Orthorhombic polymorphs of 1-phenyl-3-(3-Hydroxyphenyl)-2-propen-1-one

Article abstract of DOI:10.1007/s10870-011-0218-0

Chalcones, 1,3-diphenyl-2-propene-1-ones, exist naturally and synthetically, and are characterized by the linkage of two aromatic rings joining a three carbon α-β-unsaturated carbonyl entity. We report the observation of two new polymorphs of a hydroxy ch

Full text of DOI:10.1007/s10870-011-0218-0

J Chem Crystallogr (2012) 42:159–164
DOI 10.1007/s10870-011-0218-0
ORIGINAL PAPER
Orthorhombic Polymorphs of 1-Phenyl-3-(3-Hydroxyphenyl)-2-
Propen-1-One
•
Geremia Jennings Mark D. Smith Shan-Ming Kuang
•
•
•
•
•
L. Mark Hodges John Tyrell R. Thomas Williamson
Pamela Seaton
Received: 24 June 2011 / Accepted: 17 November 2011 / Published online: 2 December 2011
ꢀ Springer Science+Business Media, LLC 2011
Abstract Chalcones, 1,3-diphenyl-2-propene-1-ones, exist
naturally and synthetically, and are characterized by the
linkage of two aromatic rings joining a three carbon
a-b-unsaturated carbonyl entity. We report the observation
of two new polymorphs of a hydroxy chalcone, C6H5–CO–
CH=CH–C6H4 (m-OH), identified as a result of a Claisen–
Schmidt synthesis and manual screening technique. One
polymorph of this compound has been reported previously
and exists in the monoclinic system, space group P2/n, with
the two orthorhombic forms. The conformation of the C=C
(C2–C3) is E for both orthorhombic forms.
Keywords X-ray single crystal structure Á
Chalcone Á Polymorphs Á 1,3-diphenyl-2-propen-1-one Á
Hydroxyl derivatives of chalcones
Introduction
˚
unit cell parameters a = 13.295(6) A, b = 5.659(2) A,
˚
3
˚
˚
c = 16.144(8) A, b = 109.73(5)ꢁ, V = 1143.3(9) A , and
Z = 4. Two crystalline forms (II and III) reported herein,
are polymorphs of the reported monoclinic form (I). Form
II exists in the orthorhombic system, space group Pca21,
Chalcones, chemically 1,3-diaryl-2-propene-1-ones, are
structurally simple compounds that exist naturally in petal
pigments and have also been observed in the fruit, bark,
nut, and root of a variety of plants, such as the Angelica
and Glycyrrhiza found in Africa, Asia, and South America
[1]. They are also readily synthesized via Claisen–Schmidt
condensation of appropriately substituted acetophenone
and benzaldehyde under acidic, basic, or solvent-free
conditions [2]. Structurally they are characterized by
the linkage of two aromatic rings joining a three carbon
a-b-unsaturated carbonyl, or ‘‘enone’’ moiety. This
molecular scaffold serves as a unique template in a variety
of synthetic modifications, and provides an ideal frame-
work as precursors for the synthesis of heterocyclic com-
pounds such as flavonoids and other chemical analogs,
such as curcumin [3].
˚
with unit cell constants a = 11.631 (2) A, b = 13.163 (3)
3
˚
˚
˚
A, c = 7.3977 (14) A, V = 1132.6 (4) A , and Z = 4.
Form III also crystallizes in the orthorhombic system,
however in space group Pbca, with unit cell parameters
˚
a = 11.8100(8) A, b = 7.4075(5) A, c = 25.8729(19) A,
3
V = 2263.4(3) A , and Z = 8. Variations in the hydrogen
˚
˚
˚
bonding connectivity help to distinguish these two forms
from the monoclinic, whereas crystal packing differentiates
G. Jennings (&) Á S.-M. Kuang Á L. Mark Hodges Á
R. Thomas Williamson
Pharmaceutical Technical Development Actives (PTDA-FL),
Roche Carolina Inc., 6173 East Old Marion Highway,
Florence, SC 29506-9330, USA
Natural and synthetic based chalcones have attracted
much attention in recent years as a result of their ubiquity and
extensive use in a number of pharmacological and biological
applications. Documented reports of derivatives and analogs
of these benzylideneacetophenone suggest activities as anti-
tumorogenic [4, 5], anti-Parkinsonism activities [6], anti-
fungal [7, 8], and anti-tuberculosis [9, 10] agents. Moreover,
more recent indications as anti-HIV and food and drug
preservative usages have also been evaluated [11].
e-mail: geremia.jennings@roche.com
M. D. Smith
Department of Chemistry and Biochemistry, University of South
Carolina-Columbia, Columbia, SC 29208, USA
J. Tyrell Á P. Seaton
Department of Chemistry and Biochemistry, University of North
Carolina-Wilmington, Wilmington, NC 28403, USA
123

