Ortho-substituent effects on diphenylurea packing motifs

Article abstract of DOI:10.1021/acs.cgd.7b00757

Hydrogen bonding between urea groups is a widely used motif in crystal engineering and supramolecular chemistry studies. In an effort to discern how the steric and electronic properties of substituents affect the molecular conformation and crystal packing

Full text of DOI:10.1021/acs.cgd.7b00757

Article
pubs.acs.org/crystal
Ortho-Substituent Effects on Diphenylurea Packing Motifs
Marina A. Solomos, Taylor A. Watts, and Jennifer A. Swift*
Department of Chemistry, Georgetown University, 37th and O Streets NW, Washington, DC 20057-1227, United States
S
* Supporting Information
ABSTRACT: Hydrogen bonding between urea groups is a widely used
motif in crystal engineering and supramolecular chemistry studies. In an
effort to discern how the steric and electronic properties of substituents
affect the molecular conformation and crystal packing of ortho-
substituted N,N′-diphenylureas (oPUs), herein we report the synthesis,
characterization, and polymorph screening of eight members of this
family. Of the 16 total oPU structures known (including nine structures from this study and seven previously reported), only two
are isostructural. These 16 structures are sorted into three general architecture types based on their hydrogen bond topologies. In
Type I, urea molecules related by translation form linear one-dimensional (1D) hydrogen bonded chains. In Type II, urea
molecules rotate about a 1D hydrogen bond axis forming twisted chains. Urea groups do not hydrogen bond to one another in
Type III. Energy calculations performed at the B3LYP/6-31G(d,p) level show a higher rotational barrier about the amide bond in
oPUs compared to meta-substituted diphenylureas (mPUs), which may explain the smaller range of torsion angles observed in
oPUs compared to mPUs. Although ortho-substitution does not seem to limit the hydrogen bonding between urea groups in
most cases, a notably higher percentage of oPU phases are polar compared to PUs with other substitution patterns. This suggests
restricted conformations might offer some advantage in achieving acentric materials.
expand our structure analysis set, we prepared eight oPUs,
screened them for polymorphism, and determined nine new
single crystal structures. Analysis of all new and previously
reported crystal structures revealed 15 unique packing arrange-
ments and only one isostructural pair. Calculations validate our
assumption that ortho-substituents present a significant steric
barrier to rotation about the amide bond and hydrogen
bonding between urea groups.
INTRODUCTION
■
N,N′-Phenylurea (PU) is an interesting core unit that appears
in a wide range of chemical compounds with diverse
applications. It is found in pharmaceuticals developed to treat
diseases ranging from African sleeping sickness1 to psoriasis2
and cancer.3,4 PUs have also attracted negative attention for
their persistence in the environment due to their use as
herbicides5−7 and as antibacterial ingredients in personal care
products (e.g., triclocarban).8−10 The persistence of hydrogen
bonding between urea groups has also enabled the assembly of
urea-based supramolecular materials such as gels, tubes, and
capsules.11−13 In the crystalline state, PUs have served as model
systems for crystal polymorphism studies14−19 and been
explored as possible nonlinear optical materials.20−23
To better exploit the properties of PUs in these various
applications, some of our recent efforts have focused on
defining under what conditions the urea hydrogen bonding
motif ceases to be reliable. This idea was first probed by Etter in
the late 1980s in studies which showed that some diphenylureas
with electron withdrawing substituents cocrystallized with other
strong hydrogen bond donor and acceptor molecules.16,24,25
More recently, we showed that the ability to disrupt urea
hydrogen bonding in a series of meta-substituted diphenylureas
(mPUs) with the strong hydrogen bond acceptor triphenyl-
phosphine oxide (TPPO) can be reasonably well predicted
based on differences in the relative energies of urea···urea and
urea···TPPO dimers.26
EXPERIMENTAL SECTION
■
Materials. All 2-X-isocyanate and 2-Y-aniline reagents were
obtained from Sigma-Aldrich (97−99%) or Combi-Blocks and used
without further purification. All solvents used in synthesis and
