β-Chain Hydrogen-Bonding in 4-Hydroxycoumarins

Article abstract of DOI:10.1007/s10870-019-00813-5

Abstract: In the solid state, some 3-substituted 4-hydroxycoumarins β-ketoester enols form infinite translational hydrogen-bonded β-chains with varying degrees of alignment between adjacent delocalized systems. Nine related structures have been studied. A

Full text of DOI:10.1007/s10870-019-00813-5

Journal of Chemical Crystallography
https://doi.org/10.1007/s10870-019-00813-5
ORIGINAL PAPER
β‑Chain Hydrogen‑Bonding in 4‑Hydroxycoumarins
Truc‑Vi H. Duong1 · Todd S. Carroll1 · Daniel S. Bejan2 · Edward J. Valente1
Received: 17 August 2019 / Accepted: 31 October 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
In the solid state, some 3-substituted 4-hydroxycoumarins β-ketoester enols form infnite translational hydrogen-bonded
β-chains with varying degrees of alignment between adjacent delocalized systems. Nine related structures have been stud-
ied. At the strongest, intermolecular associations are polar, purely translation neighbors interact essentially along a 717 pm
crystallographic repeat with shortened 260 pm intermolecular O·OH-bond contacts. Four distinctive features characterize these
structures: (1) moderately delocalized β-ketoester enol structures, (2) translational misalignment angles between oxygen
donors and acceptors less than 10°, (3) buttressing intermolecular C–H·O contacts co-planar with and near the intermolecular
O–H·O interactions, and (4) fully extended ketoester enol hydrogen-bond (ap-anti-anti) geometries. For non-polar β-chains
in related coumarin systems, β-ketoester enol alignments are typically poorer, involve hydrogen-bonding between glide
relatives, ap-syn-(anti) geometry, and the intermolecular O·OH-bond contacts are longer.
Graphic Abstract
Substituted 4-hydroxycoumarins related to phenprocoumon can form well-aligned polar translational β-chains between
enolones showing resonance assisted Hydrogen-bonding and a 717 pm repeat along a crystallographic axis.
Keywords Hydrogen-bonding · Ketoester enol · Supramolecular · Coumarin · 4-Hydroxycoumarin · β-Chains ·
Phenprocoumon
Introduction
* Edward J. Valente
valentee@up.edu
Stronger hydrogen-bonded assemblies between neutral
molecules are often found where the interacting systems
are (nearly) coplanar and hydrogen-bonding is cooperative.
Thus, carboxylic acids form planar intermolecular comple-
mentary hydrogen-bonded dimers, and β-diketone enols
1
2
Department of Chemistry, University of Portland, 5000 N.
Willamette Blvd., Portland, OR 97203, USA
Science Programs, Washington State University, Vancouver,
WA 98686, USA
Vol.:(0123456789)
1 3

Journal of Chemical Crystallography
commonly form rings and homodromous chains linked by
hydrogen-bonds [1, 2]. In these neutral O–H·O interactions,
the bond angles at H are typically 150–175°, and O·OH-bond
distances are less than about 265 pm. Stronger hydrogen-
bonding has been called “resonance-assisted” from the
alignment of the π-systems and a diminished barrier to
proton exchange [3]. Alternative explanations invoke the
importance of charge delocalization and the alignment of the
adjacent σ-frameworks [4, 5]. There has been some success
in gauging the strength of hydrogen-bonding and correlat-
ing π-interactions with small diferences in the pKas of the
interacting groups [6, 7]. But in β-diketone enols systems
with resonance assisted hydrogen-bonding (RAHB), these
strategies were typically not applied as the pKa properties
of the donors and acceptors were not readily estimated. In a
computational approach to understanding RAHB, a study of
bond critical points suggested a covalent character to these
interactions especially given the geometric requirements [8].
In contrast, computations have also stressed the importance
of electrostatic (dipolar) interactions between π-systems [9].
In an extensive crystallographic study of 5- and 6-ring
structures incorporating β-diketone enols and β-ketoester
enols, these two neutral classes of hydrogen-bonded systems
were found to form chains (β-chains) with stronger O·OH-bond
contacts (245–269 pm) [3, 10]. The consistent theme in
these supramolecular structures was interactions between
translation, screw and glide relatives linking (nearly) copla-
nar π-systems through an almost linear hydrogen-bonded
geometry. In the supramolecular and crystallographic con-
text, translation referred to an interaction between molecules
related by “pure translation” and through the translational
components of a screw or glide operation. For molecules
linked by translation, diketone enols had antiperiplanar (ap)
arrangements, and among the 5-ring systems, nearly linear
hydrogen-bonding geometry was maintained by a donor
syn and acceptor anti arrangements (Fig. 1). Vertinolide, a
substituted cyclopentandione, formed translational β-chains
with molecules inclined at about 20° (angle a, Fig. 1), con-
sistent with a more optimal interaction of donor and acceptor
oxygens and a 650 pm repeat [11].
The 6-ring systems (cyclohexandione enols) did not
form simple translational β-chains apparently because of
intermolecular repulsions [3]. For example, the enol of
2-methyl-1,3-cyclohexandione had ap-anti-anti confgura-
tion, and formed β-chains linking well-aligned glide rela-
tives (a: 4°). A crystallographic axis essentially coincided
with the hydrogen-bonding direction and a 685.4 pm repeat
between molecules [3, 12]. Among other 6-ring systems, the
β-ketoester enol represented by 4-hydroxycoumarins (1) may
be promising. Unsubstituted 4-hydroxycoumarin crystallizes
as a hydrate without forming β-chains and the enol formed
hydrogen-bonds with and through its water of crystallization
[13]. Some 3-substituted derivatives of 4-hydroxycoumarins
however have shown a tendency to form hydrogen-bonded
translational or glide β-chains and to adopt ap-anti-anti and
ap-syn-(anti) configurations [14–17]. Other 4-hydroxy-
coumarin derivatives belonging to the dicoumarol family
form intramolecular hydrogen-bonded rings between two
enolones [18–27]. Dicoumarol enolone systems do not form
planar arrangements, and show ordinary weak hydrogen-
bonded geometries. Enolones in other 4-hydroxycoumarin
derivatives form intramolecular interactions with 3-substitu-
ent hydrogen-bond acceptors [28–31].
4-Hydroxycoumarin structures which showed pure trans-
lational RAHB include phenprocoumon (marcoumar, 2) [14,
16]. Both racemic and enantiomeric phenprocoumon form
well-aligned β-chains with their enolones. Curiously, these
phases are pseudoisomorphorous suggesting the importance
of the hydrogen-bonding β-chains in their supramolecular
structures. As these types of 4-hydroxycoumarin derivatives
have not been examined for the efects of structural altera-
tions on β-chain alignment, this area of interest forms the
subject of the present work. Compounds examined include
the 3-substitutied 4-hydroxycoumarins (3–11) related to
phenprocoumon, 2 (Fig. 2).
Experimental
Substances were obtained from Sigma-Aldrich Company or
TCI America, and used as received. Nuclear magnetic reso-
nance spectra were recorded on Varian or Bruker 400 MHz
instruments. Infrared spectra were recorded on a Thermosci-
entifc Smart iTR spectrometer. Melting points were deter-
mined on a Stanford Research Systems Digimelt, and are
uncorrected. Optical rotation was measured in a 0.25 dm cell
on an Optical Activity AA-5. Racemic 2 (mp 179–180 °C)
was prepared by the method of Pohl, and resolved with
(+)-quinidine giving the (S)-isomer, mp 170–171 °C, lit
170–171 °C [32, 33]. Compounds 3–6 were prepared from
4-hydroxycoumarin (1) and the appropriate secondary ben-
zylic alcohols or benzyl bromides [34, 35]. After resolv-
ing warfarin, the dithioketal of (−)-(S)-warfarin (8) was
O
O
anti
H
a
O
syn
ap
H
H
O
O
O
O
H
ap
O
O
H
anti
O
O
H
O
anti
Fig. 1 Cyclopentandiones with ap-syn-anti structures show minor
misalignments (angle a) between translational relatives. Cyclohexan-
diones with ap-anti-anti structures relate glide relatives
1 3