160
J Chem Crystallogr (2012) 42:159–164
This paper documents the observation and crystal
SADABS programs [14]. Final unit cell parameters were
determined by least-squares refinement of approximately
3,000 reflections from the corresponding data set. Direct
methods structure solution, difference Fourier calculations
and full-matrix least-squares refinement against F2 were
performed with the SHELXTL software package [15].
The molecular structure of C6H5–CO–CH=CH–C6H4
(m-OH), forms II and III, with assigned atom-numbering
scheme is illustrated in Fig. 1. The conformation of C2–C3
is E for all orthorhombic forms, which is characteristic to
these compounds. An overlay of the simulated diffraction
patterns of all observed polymorphs of 1-phenyl-3-
(3-hydroxyphenyl)-2-propen-1-one is given in Fig. 2. The
experimental X-ray pattern of forms I, II, and III consistent
with the corresponding simulated X-ray pattern, calculated
using atomic coordinates, and is therefore indicative of a
single crystalline phases for all observed polymorphs. A
summary of the crystallographic data is provided in
Table 1 and selected bond lengths and bond angles are
structures of two new polymorphic modifications of
1-phenyl-3-(3-hydroxyphenyl)-2-propen-1-one C6H5–CO–
CH=CH–C6H4(m-OH). The monoclinic form, herein
referred to as Form I, previously reported by Turowska-
Tyrk et al. is also briefly discussed [12]. The two ortho-
rhombic polymorphs identified in this work are novel forms
and, to the best of our knowledge, have not yet been
reported in the literature. Slight variations in the molecular
geometry, specifically, the planarity orientation of the
hydroxyl proton, differentiates the monoclinic and ortho-
rhombic forms, and variation in crystal packing help to
distinguishes the two orthorhombic polymorphs.
Experimental
Commercially available starting materials were used to
produce the chalcone based derivatives. These materials
were accepted based on vendor certificate of analysis
(CoA) data and used without further purification. The
synthesis was conducted using a modified version of a
Claisen–Schmidt condensation as reported by B. N. Ach-
arya et al. [13]. These reactions are frequently referenced in
organic synthesis for the formation of carbon–carbon
bonds.
A solution of acetophenone (1.00 g, 8.32 mmol) and
3-hydroxybenzaldehyde (1.27 g, 8.32 mmol) dissolved in
methanol (3.95 g) was added to a flask containing sodium
methoxide in methanol (25 wt%, 7.19 g, 33.29 mmol). The
resulting mixture was stirred overnight at room tempera-
ture. The reaction was neutralized using dilute acid and the
resulting crude product was collected by filtration.
Recrystallization in methanol followed by slow overnight
cooling afforded compound 1 (Form II) as a yellow solid.
Two additional polymorphic modifications were also
noted, Forms I and III. Form III, is produced by recrys-
tallization of Form II in ethanol, DMA and DMF. This
polymorph is generated by equilibration of Form II in a
variety of organic and aqueous based mixtures such as
methanol, ethyl acetate, DMSO, H2O, H2O/ACN, and
Fig. 1 Molecular structure of compound 1, C6H5–CO–CH=CH–
C6H4 (m-OH), with atomic numbering scheme. Displacement ellip-
soids drawn at the 50% probability level. Form III is shown, form II is
essentially identical
ꢁ
MeOH/H2O (5:1) at RT C. It is also readily observed
through slurry of Form II in acetone. The monoclinic
polymorph, Form I, is reportedly observed as a result of
recrystallization in a methanol–water (5:1) mixture; how-
ever, we are only able to isolate Form I, in an acicular
crystal habit, by recrystallization of Form II in toluene.
X-ray diffraction intensity data from two plate-like
crystals, corresponding to polymorphs II and III, were
measured at 296 (2) K using a Bruker SMART APEX
˚
diffractometer (Mo Ka radiation, k = 0.71073 A) [14].
The raw area detector data frames were reduced and
corrected for absorption effects with the SAINT? and
Fig. 2 Overlay of simulated X-ray diffraction patterns of C6H5–CO–
CH=CH–C6H4 (m-OH) polymorphs I, II, and III
123

