þ
g
y
C]O (22)
C9eC10 (15)
1030
CH2 (24) þ
e
1006
966
934
920
909
e
1012
976
969
961
931
927
980
945
938
930
901
897
r
n
CH3-IP (32)
962
928
916
908
898
C10eC11 (20) þ
r
CH3-IP (17)
g
r
r
n
CCH-R (83)
CH3eCO (44) þ
CH3-IP (39)
C1eC9 (17) þ
n C7eC8 (25)
g
CCH-R (15) þ
CC-R (10)
C11eO4 (10)
dCCC-R (11)
e
880
e
915
904
886
875
g
g
CCH-R (27) þ
n
n
873
CCH-R (29) þ
e
836
796
776
743
723
689
635
608
588
551
515
501
477
454
420
e
879
825
804
776
746
693
642
614
590
571
543
512
494
475
424
413
851
799
778
751
722
671
621
594
571
553
526
496
478
460
410
400
n
C9eC10 (30) þ
r
CH2 (16)
790
e
g
CCH-R (83)
ns C(CH3)2 (21)
741
e
d
g
n
CCC-R (20)
CCC-R (51)
C7eC5 (38) þ
C]O (21)
CCC-R (31)
CC]O (35) þ
685
634
604
580
549
e
d
CCC-R (17) þ
C7eC8 (11)
n CC-R (11)
g
d
d
n
ns C(CH3)2 (14) þ
d C10eC11eC13 (13)
g
g
d
t
d
d
CCC-R (29)
CCC-R (41)
O2eC2eC3 (70)
O3eH (51)
507
471
e
e
C13eC20eO4 (31) þ
r CH2 (12)
380
C8eC7eC5 (49)
e
e
e
e
e
e
e
e
e
e
365
346
335
322
221
196
164
129
107
372
356
345
340
238
204
156
151
108
360
345
334
329
230
197
151
146
105
t
d
d
n
t
d
t
d
t
O2eH (89)
C9eC10eO3 (41)
C(CH3)2 (55)
CC-R (28) þ
O4eH (52) þ
C19eC10eC11 (29) þ
CH3eCO (93)
d
CCC-R (24) þ
t
d C8eC]O (21)
CH3 eIP (10)
t CCCC-R (20)
C7eC5eC6 (35) þ
CCCC-R (75)
d C9eC10eC11 (21)

D.M. Gil et al. / Journal of Molecular Structure 1217 (2020) 128393
9
Table 4 (continued )
IR (solid)
Raman (solid)
68
Calculated
Assignment of modes (PED ꢃ 10%)c
Unscaleda
Scaledb
69
71
t
C8eC7eC5eC6 (61)
e
a
Calculated vibration frequencies at B3LYP/6e311þþG(d,p) level of theory.
b
c
Scale factor used 0.9679.
n: stretching, d: bending, g: out-of-plane bending, r: rocking, t: torsion modes; s: symmetric, a: antisymmetric; R: ring; IP: isopentyl group.
assigned to the antisymmetric CH3 stretching mode of the acetyl
group. These assignments are in agreement with reported data in
literature [17,18] and with the calculated values (see Table 4). The IR
absorption band at 1343 cmꢁ1 is assigned to symmetric CH3
bending mode corresponding to the methyl group attached to the
C]O moiety. The title molecule contains one methylene group. The
IR absorption band at 2965 cmꢁ1 is assigned to the CH2 symmetric
stretching mode, which agrees well with the computed value at
2959 cmꢁ1 (scaled value). The CH2 bending mode is associated with
the IR and Raman bands observed at 1434 cmꢁ1, in agreement with
the calculated value (1431 cmꢁ1).
spectrum shows strong absorptions at 1289, 1078 and 1064 cmꢁ1
,
with Raman counterparts at 1284, 1074 and 1062 cmꢁ1, which are
attributed to CeO stretching modes.