Journal of Chemical Crystallography
Fig. 2 4-Hydroxycoumarin
(1) and selected 3-substituted
derivatives
prepared, mp 192–193 °C, lit. 193–195 °C [36]. Structural
information for compounds ( )-2, ( )-7 and ( )-11 were
taken from the literature [14, 15, 17]. In addition, two more
derivatives were prepared to test the structural trends found
in the previous group. These include 3-benzyl-4-hydroxy-
coumarin (9) and 3-(1-phenyl-3,3-dimethylbut-1-yl)-4-hy-
droxycoumarin (10). Syntheses of compounds not previously
reported or using newer methods are given below.
Partial resolution of 3. Racemic 3 (50 mg, 0.18 mmol)
was combined with (+)-quinidine (60 mg, 0.18 mmol) in
CHCl3, heated briefy to boil, then allowed to cool and
then stand at − 10 °C for 12 h. The white precipitate was
fltered, and redissolved in CHCl3 with heating, and the
cycle repeated twice. This less-soluble salt was partitioned
between CHCl3 and 1 N NaOH, and the aqueous phase was
then separated and acidifed with 3 M HCl. The white solid
obtained was levorotatory, and successive recrystallizations
did not improve the rotation above an approximate 40%
ee; [α]2D5 −65°, c 1.0, 1 M NaOH. Crystals of this possibly
eutectic phase, (−)-3, were obtained from acetone:water
(9:1).
3‑(1‑Phenyl‑1‑ethyl)‑4‑hydroxycoumarin (3)
To a stirred mixture of 0.162 g 1 (1.00 mmol) and 0.122 g
(1.00 mmol) 1-phenyl-1-ethanol in 15 mL nitromethane,
0.050 g (0.22 mmol) of trimethylsilyl trifuoromethane-
sulfonate was added at room temperature [35]. Successive
assays every 20 min during the reaction by thin layer chro-
matography [SiO2, CHCl3:EtOAc (10:1)] show the product
component (Rf 0.8) no longer increasing after 1 h. The mix-
ture was ended by addition of water, and the aqueous phase
made basic with 3 M NaOH and extracted. The nitrometh-
ane layer contained unreacted alcohol, which was removed.
Acidifcation of the aqueous phase (3 M HCl) produced
a white precipitate which was fltered by suction, and the
solid obtained was then washed with two portions of boiling
water. 4-Hydroxycoumarin is more soluble in hot water than
product 3. The remaining white solid, 81 mg (30%) and mp
202–204 °C, was recrystallized from acetone:water (9:1).
IR (cm−1): 3350, νOH; 1650.8, νC=O; 1607.4, νC=C; 1H-
NMR: (CDCl3, 26 °C) δH: 7.2–7.7, multiplets, 9H; 6.1, s(br),
OH; 4.74, q, 1H, benzyl-H; 1.67, d, 3H, methyl.
3‑(1‑Phenyl‑2‑methylprop‑1‑yl)‑4‑hydroxycoumarin
(4)
In a sealable reaction tube, 0.162 g 1 (1.00 mmol),
0.172 g (1.00 mmol) p-toluenesulfonic acid, and 0.150 g
(1.00 mmol) 2-methyl-1-phenyl-1-propanol in 15 mL
dichloromethane were combined. To this mixture, 20 mg
(0.08 mmol) of FeCl3·6H2O was added and the tube sealed
and heated to 45 °C for 12 h, following a literature method
[34, 37]. After cooling, the deep yellow colored mixture
was combined with 30 mL water which was then made basic
with 3 M NaOH. The organic layer was removed, and the
aqueous portion was fltered to remove iron(III) hydroxide.
The fltrate was acidifed with 3 M HCl to produce a white
precipitate. The precipitate was washed with hot water to
remove unreacted 4-hydroxycoumarin, and the solid residue
1 3