J Chem Crystallogr (2012) 42:159–164
161
Table 1 Crystal data and structure refinement for polymorphs I, II and III
Polymorph
Ia
II
III
Empirical formula
Formula wt.
C15H12O2
224.25
CCDC No.
209763
825808
825010
Temperature (K)
293(2)
296(2)
296(2)
˚
Wavelength (A)
0.71073
0.71073
0.71073
Crystal system, space group
Unit cell dimensions
Monoclinic, P2/n
Orthorhombic, Pca21
Orthorhombic, Pbca
˚
a (A)
13.295(6)
5.659(2)
11.631(2)
13.163(3)
7.3977(14)
11.8100(8)
7.4075(5)
˚
b (A)
˚
c (A)
16.144(8)
109.73(5)
1143.3(9)
4, 1.303
25.8729(19)
b (ꢁ)
Volume (A )
Z, calculated density (Mg/m3)
3
˚
1132.6(4)
4, 1.315
2263.4(3)
8, 1.316
F (000)
472
472
944
Crystal dimensions (mm)
H Range for data collection (ꢁ)
Limiting indices
0.40 9 0.10 9 0.08
Hmax = 26
0.42 9 0.32 9 0.08
1.55–25.02
0.30 9 0.22 9 0.04
1.57–25.02
-14 B h B 14,
-16 B h B 16,
-6 B k B 4, -19 B l B 19
-13 B h B 13,
-15 B k B 15, -8 B l B 8
-8 B k B 8, -30 B l B 30
Reflections collected/unique
Data/restraints/parameters
Goodness-of-fit on F2
R indices (all data)
6517/2214
10714/1090
21080/1997
2214/–/203
1090/1/158
1997/0/158
0.93
1.051
1.051
R1 = 0.134, wR2 = 0.133
R1 = 0.059, wR2 = 0.113
R1 = 0.0370, wR2 = 0.0710
R1 = 0.0319, wR2 = 0.0682
R1 = 0.0679, wR2 = 0.1044
R1 = 0.0460, wR2 = 0.0949
R indices [I [ 2r (I)]
a
Turowska-Tyrk et al. [12]
shown in Table 2. Crystal structure data for the monoclinic
form is transcribed from a previous assignment [12].
˚
Table 2 Select bond lengths (A) and bond angles (ꢁ) for polymorphs
I, II and III
Polymorph
Ia
II
III
C(1)–O(1)
C(1)–C(2)
C(1)–C(10)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
C(4)–C(9)
C(5)–C(6)
C(6)–O(2)
C(6)–C(7)
C(8)–C(9)
C(10)–C(15)
C(10)–C(11)
C(11)–C(12)
C(12)–C(13)
C(13)–C(14)
C(14)–C(15)
1.224
1.476
1.473
1.325
1.456
1.386
1.387
1.381
1.366
1.386
1.372
1.383
1.400
1.383
1.373
1.370
1.364
1.223(2)
1.470(3)
1.493(3)
1.322(2)
1.462(3)
1.393(3)
1.395(3)
1.386(3)
1.364(2)
1.381(3)
1.373(3)
1.388(2)
1.390(3)
1.383(3)
1.368(3)
1.375(3)
1.382(3)
1.227(2)
1.470(3)
1.490(2)
1.316(2)
1.462(2)
1.389(2)
1.395(2)
1.381(2)
1.361(2)
1.380(3)
1.374(3)
1.388(3)
1.390(3)
1.381(3)
1.371(3)
1.373(3)
1.380(3)
Results and Discussion
The monoclinic form, Form I, has been identified and is
reported in the literature. Form I adopts the space group
˚
P2/n with unit cell parameters a = 13.295(6) A, b =
˚
˚
5.659(2) A, c = 16.144(8) A, b = 109.73(5)8, V =
3
1143.3(9) A , and Z = 4 [12]. In Form I, hydrogen bond-
˚
ing links molecules into a discrete dimeric structure where
the two molecules are related by an inversion center.
Form II exists in the orthorhombic crystal system. Space
groups Pca21 and Pbcm were indicated by the pattern of
systematic absences in the intensity data. The acentric group,
Pca21, was confirmed by obtaining a reasonable and stable
solution and refinement, and verified by ADDSYM program
implemented in PLATON [16–18], which found no missed
symmetry elements. The asymmetric unit consists of one
molecule and non-hydrogen atoms were refined with aniso-
tropic displacement parameters. Hydrogen atoms bonded to
carbon were placed in geometrically idealized positions and
Bond distances for form I refer to the atom numbering scheme used
for forms II and III
a
˚
included as riding atoms, with d (C–H) = 0.93 A and
Turowska-Tyrk et al. [12]
123