3.5. Electronic spectra
The electronic spectrum for the title compound was calculated
in ethanol as solvent at B3LYP/6e311þþG(d,p) approximation. The
observed and calculated electronic transitions of high oscillator
strengths are listed in Table 5. The comparison between experi-
mental and computed UVevisible spectra of 3-(2,3-dihydroxy-
isopentyl)-4-hydroxyacetophenone is shown in Fig. 9. The low in-
tensity band at 224 nm in the experimental spectra is assigned to
HOMO-1 to LUMOþ1 electronic transition, in accordance with the
computed value (217 nm). The sharp and strong absorption band at
278 nm, matches well with the calculated value at 270 nm and
arises mainly from HOMO to LUMO excitation and contains con-
tributions from electronic transition among HOMO-2 / LUMO
orbitals. The shoulder observed at 263 nm in the experimental
spectrum (calculated: 258 nm, f ¼ 0.1153) is mainly attributed to
transition from HOMO-2 / LUMO and HOMO / LUMOþ1 or-
bitals. The HOMO corresponds to a p-type orbital character over the
3.4.3. CeH vibrations
The aromatic CeH stretching modes generate multiple bands in
the region 3100-3000 cmꢁ1 [41]. For the title compound, the IR
absorption bands observed at 3085 and 3056 cmꢁ1 (3077 cmꢁ1 in
Raman) are assigned to CeH stretching mode of the phenyl ring.
These results are in accordance with the computed values (see
Table 4) and with reported values for similar compounds [39e44].
The bands corresponding to the CeH in-plane bending vibrations
appear in the 1350-1000 cmꢁ1 range [39e44] and usually appear
mixed with CeC stretching modes. For the title compound, the IR
bands at 1215 and 1183 cmꢁ1, with counterparts in Raman at 1209
and 1167 cmꢁ1 are attributed to CeH in-plane bending modes. The
bands located at 934, 880 and 796 cmꢁ1 in the IR spectrum (928,
873 and 790 cmꢁ1 in Raman) are assigned to CeH out-of-plane
bending modes.
oxygen atoms from the carbonyl and hydroxyl groups and a
bonding system localized over phenyl ring (see Fig. 9). The LUMO
has also symmetry localized over the same moieties. The band
p
p
gap between HOMO and LUMO frontier molecular orbitals is a very
useful parameter which determines the chemical reactivity of
molecules [46,47]. For the title molecule, the computed HOMO-
LUMO energy gap in ethanol as solvent was found to be 3.645 eV.
This strong HOMO to LUMO interaction results in intramolecular
charge transfer band in the electronic absorption spectrum.
3.4.4. Skeletal vibrations
The C]O stretching mode is very sensitive to intra and inter-
molecular interactions. The observed band at 1655 cmꢁ1 in the IR
spectrum, with counterpart in Raman at 1643 cmꢁ1, reflects that
the C]O group is involved in the formation of a dimer via C]O/H
hydrogen bonding interactions, as was deduced from the crystal
structure. These results are in agreement with the computed value
(1679 cmꢁ1) and with the values previously reported for similar
compounds [30e45], in which the C]O group is involved in
intramolecular hydrogen bonds. The CeC stretching modes of the
alkyl chain produce bands at 966, 836, 776 and 689 cmꢁ1 in the IR
spectrum and at 1242, 962, 898 and 685 cmꢁ1 in Raman. In the
region between 1600 and 1300 cmꢁ1 the characteristic signals
attributed to the CeC stretching modes of the phenyl ring, are
observed in both, the IR and Raman spectra (see Table 4). The IR
3.6. NBO analysis
The Natural Bond Orbital (NBO) analysis is an important tool for
interpretation of intra and intermolecular interactions and also
provides a convenient basis for investigating charge transfer or
hyperconjugative interactions in different molecular systems. The
larger value of E(2) (interaction energy) indicates the more donating
tendency from electron donors to electron acceptors [48]. NBO
analysis has been performed for the three possible conformations
of the title compound at B3LYP/6e311þþG(d,p) approximation.
The results of second-order perturbation theory analysis of the Fock
Table 5
Experimental and calculated absorption wavelengths and oscillator strength for 3-(2,3-dihydroxy-isopentyl)-4-hydroxyacetophenone.