Journal of Chemical Crystallography
was recrystallized from acetone or ethanol. Yield 0.086 g,
29%, mp 203.6–206.0 °C (decomp.); IR (cm−1): 3233.9,
Crystallography
1
νOH; 1651.9, νC=O; 1606.4, νC=C; H-NMR (CDCl3,
Single-crystal X-ray difraction data were collected on speci-
mens of (−)-2, ( )-3, (−)-3, ( )-4, ( )-5, ( )-6, (−)-8, 9,
and ( )-10 on an Rigaku-Oxford Gemini single-crystal
X-ray difractometer. The assignment of absolute confgu-
ration for (−)-2 and (−)-8 rests on the known absolute con-
fgurations for these phases based on their synthesis and
optical rotations [33, 36]. Therefore, it was not necessary to
establish confgurations by anomalous dispersion, and Mo
Kα radiation was used for these structures. The Flack param-
eter for (−)-8 was −0.03(9), and provided support that the
assigned S confguration is correct. The absolute confgura-
tion of (−)-3 was assigned based on the sign of its optical
rotation and a similar application of the resolution method
compared to 2; the Flack parameter for the Cu Kα data set
for (−)-3 was −1.8 (10) consistent with a weak anomalous
signal and the partial resolution of the sample (vide infra).
It should perhaps be noted that attempted resolution of the
homologs with longer alkyl side chains, compounds 4, 5
and 6, using (+)-quinidine failed to produce less soluble
diastereomeric salts. The structures reported here are of the
racemates. Most structures were determined at ambient tem-
peratures, or with a cryojet capable of 101 K as for ( )-6
and (−)-2. The original study on (−)-2 showed consider-
able librational freedom, which might have be associated
with disorder or a phase change [16]. Relevant experimen-
tal details are given in Tables 1, 2 and 3. Intensities were
corrected for absorption with an analytical function based
on the shape and size of the crystals [40]. Structures were
discovered with SHELXS and refned with SHELXL [41].
Metrics on the β-enolone chains were developed in part with
MERCURY, and these are given in Table 4 [42].
25 °C) δH: 7.2–7.7, multiplets, 9H; 6.5, s(br), OH; 4.17, d,
1H, benzyl-H; 2.9, m, 1H, CH(Me)2; 1.04, d, 6H, methyls.
3‑(1‑Phenylbut‑1yl)‑4‑hydroxycoumarin (5)
1-Phenyl-1-bromobutane (1.30 g, 6.1 mmol) and 0.162 g
(1.00 mmol) 1 were combined and heated (oil bath) and
stirred at 150 °C for 1 h, in a method based on the literature
[32]. After cooling, the deep reddish mixture was taken up
in 30 mL 1.0 M NaOH and extracted with dichloromethane.
The aqueous phase was acidifed with 3 M HCl, and the pre-
cipitate was fltered and washed with hot water. The white
solid obtained was recrystallized from acetone or ethanol,
yield 0.118 g (40%), mp 141–142 °C; IR (cm−1): 3341.0
1
νOH; 1649.7, νC=O; 1602.2, νC=C; H-NMR (CDCl3,
25 °C) δH: 7.2–7.7, multiplets, 9H; 6.4, s(br), OH; 4.50, t,
1H, benzyl-H; 1.40, m, 2H, CH2; 1.10, t, 3H, methyl.
3‑(1‑Phenylpent‑1yl)‑4‑hydroxycoumarin (6)
This compound was prepared in a manner similar to that
used for 5. Mp 135.0–136.5 °C; IR (cm−1): 3280.5, νOH;
1653.7, νC=O; 1608.5, νC=C; 1H-NMR (CDCl3, 25 °C) δH:
7.2–7.7, multiplets, 9H; 5.9, s(br), 1H, OH: 4.60, t, 1H, ben-
zyl-H; 1.2–1.5, multiplets, 6H, (CH2)3; 0.89, t, 3H, methyl.
3‑Benzyl‑4‑hydroxycoumarin (9)
Compound 9 was prepared by NaCNBH3 reduction of a
dicoumarol produced from benzaldehyde and 4-hydroxy-
coumarin, mp 201–202 °C, lit 201 °C [38, 39]. IR (cm−1):
IR (cm−1): 3309.0, νOH; 1655.1, νC=O; 1608.4, νC=C;
1H-NMR: (d6-DMSO, 25 °C) δH: 7.2–7.5, multiplets, 4H,
coumarin-H’s; 7.28, s, 5H, phenyl-H’s; 6.4, s(br), 1H, OH;
5.15, s, 2H, benzyl-H’s.
Models included anisotropic librational parameters for the
non-H atoms. Except for hydroxyl H’s, positions for H-atoms
were calculated and allowed to ride on neighboring atoms
together with an isotropic librational parameter set at 120%
of the Ueq of the neighboring atom, 150% for methyl H’s.
Enol (O)H-atoms were located in diference fourier maps
late in the refnement stages, and the positions were refned
while constraining the O–H distances to 0.86 Å according
to the usual bias; the H-atom isotropic librational parameter
was set to 150% of the Uiso of the oxygen. The structure of
(−)-2 was re-determined for this study at room temperature
(2a) and at 101 K (2b). Resolution of 3 could not be pur-
sued beyond the eutectic phase enriched in the (−)-isomer
which showed two independent molecules in the asymmetric
unit, and each formed β-chains. One chain had well ordered
(S)-enantiomers, assigned on the basis of its levorotatory
properties in comparison with (S)-(−)-phenprocoumon
[33]. The second chain was modeled with overlapped (S)
and (R) molecules. Its coumarins were essentially super-
posed and aligned in the same axial directions, with phenyl
3‑(1‑Phenyl‑2‑methylprop‑1yl)‑4‑hydroxycoumarin
(10)
This substance was produced using the same method as
for 4 but with 1-phenyl-3,3-dimethyl-1-propanol (made by
reduction of 3,3-dimethylbutanal with phenyl magnesium
bromide). Mp 215.4–216.5 °C; IR (cm−1): 3218.5, νOH;
1
1671.1, νC=O; 1620.7, νC=C; H-NMR (CDCl3, 25 °C)
δH: 7.66, d,1H, H8; 7.50, t, 1H, H6; 7.38, t, 1H H7; 7.30,
d, 1H, H5; 7.26, s, 5H, phenyl; 4.71, t, 1H, benzyl-H; 3.50,
s(br), 1H, OH; 2.29, dd, 1H, H–C–H; 2.04, dd, 1H, H–C–H;
1.56, s, 8H, methyls.
1 3