162
J Chem Crystallogr (2012) 42:159–164
˚
Table 3 Geometries of hydrogen bond, for polymorphs I, II and III (A, ꢁ)
Polymorph
D–H…A
D–H
H…A
D…A
D—H…A
Ia
II
III
a
O(2)–H(2A)…O(1)#1
O(2)–H(2A)…O(1)#1
O(2)–H(2A)…O(1)#1
1.032
1.753
2.775
170
0.87(2)
0.92(3)
1.91(2)
1.87(3)
2.752(2)
2.784(2)
160(3)
170(2)
Turowska-Tyrk et al. [12]
Uiso,H = 1.2Ueq C. The hydrogen atom bonded to oxygen
(H2A) was located in a difference map and refined freely.
Because of the absence of any atoms heavier than oxygen in
the crystal, Friedel opposites were merged during refinement
and the absolute structure could not be reliably determined.
Polymorph III crystallizes in the orthorhombic system in
space group Pbca, as determined uniquely by the pattern of
systematic absences in the intensity data. Non-hydrogen
atoms were refined with anisotropic displacement param-
eters and the asymmetric unit consists of one molecule.
Hydrogen atoms bonded to carbon were placed in geo-
metrically idealized positions and included as riding atoms
direction in both compounds (Fig. 3a), which may be
contrasted with that of Form I, where a molecular dimer is
the repeating motif (Fig. 3b).
Although both forms II and III exist in the orthorhombic
crystal system, Form II is a non-centrosymmetric packing
variant of Form III. Differences in unit cell volume facil-
itate the distinct packing arrangements of these two poly-
3
˚
morphs, Form II (1132.6 A ) possessing half the unit cell
3
volume of Form III (2263.4 A ). This smaller unit cell is
˚
evident when comparing the lattice parameters, where axes
a and b are comparable, but the c-axes differ by half the
length, as indicated in Table 1. The pattern of the hydrogen
bonding is equivalent in these two structures and accounts
for similarities along the crystallographic a-axis. A com-
parison of three adjacent symmetry-equivalent hydrogen-
bonded chains formed from OH—O hydrogen bonding is
given in Fig. 4. Views nearly perpendicular to (upper
figures) and parallel to (lower figures) a layer of chains are
illustrated in Fig. 5. Adjacent chains in polymorph II
(Pca21, left) are related by an axial translation (b axis).
Adjacent chains in Form III (Pbca, right) are related by
glide mirror plane symmetry. The glide plane is parallel to
and bisects the layers of chains. The consequence of this
glide symmetry is a repeat unit of two equivalent chains in
˚
with d (C–H) = 0.93 A and Uiso,H = 1.2Ueq C. The
hydrogen atom bonded to oxygen (H2A) was located in a
difference map and refined freely.
The molecular structure of this hydroxyl chalcone
consists of a phenyl and a hydroxyl (phenyl) ring joined by
a –C (=O–)–CH=CH entity. The dihedral angle between
the {C4–C9} and {C10–C15} ring planes is 10.0ꢁ,
18.07(9)ꢁ, and 12.52 (10)ꢁ for Forms I, II and III, respec-
tively. In the extended orthorhombic structures, molecules
interact via hydrogen bonding of the carbonyl and hydroxyl
groups (Table 3). These (molecular) links form infinite
zigzag chains running along the crystallographic a-axis
Hydrogen bonding links molecules into
(b)
(a) Hydrogen bonding links molecules into infinite chains
running along the crystallographic a-axis direction
dimmer motif
Fig. 3 Hydrogen bonding scheme of polymorphs a: II and III. b: I
123