Wavelength (nm)
Experimental
Oscillator strength
Assignment
Calculated
224
263 s h
217
258
0.0025
0.1153
HOMO-1 / LUMO þ1 (100%)
HOMO-2 / LUMO (57%)
HOMO / LUMO (17%)
HOMO / LUMOþ1 (23%)
278
270
0.2299
HOMO / LUMO (80%)
HOMO-2 / LUMO (13%)

10
D.M. Gil et al. / Journal of Molecular Structure 1217 (2020) 128393
Fig. 9. Comparison between experimental and computed UVeVis spectra for 3-(2,3-dihydroxy-isopentyl)-4-hydroxyacetophenone. HOMO and LUMO frontier molecular orbitals
with their corresponding energies are also given.
Table 6
packing is stabilized by O2eH2/O3, O3eH3/O4 and O4eH4/O1
hydrogen bonds. In addition, the supra-molecular packing were
also stabilized by weak CeH/O and CeH$$$p and interactions. The
molecular structure of the title compound was optimized and the
vibrational wavenumbers were determined theoretically and the
normal modes of vibration were assigned by using the potential
energy distribution (PED) analysis. TD-DFT calculations have been
performed to assign the electronic transitions showing a very good
agreement with the observed UVeVisible spectrum.
Second-order perturbation theory analysis of the Fock matrix for 3-(2,3-dihydroxy-
isopentyl)-4-hydroxyacetophenone calculated by NBO approach at B3LYP/
6e311þþG(d,p) level of theory.
Interactiona
E(2)b
CI
CII
CIII
LP O1 /
LP O1 /
LP O2 /
LP O3 /
LP O4 /
LP O4 /
s
s
p
* C7eC8
* C5eC7
* C2eC3
90.58
90.20
126.0
32.73
29.42
30.22
90.29
90.49
148.7
35.65
27.50
31.18
87.95
90.37
148.3
31.81
32.10
27.71
s* C9eC10
s* C11eC12
s* C11eC13
Credit author statement
a
LP denotes lone pair on the specified atom. See Fig. 2 for atoms numbering
Diego M. Gil: Conceptualization, Investigation, writing-original
draft preparation, writing-review and editing. Emilio Lizarraga:
Synthesis of the compound and analysis of NMR spectra. Gustavo A.
Echeverría and Oscar E. Piro: Crystal structure determination and
scheme.
b
Energy values in kJ molꢁ1
.
matrix are listed in Table 6.
ꢀ
ꢀ
Formal analysis. Cesar A.N. Catalan: Analysis of NMR spectra,
writing-review and editing.
The lone pair of O1 oxygen donates its electrons to the s-type
anti-bonding orbitals
energies in the ranges 87.95e90.58 and 90.20e90.49 kJ molꢁ1
respectively. The interaction between the LP O2 and the * C2eC3
gives more stabilization of the molecule in the three possible
conformation being more relevant in CII and CIII conformers. This
interaction is an indicative of the double bond character of the
C2eO2.
s* C7eC8 and s* C5eC7 with stabilization
,
Declaration of competing interest
The authors declare no conflicts of interest.
Acknowledgments
p
The authors thank ANPCyT (PICT 2016e0226) and SCAIT (Project
D639/2), CONICET (PIP 11220130100651CO) and UNLP (Grant to
Project 11/X857) of Argentina for financial support. G.A.E., D.M.G.
and O.E.P are research fellows of CONICET.
4. Conclusions
The
compound
3-(2,3-dihydroxy-isopentyl)-4-hydroxya-
cetophenone was synthesized and characterized by 1H NMR, IR,
Raman and UVevisible spectroscopies. The crystal structure has
been elucidated by single crystal X-ray diffraction methods. The
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.molstruc.2020.128393.
substance crystalizes in the triclinic P1 crystal system with Z ¼ 2
molecules per unit cell. The structure reveals weak non covalent
contacts along with hydrogen bonding interactions that form the
supra-molecular assembly. A detailed exploration of the intermo-
lecular interactions that stabilize the crystal packing has been
evaluated by using the Hirshfeld surface analysis and their associ-
ated 2D fingerprint plots. These results reveal that the crystal
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