Journal of Chemical Crystallography
Table 1 Selected
(−)-2a
(−)-2b
(
)-3
(−)-3
crystallographic information
for structures (−)-2a, (−)-2b,
Formula
C18·H16·O3
280.31
71.073
592
C18·H16·O3
280.31
71.073
592
C17·H14·O3
266.30
154.184
560
C17·H14·O3
266.30
154.184
560
(
)-3, (−)-3
Formula weight
Wavelength, pm
F(000)
Size (mm)
Crystal system
Space group
Temperature (K)
Cell constants
a (Å)
0.60, 0.18, 0.15 0.51, 0.24, 0.19 0.31×0.07 × 0.06 0.58, 0.21, 0.02
Monoclinic
P 21
298 (2)
Monoclinic
P 21
101 (2)
Monoclinic
P 21/a
297 (2)
Monoclinic
P 21
298 (2)
7.1717 (4)
17.7827 (10)
11.7390 (7)
90
92.835 (5)
90
7.1400 (4)
17.5868 (9)
11.4540 (7)
90
92.017 (6)
90
7.1953 (7)
24.879 (3)
8.1286 (13)
90
112.406 (15)
90
7.1639 (5)
28.8783 (17)
7.3929 (6)
90
116.208 (10)
90
b (Å)
c (Å)
α (o)
β (o)
γ (o)
Volume (Å3)
Z, density (Mg/m3)
1495.27 (15)
4, 1.245
0.084
1437.38 (14)
4, 1.295
0.088
1345.2 (3)
4, 1.315
0.728
1372.2 (8)
4, 1.289
0.712
μ (mm−1
)
Data, Rmerge
Unique data, I>2σI
Completeness (%), max. θ (°) 99.8, 30.57
R, wR (unique data)
R (I>2σI)
9311, 0.031
6490, 3001
8737, 0.055
6126, 4083
99.8, 30.57
0.093, 0.144
0.066
4945, 0.042
1683, 1222
99.6, 55.00
0.086, 0.166
0.065
7308, 0.040
4120, 2946
98.9, 61.4
0.066, 0.116
0.043
0.108, 0.104
0.049
Parameters, restraints
Goodness-of-ft
Δρ(fnal) (e−/Å3)
381, 1
1.001
+0.22, −0.14
381, 1
1.003
+0.46, −0.26
184, 1
1.038
+0.19, −0.17
401, 42
1.014
+0.15, −0.13
Estimated standard deviations in parentheses. For (−)-3, occupancy factor for (S)-isomer in second chain
is 0.215(1) or 0.608 (S)-isomer for the phase; absolute structure parameter −1.8(10); extinction parameter
0.00165(15)
and methyl groups on the 3-substituent carbon disordered
between the two confgurations. Constraints were employed
during refnement to model overlapping phenyl and methyl
groups of the enantiomers, and a partial occupancy factor
was included which converged to 0.282 (9) for the minor
(R)-enantiomer. Thus, the eutectic crystal composition was
0.718 (9) (S)-isomer. The exact nature of this phase (co-
crystal, solid solution, twin) is not known.
required restraints, or had lower resolution. For compound 6,
the butyl side chain is disordered over gauche and anti chain
conformations at room temperature (6b), with the major
conformer (gauche) refned with an occupancy of 0.564 (11)
for the terminal methyl group; at 101 K, the gauche butyl
chain is ordered (6a). For compound 8, the model included
disordered ethylene links between dithiolan sulfurs. These
were refned with partial occupancy factors which refned
to 0.52 (3) and 0.65 (3) for the two independent molecules
in the asymmetric unit. For compound 10, the dimethylpro-
pyl side chain appeared disordered but the structure refned
for the major enantiomer at 0.843 (4) occupancy with the
complement representing the opposite enantiomer occu-
pying the same location. Crystallographic information for
the structures (2a, 1038546; 2b,1038547; ( )-3, 1946868;
(−)-3, 1946872; 4, 1946869; 5, 1038548; 6a, 1946871;
6b, 1039116; 8, 1038545; 9, 1946873; 10, 1946870) have
been deposited with the Cambridge Crystallographic Data
Center. CCDC data can be obtained from the Cambridge
Crystals of compound 4 are triclinic but with a≈b and
γ very near 90°; all seven specimens examined showed
pseudo-merohedral twinning, multiple domains, and/or non-
crystallographic symmetry. For one specimen, reported here,
the structure was afected by non-crystallographic symmetry
only, and the two components could be modeled: four mole-
cules comprising the asymmetric unit with major occupancy
0.836 (6), and with the minor component of the same atoms
shifted by exactly (½ + x, y, z). The shifted structure was
included with atom positions and Uijs fxed, and adjusted
after every few cycles refning the major atom positions and
Uijs. The model converged satisfactorily while other models
1 3