J Chem Crystallogr (2012) 42:159–164
163
Form II, Pca21
Form III, Pbca
Fig. 4 Comparison of the crystal packing for polymorphs II and III. Views nearly perpendicular to (upper figures) and parallel to (lower figures)
a layer of chains
Form II, Pca21
Form III, Pbca
Fig. 5 Packing diagrams perpendicular to three adjacent layers of hydrogen bonded chains for polymorphs II and III. Views perpendicular to
the propagation direction of the chains
Form III, compared to a repeat unit of one chain in Form II,
and a doubling of one axial length (the c axis in form III).
This packing also results in the centrosymmetric structure
of polymorph III versus an acentric structure of polymorph
II (Fig. 5).
Crystals of 1-phenyl-3-(3-hydroxyphenyl)-2-propen-1-
one can be isolated in one of three polymorphic forms. We
report herein, the unique observation of the two ortho-
rhombic forms of this hydroxy chalcone, Forms II and III.
Although Form II and Form III both exist in the
123

164
J Chem Crystallogr (2012) 42:159–164
3. Mandge S, Singh H (2007) Trends Appl Sci Res 2(1):52–56
4. Anto R, Sukumaran, Kuttan K, Rao G (1995) Cancer Lett 97:
33–37
5. Bazzaro M, Anchoori R, Mudiam M, Issaenko O, Kumar S
(2011) J Med Chem 54:449–456
6. Mahajan S, Patil C (2010) Int J Pharm Res 2(3):39–43
7. Lahtchev K, Batovska D, Parushev S, Ubiyvovk V, Sibirny A
(2008) Eur J Med Chem 43:2220–2228
8. Begum A, Roy N, Laskar R, Roy K (2009) Med Chem Res 20:
184–191
orthorhombic system and possess comparable plate-like
morphologies, they vary in unit cell parameters, space
groups, and packing, and as such are considered poly-
morphs. Variations in the hydrogen bonding connectivity
help to distinguish these two forms from the monoclinic
form I, where a dimer pattern is the repeating motif, and
crystal packing differentiate the two orthorhombic forms.
9. Sivakumar P, Geetha-Babu S, Mukesh D (2006) Chem Pharm
Bull 55:44–49
10. Powers D, Casebier D, Fokas D, Ryan W (1998) Tetrahedron 4:
4085–4096
Supplementary Material
X-ray crystallographic data reported in this paper is
deposited with the Cambridge Crystallographic Data Cen-
ter as supplementary publication numbers CCDC 825010
and 825808. Copies of available material can be obtained,
free of charge, on application to the Director, CCDC, 12
Union Road, Cambridge CB21EZ, UK.
11. Wu J, Wang X, Yi Y, Lee K (2003) Bioorg Med Chem Lett 13:
1813–1815
12. Turowska-Tyrk I, Grzesniak K, Trzop E, Zych T (2003) J Solid
State Chem 174:459–465
13. Acharya B, Saraswat D, Tiwari M, Shrivastava A (2010) Eur J
Med Chem 45:430–438
14. SMART Version 5.630 (2003) SAINT? Version 6.45 and
SADABS Version 2.10. Bruker Analytical X-ray Systems, Inc.,
Madison, Wisconsin, USA
15. Sheldrick GM (2008) Acta Cryst A64:112–122
16. Le Page Y (1987) J Appl Crystallogr 20:264–269
17. Spek A (1988) J Appl Crystallogr 21:578–579
18. PLATON (1988) A Multipurpose Crystallographic Tool. Utrecht,
University Utrecht, The Netherlands
Acknowledgments The authors would like to express a sincere
appreciation to the colleagues of PTDA-Fl for the use of their facilities
and for all of their intellectually based support and contributions.
Honorable mention is givento M. Cedilote, A. O’Connor, J. Lawrimore,
C. Pavy, P. Zhang, J. Suchy, E. Dong, W.T. English, Y. Robinson, D.
English, and S. Eaddy.
References
1. Ni L, Meng C, Sikorski J (2004) Expert Opin Ther Pat 14:
1669–1691
2. Rateb N, Zohdi H (2009) Synth Commun 39:2789–2794
123