Journal of Chemical Crystallography
Table 2 Relevant
(
)-4
(
)-5
( )-6a
crystallographic information for
structures ( )-4, ( )-5, ( )-6a
Formula
C19·H18·O3
294.34
154.184
1248
C19·H18·O3
294.34
154.184
624
C20·H20·O3
308.38
71.073
Formula weight
Wavelength, pm
F(000)
656
Size (mm)
Crystal system
Space group
Temperature (K)
Cell constants
a (Å)
b (Å)
c (Å)
α (°)
β (°)
0.30, 0.27, 0.065
Triclinic
P -1
0.25, 0.20, 0.06
Monoclinic
P 21/c
0.50, 0.15, 0.05
Monoclinic
P 21/c
297 (2)
298 (2)
101 (2)
14.0211 (4)
14.2240 (3)
16.2128 (5)
77.010 (2)
77.467 (2)
89.999 (2)
3071.55 (14)
8, 1.273
8.9658 (2)
15.0854 (3)
12.2266 (3)
90
106.939 (3)
90
1581.94 (6)
4, 1.236
0.665
8.7908 (6)
15.5548 (8)
12.3554 (11)
90
107.965 (8)
90
1607.1 (2)
4, 1.275
0.085
γ (°)
Volume (Å3)
Z, density (Mg/m3)
μ (mm−1
)
0.685
Data, Rmerge
10566, 0.016
7458, 6699
99.8, 56.2
0.079, 0.171
0.074
5999, 0.017
2847, 2434
98.8, 67.9
0.043, 0.113
0.038
13718, 0.056
3232, 2390
99.8, 26.2
0.072, 0.128
0.048
Unique data, I>2σI
Completeness (%), max. θ (°)
R, wR (unique data)
R (I>2σI)
Parameters, restraints
Goodness-of-ft
1594, 0
1.118
+0.31, −0.29
200, 0
1.043
+0.14, −0.14
209, 0
1.064
+0.24, −0.22
Δρ(fnal) (e−/Å3)
Estimated standard deviations in parentheses. For ( )-4, major component: 0.836 (6); balance fxed and
translated by ½+x., y, z
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033).
congruence. Between hydrogen-bond donor and acceptor
atoms, the extent of misalignment of β-chain relatives can
also be described by the distance d of the acceptor oxygen
from the plane of the donor β-ketoester enol π-system. In
simple translational β-chains with one molecule compris-
ing the repeat, the angles (b, b′, b″) are all zero necessarily.
Alignments can be degraded where the demands of packing
and other intermolecular interactions occur and possibly also
where glide planes (or screw axes) operate along the interac-
tion direction.
Discussion
To compare the alignment and dimensional features of
the β-chains in 4-hydroxycoumarin structures related to
phenprocoumon (2), several descriptors and measurements
are useful (Fig. 3). Enolone ene confgurations are gener-
ally antiperiplanar (ap). In the hydrogen-bonding between
enolones, the donor H-atoms can be syn or anti within the
donor system, and syn or anti with respect to the accep-
tor oxygen according to the interaction geometry. In ( )-2
for example, the confguration is ap-anti-anti. Neighboring
donor and acceptor oxygens may deviate from co-linearity
by molecular displacement forming angle a. The nearly
planar β-ketoester enols may be rotated from a common
(coumarin) plane through pitch angle b, roll angle b′, and
yaw angle b″. Clearly, the pitch and roll angles b, b′ may
not be large for efective intermolecular π-system (RAHB)
A useful descriptor correlated with the degree of delocali-
zation within a ketoester enol fragment was the sum of the
diferences between the terminal and internal enolone bond
lengths (Q). For typical diketone/enol delocalization absent
hydrogen-bonding, Q took values near 20 pm (range −32
to +32 pm) [3, 43]. Smaller Q values indicated less bond-
length disparity and therefore greater π-delocalization. The
strength of inter- and intramolecular hydrogen-bonding cor-
related with the degree of delocalization. Applying these
criteria to the β-enolone structure of the cyclopentandione
enol vertinolide, translation-relatives were well aligned but
1 3

Journal of Chemical Crystallography
Table 3 Relevant
(
)-6b
(−)-8
9
( )-10
crystallographic information for
structures ( )-6b, (−)-8, 9 and
( )-10
Formula
C20·H20·O3
308.36
154.184
656
C21·H20·S2 O3
384.52
71.073
C16·H12·O3
252.27
154.184
528
C21·H22·O3
322.40
154.184
344
Formula weight
Wavelength, pm
F(000)
404
Size (mm)
Crystal system
Space group
Temperature (K)
Cell constants
a (Å)
b (Å)
c (Å)
α (°)
β (°)
0.50, 0.15, 0.05 0.10, 0.10, 0.10 0.44, 0.12, 0.050 0.56, 0.21, 0.10
Monoclinic
P 21/c
297 (2)
Triclinic
P 1
297 (2)
Monoclinic
P 21/c
298 (2)
Triclinic
P -1
298 (2)
9.0508 (5)
15.8790 (17)
12.2427 (12)
90
105.746 (14)
90
7.1587 (3)
10.9988 (5)
12.2591 (7)
89.054 (4)
83.483 (4)
81.982 (4)
949.63 (8)
2, 1.345
11.7799 (9)
8.3091 (4)
13.0819 (7)
90
106.701 (7)
90
7.1717 (4)
10.0712 (10)
12.8495 (12)
84.958 (8)
80.588 (6)
84.575 (6)
909.00 (13)
2, 1.178
γ (°)
Volume (Å3)
Z, density (Mg/m3)
1693.5 (4)
4, 1.209
1226.46 (13)
4, 1.366
μ (mm−1
)
0.643
0.298
0.770
0.619
Data, Rmerge
Unique data, I>2σI
Completeness (%), max. θ (°) 96.4, 68.3
R, wR (unique data)
R (I>2σI)
6008, 0.0265
2984, 2076
12633, 0.038
4737, 4227
83.6, 24.3
0.052, 0.104
0.046
6359, 0.035
2422, 1758
99.5, 72.6
0.065, 2422
0.045
5671, 0.019
3477, 2783
96.6, 72.4
0.060, 0.129
0.050
0.078, 0.176
0.062
Parameters, restraints
Goodness-of-ft
Δρ(fnal) (e−/Å3)
219, 2
1.075
+0.25, −0.22
510, 7
1.015
+0.19, −0.16
174, 0
1.006
+0.17, −0.16
264, 70
1.027
+0.18, −0.14
Estimated standard deviations in parentheses. For (−)-8, absolute structure parameter −0.03 (9), extinction
coefcient 0.0069(13), and major dithiolan ketal conformer: 0.52 (3). For ( )-6b, major side-chain butyl
conformer [anti; torsion -162.3 (9)°] 0.613 (1), and minor [gauche, torsion −87.4 (6)°]. For ( )-10, major
conformer 0.843 (4), extinction parameter 0.0039 (8)
donors and acceptors were displaced as required for ap-syn-
anti confguration with (a: 20°, b′s: 0°, d: 0 pm, Q -19.1 pm)
[7]. The O·OH-bond was of ordinary length at 269 pm. In con-
trast, for 2-methyl-1,3-cyclohexandione enol, glide-related
molecules showed arguably improved system alignment [8].
Hydrogen-bonded donors and acceptors adopted ap-anti-anti
confguration, a π-system alignment described by a: 9°, b:
180°, b′ 0°, b″ 21°, d: 0 pm, and Q -17.2 pm, and a shorter
259 pm O·OH-bond distance. This greater delocalization of
the π-systems, and better alignment through the hydrogen-
bonding were consistent with a RAHB efect [2].
derivatives of 4-hydroxycoumarin without β-chains, Q is
typically larger such as in a warfarin cyclic methyl ketal
where it is 26 pm [44].
Phenprocoumon
Molecular packing and interactions in the crystal structures
of ( )-2 and (−)-2a are similar. Both structures form well-
aligned translational β-chains with a 717 pm repeating unit,
and the racemate shows polar β-chains, (S) with (S) and
(R) with (R) [10, 12]. The dominant hydrogen-bonding pat-
terns are infnite chains with motif C11(6) [45]. Since the
spatial width of the side chain phenyl and ethyl groups are
dimensionally smaller than the 4-hydroxycoumarin, the
herringbone packing features in the layers perpendicular to
the hydrogen-bonding direction leave considerable space
for librational motions, more in the enantiomer which has
a lower density and lower melting point than the racemate
(vide supra and Table 1).
Table 4 presents the alignment and delocalization data
for the 4-hydroxycoumarin derivatives 2–11 studied here.
Enolone alignment in these β-chains is linked to a maximal
translational repeat distance of 717 pm along the interac-
tion direction. Table 4 additionally reports on whether the
β-chains of neighboring and interacting molecules have the
same chirality (polar) or alternating chirality (non-polar),
and the crystallographic relationship (pure translation,
or glide) between relatives along the chain. In contrast,
1 3

Journal of Chemical Crystallography
Table 4 Structural features for intermolecular H-bonding in selected chiral and racemic 3-substituted 4-hydroxycoumarins
bpitch, bꢀroll, bꢀꢀ (°, °, °)
Compound temp. (K) Space group H-bond axis, O·OH-bond
Q (pm) a (°)
d (pm) β-chain type
yaw
repeat (pm)
distance
(pm)
β-Enolone hydrogen-bonding confguration: ap-anti-anti
( )-2 [14]
P 21/n
c
261.7
15.9
7.1
0, 0, 0
36
Transl., polar
Transl., polar
Transl., polar
Transl., polar
Transl., polar
Transl., polar
295
717.7
(−)(S)-2a
P 21
a
260.6
262.7
17.0
16.9
6.6
7.4
0, 0, 0
0, 0, 0
15
43
298
717.2
(−)(S)-2b
P 21
a
258.3
15.7
6.7
0, 0, 0
9
101
714.0
261.9
17.6
8.2
0, 0, 0
50
(−)(S)-8
P 1
a
261.1
267.2
264.0
20.2
20.8
17.1
7.3
9.1
7.1
0, 0, 0
0, 0, 0
0, 0, 0
61
297
715.9
61
( )-3
P 21/a
P -1
a
1
297
719.5
( )-10
a 717.2
262.6
18.3
7.2
0, 0, 0
23
298
(−)-3
P 21
a
264.1
262.6
23.8*
12.2*
‹18.0›
14.5
14.4
0, 0, 0
0, 0, 0
57
62
Transl.
polar
298
716.4
eutectic
72% (S)
( )-4 297
P -1
a 2
268.2
269.4
270.4
271.4
266.0
17.5
17.8
18.4
19.0
16.0
12.1
12.7
13.7
14.1
12.5
−1, 22, 0
−1, 23, 0
105
115
136
140
80
Transl., nonpolar
(701.0)
( )-11 [15] 298
9 298
P bca
P 21/c
a
180, 0, 10
60, 15, 15
Glide, polar
Glide
2 (707.7)
c
270.9
18.1
19.5
186
2 (654.1)
β-Enolone hydrogen-bonding confguration: ap-syn-(anti)
( )-6a 101
( )-6b 298
( )-5 298
P 21/c
P 21/c
P 21/c
C 2/c
c
267.3
267.9
269.6
270.2
20.5
20.7
20.6
19.5
14.5
15.7
16.6
18.4
−117, 18, −30
−117, 18, −30
−64, 21, −30
−9, −56, 7
173
184
25
Glide, nonpolar
Glide, nonpolar
Glide, nonpolar
Glide, nonpolar
2 (617.8)
c
2 (612.1)
c
2 (611.3)
( )-7 [17] 293
c
225
2 (534.2)
See text for term defnitions
In racemic phenprocoumon, ( )-2, coumarins have
ap-anti-anti configuration and hydroxys are hydrogen-
bonded to lactone carbonyl oxygens in a translation
neighbor with shortened O·OH-bond 261.7 pm (Table 4)
[10]. Oxygens are almost aligned with the crystallo-
graphic axis (a: 7.1°) with moderate delocalization in the
β-ketoester enol (Q = 15.9 pm). Adjacent molecules also
show C(5)–H···O,O′(ester) interactions supporting adjacent
stronger O–H·O contacts. The C(–H)·O,O′ distances are 332
and 362 pm, and while longer and weaker than O–H·O con-
tacts, nevertheless they are probably important as they occur
nearly in the coumarin ring plane. Coumarins are stacked
with π-system contacts at typical separations of 347 pm. But
the narrower width of the phenyl ring (~400 pm) compared
+b"
+b
a
d
+b'
Fig. 3 Parameters for misalignment of translational 4-hydroxycou-
marin β-ketoester enols illustrated for ap-anti-anti confguration
1 3

Journal of Chemical Crystallography
to the coumarin system (715 pm) represents a size mismatch
that permits looser packing and vibrational freedom for the
side chain groups relative to the RAHB interactions that
dominate the translational symmetry. The largest principal
components of the atomic librations (U33) are parallel to
the RAHB direction along the c-axis (Fig. 4). The average
U33 for the fve enolone non-H atoms (along the β-chain) is
0.0378(3) Å2, while the distal three carbons of the side-chain
phenyl rings have average U33’s nearly six times larger at
0.224(25) Å2. The alternative explanation of a static disorder
of side-chain groups seems less likely.
with repeat distance 717.2 pm. Coumarins are oriented in
opposing directions along the a axis in two polar strands,
and delocalized enols were aligned for RAHB with a: 7°,
d: 29 pm, Q = 17 pm in one strand, and a: 7°, d: 50 pm,
Q=17 pm in the other. The hydrogen-bonding schemes are
the same as in the racemate with enolone hydrogen-bonds
assisted by peri C–H interactions with the neighboring lac-
tone oxygens. The O·OH-bond distances are shortened at 260.6
and 262.7 pm. As found in the racemate, librations of the
distal side chain phenyl carbons are considerable (Fig. 5).
The average U11 for the fve enolone non-H atoms in each
chain were 0.0308 (4) Å2, and 0.0424 (29) Å2, while the
average U11 of the distal three carbons of the phenyl rings
were at least four times larger at 0.210 (46) Å2, and 0.164
(37) Å2, respectively. Packing efciency in the enantiomer
(at 298 K, cell volume 1495.3 Å3, mp 170–171 °C) was
slightly less than in the racemate (at 295 K cell volume
1467.7 Å3, mp 179–180 °C).
The crystal structure of the (−)(S)-2a (at 298 K) is similar
to that of the racemate. The polar β-chains of (R)-enantiom-
ers of the racemate are replaced with a second β-chain of
(S)-enantiomers. For this study, we have re-determined (−)-
(S)-2a because of the relatively large librations found in the
original report [12]. Both independent β-chains have ap-anti-
anti confgurations related by translations along the a-axis
Often, large thermal motion occurs where crystal pack-
ing is in transition to a more stable form. On cooling crys-
tals of (−)-(S)-phenprocoumon (2a) from 296 to 193 K, no
evidence of a phase transition was detected by diferential
scanning calorimetry. When a crystal was cooled to 101 K,
the difraction pattern showed the same lattice as at room
temperature. Cell volume was reduced to 1437.4 Å3, most
of which resulted from reduction in the cell repeats orthogo-
nal to the axial hydrogen-bonding direction. The β-chain
O·OH-bond’s were only reduced slightly to 258.3 pm and
261.9 pm, respectively (Table 2). The average U11 for the
fve enolone non-H atoms in each chain were 0.0116 (18)
Å2, and 0.0252 (40) Å2, while the average U11 of the distal
three carbons of the phenyl rings were still at least twice as
large at 0.119 (37) Å2, and 0.054 (15) Å2, respectively, at
this lower temperature.
Fig. 4 Side-chain phenyl groups are not as wide as 4-hydroxycou-
marins allowing ap-anti-anti β-chains. [R=methyl (3), ethyl (2),
i-propyl (4), 2′,2′-ethandithioprop-1′-yl (8), 2′,2′-dimethylprop1′-yl
(10)]
Fig. 5 Translational hydrogen-
bonding in one of the two polar
chains of (−)(S)-phenprocou-
mon (2a) at 298 K showing
ap-anti-anti confguration and
the considerable librations in
the side chains
1 3

Journal of Chemical Crystallography
y, z) symmetry along the β-chain direction which was sat-
isfactorily modeled. The lattice is triclinic, space group P
-1, with a ≈ c, and γ ≈ 90.0°. Alignment of the coumarins
is poorer than in 2 or 3, for example (Table 4), with a
about 12–14°, the β-chains were slightly corrugated by
a molecular roll (b’ about 22°) and the O·OH-bond’s are
on average longer (272 pm) than in 2 and 3. The shorter
semi-repeat was consistent with the misalignment. Cou-
marins of 4 are stacked with weak contacts between their
π-systems with parallel pairs alternating with pairs 10.9°
from parallel, and ring separations of about 370 and
365 pm, respectively.
Other Coumarins
Translational Chains
The structures of ( )-3, (−)-3, ( )-4, (−)-8, 9 and ( )-10
all show translational β-chains and ap-anti-anti confgu-
rations of their enolones. In structure ( )-3, polar trans-
lational β-chains are present with repeat distance 720 pm
and O·OH-bond’s of 264 pm. Compound 3 was partially
resolved with (+)-quinidine and after isolation, recrys-
tallization did not improve the enantiomeric enrichment
beyond a putative eutectic composition. This partially
resolved phase is chiral and it is styled here as (−)-3, and
crystals occur in the non-centrosymmetric space group
P21 with repeat distance 716 pm. The structure shows
two inequivalent polar translational β-chains, one ordered
with (S)-enantiomers. The second β-chain is also polar but
with (S)-isomer occupancy 0.215 (1), and therefore this
phase is 60.7% (S) and 39.3% (R). In the second chain,
librations are greater for the side chain atoms of the (S)
molecule compared those of the (R), suggesting that the
side chains of the (S)-isomers are less tightly packed. A
similar disparity in packing efciency and in librational
freedom was observed between the racemate and enantio-
meric phases of 2 (vide supra). Apparent overlap of the
side chain phenyl and methyl groups was modeled with
the help of restraints during refnement. But the overlap
of the coumarins was essentially perfect within the reso-
lution of the determination. This was consistent with the
importance of the hydrogen-bonded β-enolone interactions
in the organization of the structure. The bond metrics for
(−)-3 are however less accurate; the average Q is 18 and
coumarins are well aligned with slightly shorter O·OH-bond
contacts and a modest claim for RAHB. Coumarins of (−)-
3 are stacked with weak contacts between their parallel but
ofset π-systems, and ring separations of about 350 pm.
In the chiral structure (S)-(−)-8, space group P 1, there
are two independent molecules in the asymmetric unit each
of which form (polar) translational β-chains with good
alignment of the enolones. Acceptor oxygens are displaced
by 61 pm from the donor enolone plane but otherwise the
chains are well aligned and consistent with the 716 pm
repeat, and 264 pm average O·OH-bond distance. Coumarins
of (S)-(−)-8 are stacked with weak contacts between their
parallel but ofset π-systems, and ring separations of about
350 pm. This structure shows disorder between confor-
mations of the dithioketal ethylene bridge which acts to
reduce the accuracy in its bond metrics.
In one of two structures taken from the literature,
3-(1′-naphthyl)-4-hydroxycoumarin, ( )-11, translational
β-chains were polar with the molecules showing axial (sub-
stituted biphenyl-like) chirality [15]. Molecules were related
by a crystallographic glide (180° pitch angle b) along the
β-chains. The β-enolones had ap-anti-anti confguration, as
with the other polar chain structures, but enolone alignment
was poorer. Modest molecular yaw (b″ 10°) was consist-
ent with a slightly shortened 708 pm semi-repeat, and the
slightly longer 266 pm O·OH-bond distance. This structure
showed that a glide relationship between hydrogen-bonded
4-hydroxycoumarins still employed the ap-anti-anti con-
fguration like that in Fig. 5. Coumarins in 11 were stacked
parallel but ofset, and with an interplanar spacing of about
365 pm. More typically in the group studied, racemic struc-
tures had non-polar enolone chains with glide relations.
Transitional Structures
Structures 4 and 9 form a transitional group between struc-
tures with the polar (translation) and non-polar (glide)
β-enolone hydrogen-bonded chains, but retaining ap-anti-
anti configurations. Modest molecular misalignments
between enolones are accompanied by slightly shorter crys-
tallographic repeating distances along the enolone chain
(Table 4).
Glide Related Chains
Compounds 5, 6 and 7 all have longer side chains on the
3-substituent carbon. These racemates each show non-polar
β-chains with hydrogen-bonding between glide relatives,
and ap-syn-(anti) confgurations in contrast to structures of
2–4, 8, 9. Structures 5–7 show considerable misalignments
(higher a and b values), less enolone delocalization (higher
Q values), weaker hydrogen-bonding (averaging O·OH-bond
269 pm), and modest molecular roll and yaw resulting in
corrugated coumarin arrangements with signifcantly shorter
β-chain repeat distances (Table 4). These glide-related
β-chains were also infuenced by temperature change. While
the fully-extended form represented by structures 2a and 2b
The structure of ( )-4 shows four independent mol-
ecules in the asymmetric unit, with two non-polar transla-
tional β-chains linking (R) with (S) along the (2×702) pm
a-axis. This structure shows non-crystallographic (1/2 +x,
1 3

Journal of Chemical Crystallography
showed contraction of the cell and the O·OHbond distance
along the translational hydrogen-bonding direction on cool-
ing (from 298 to 101 K), compound 6 showed a lengthen-
ing along the β-enolone repeat direction and a very small
reduction in the O·OHbond contact distance on cooling. The
β-chain is illustrated for structure 6b in Fig. 6. Coumarins of
5, 6, 7 are stacked with weak contacts between their parallel
but ofset π-systems, and ring separations of about 350 pm,
345 pm, and 345 pm respectively.
Alignments now show a general freedom with accommo-
dating molecular pitch, yaw and roll, ap-syn-(anti) enolone
structure, loss of buttressing C–H·O contacts, weaker
hydrogen-bonding, and contracting crystallographic repeat
distances. Coumarin ring π-stacking, typically with paral-
lel arrangements and ofsets, but occasionally at a shallow
angle, are common features of the entire group.
Testing the General Trends
General Comments
Structures 9 and 10 were examined to test some of the
β-enolone interaction features just recited and learned
from structures 2–8, 11. It seems that longer unbranched
R groups (Fig. 4) eventually lead to weakened β-chains. To
gauge this in an approximate way, we examined the struc-
ture of 3-benzyl-4-hydroxycoumarin (9) in which the side-
chain is now H, and a longer branched chain derivative 10.
Achiral 9 forms hydrogen-bonded β-chains between glide
relatives along the hydrogen-bonding direction (c axis in
P 21/c) and uses ap-anti-anti confguration and an inter-
mediate semi-repeat of 645 pm (Table 4). Delocalization
of the π-system is poorer (Q 19.5), and the hydrogen-bond
length is of the weaker variety at 270 pm. For compound
racemic 10, well-aligned polar β-chains between enolones
are found as with the examples with shorter side chains
(Table 4) and also the longer branched chain structure
(S)-(−)-8. Coumarin rings show π-stacking with parallel
arrangements, and with interplanar separations of 348 pm
in 9, and 355 pm in 10.
The polar translational β-chains are sufciently stabilizing
in structures with smaller 3-substituents to allow excellent
alignment of the coumarins (2, 2a, 2b, 8, 3) which are
supported by ap-anti-anti enolone confgurations. Delo-
calization Q’s (about 15) and O–H·O s (about 260 pm) are
consistent with previous observations on RAHB systems
[10]. In the enantiomeric phases (2a, 2b, 8, 3), one of
the two polar chains has just slightly stronger hydrogen-
bonding. The racemates studied (2, 3) have slightly higher
densities and better packing, retaining the polar β-enolone
structure. Where substituents begin to afect the alignment
of the β-enolones, modest molecular roll and yaw (cor-
rugated arrangements) and a doubling of the molecular
repeat continue to accommodate the translational asso-
ciations, but with weaker hydrogen-bonding and poorer
π-alignment (4, 9). For some larger or longer substituents,
pure translational β-enolones are replaced with non-polar
glide relations with required doubling of the molecular
repeats (typically observed along a crystallographic axis).
Fig. 6 Hydrogen-bonds between
glide relatives in the non-polar
β-chains of structure ( )-6a,
and showing ap-syn-(anti)
enolone confguration
1 3

Journal of Chemical Crystallography
5. Gora RW, Maj M, Grabowski SJ (2013) Resonance-assisted
hydrogen bonds revisited Resonance stabilization vs. charge delo-
calization. Phys Chem Chem Phys 15:2514–2522
Conclusions
3-Substituted-4-hydroxycoumarins without competing
hydrogen-bonding interactors show tendencies toward
β-chain formation. The structures examined here are
related more or less closely to phenprocoumon (2), a com-
pound with a benzylic chiral center attached at the 3-posi-
tion of 4-hydroxycoumarin. For shorter side-chains or
longer branched side-chains on the benzylic chiral carbon,
enolones align well for ap-anti-anti confgurations, show
modest π-delocalization, a translational repeat distance of
about 717 pm, and somewhat stronger hydrogen-bonding
with O·OH-bond distances below about 265 pm. These fea-
tures are consistent with resonance-assisted hydrogen-
bonding (RAHB). For longer straight-chain benzylic
substituents, non-polar β-chains are found between glide
relatives with poorly aligned enolones and using ap-syn-
(anti) confgurations, necessarily poorer π-delocalization,
and hydrogen-bonding O·OH-bond distances above 265 pm.
Crystallographic semi-repeat distances are shorter than for
the better aligned groups. Still other structures that may
be considered intermediate between these two groups have
also been found which retain ap-anti-anti confgurations,
either translational or glide relatives, but with consider-
ably diminished system alignment and weaker hydrogen-
bonding. Generally, coumarins show π-stacking with inter-
ring distances of about 355 pm.
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Acknowledgements EJV thanks the National Science Foundation
(MRI-0618148) for support of crystallographic equipment. Thanks also
go to Dr. Verner Schomaker (deceased) of the University of Washing-
ton for his encouragement, acumen, persistence and pedagogy with
difcult structures.
Compliance with Ethical Standards
Conflict of interest All the authors declare no confict of interest.
21. Stancheva S, Maichle-Mössmerb C, Manolova I (2007) Synthesis,
structure and acid-base behaviour of some 4-hydroxycoumarin
derivatives. Zeitschrift fur Naturforschung 62:737–741
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phenyl)methylene]-bis(4-hydroxy-2H-chromen-2-one). Acta
Crystallogr E 68:o265
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