crystallization experiments were reagent grade or higher and were
obtained from Sigma-Aldrich, Fischer Scientific, and Warner-Graham.
1H NMR data were collected on a 300 MHz Varian Inova
Spectrometer in d6-DMSO.
Synthesis. Symmetrical and unsymmetrical ortho-substituted
diphenylureas were synthesized according to previously reported
methods.25 For each compound, equimolar amounts of 2-X-isocyanate
and 2-Y-aniline were dissolved in benzene or dichloromethane flushed
with nitrogen and stirred at RT for 24 h. Gentle heating was often
required for full dissolution. After 24 h, the product was isolated using
vacuum filtration and recrystallized in ethanol or acetonitrile. Product
synthesis was confirmed by 1H NMR and melting point. Single crystals
used in structure determination were grown from ethanol except
where otherwise indicated.
1,3-Bis(o-trifluoromethylphenyl)urea (oCF3PU). Prepared from 2-
trifluoromethylaniline and 2-(trifluoromethyl)phenylisocyanate. Re-
crystallization in ethanol yielded colorless needles with mp = 230.0−
In the current study, we attempt to address the question of
how steric effects play a role in the urea assembly motifs. A
search of the Cambridge Structure Database V5.38 (November
2016) for low molecular weight PUs with only ortho-
substituents yielded just seven structures. In an effort to
Received: May 31, 2017
Revised: August 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.cgd.7b00757
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Table 1. Crystallographic Data for Diphenylureas with Ortho-Substituents (N = Nitro, Cl = Chloro, CF3 = Trifluoromethyl, Cy
= Cyano)
urea
β-oNPU
α-oNHPU
β-oNHPU
oClPU
oClHPU
oCF3PU
oCF3HPU
oCyPU
oCyHPU
formula
temp (K)
space group
a (Å)
C13H10N4O5
110
C13H11N3O3
100
C13H11N3O3
173
C13H10Cl2N2O
110
C13H11ClN2O
110
C15H10F6N2O
100
C14H11F3N2O
C15H10N4O
296
C14H11N3O
100
100
P1
Pc
P21/c
P2/n
Pna21
9.1866(7)
11.1288(9)
11.4667(9)
90
P21/n
Pna21
13.9832(11)
19.2797(14)
4.6241(4)
90
P21/n
P21/c
̅
9.9134(12)
11.5929(12)
12.7294(13)
109.635(9)
111.993(10)
91.207(9)
1259.4(3)
4
4.6327(3)
6.1305(4)
20.9967(15)
90
4.62450(10)
20.3783(8)
12.631
90
15.9459(10)
4.6128(2)
16.3242(9)
90
4.6101(2)
13.8352(6)
22.3435(10)
90
7.4598(4)
12.4052(7)
13.2127(8)
90
5.44700(10)
19.9264(5)
10.8499(2)
90
b (Å)
c (Å)
α (deg)
β (deg)
γ (deg)
V (Å3)
Z
92.603(2)
90
99.020(4)
90
90.520(5)
90
90
94.125(3)
90
90
100.923(4)
90
103.3450(10)
90
90
90
595.707
2
1175.62
4
1200.68
4
1172.31
4
1421.41
4
1246.62
4
1200.56
4
1145.84
4
R
0.0504
0.0238
0.0605
I
0.0426
0.1148
I
0.0480
0.1516
I
0.0404
0.0970
II
0.0432
0.1195
I
0.0572
0.1354
I
0.0428
0.1304
III
0.035
Rw
0.1166
0.0846
III
type
III
crystal habit
prism
needle
needle
needle
needle
needle
needle
prism
prism
232.0 °C. 1H NMR (DMSO-d6, ppm) δ: 7.90, (s, 2H); 7.00, (d, 2H);
6.85, (m, 4H); 6.51, (t, 2H).
1-(o-Trifluorophenyl)-3-phenylurea (oCF3HPU). Prepared from
phenylisocyanate and 2-trifluoromethylaniline. Recrystallization in
ethanol yielded colorless needles with mp = 175.5−178.8 °C. 1H
NMR (DMSO-d6) δ: 8.55, (s, 1H); 7.25, (s, 1H); 7.12, (d, 1H); 6.83,
(m, 2H); 6.64, (d, 2H); 6.48, (m, 3H); 6.17, (t, 1H).
ethanol, methanol, benzene, 2-propanol, ethyl acetate, 1:1 hexanes/
acetone, 1:1 hexanes/ethyl acetate, and chloroform. Vials with oPU
and solvent were heated for complete dissolution, then covered with
pierced Parafilm and maintained at room temperature for 2−10 days
until crystallization was evident.
Optical and hot-stage microscopy (HSM), differential scanning
calorimetry (DSC), and powder X-ray diffraction (PXRD) were used
to characterize the solid state materials. Phase transitions in bulk and
single crystal samples were identified by HSM using a HCS302 optical
hot-stage with a standard deviation of 1° up to 250° (INSTEC, Inc.,
Boulder, CO) interfaced with an Olympus BX-50 microscope. Melting
points were determined by DSC using a TA Instruments Modulated
DSC 2920. Samples were prepared in hermetically sealed aluminum
pans using 2−10 mg of crystalline sample. All runs were performed at
a heating rate of 5−10 °C/min. DSC data were analyzed with
Universal Analysis software. PXRD data was collected on bulk ground
samples at room temperature (5−40° in 2θ) on a Rigaku Ultima IV X-
ray diffractometer (Cu Kα radiation, 40 kV tube voltage, 44 mA
current). PXRD spectra were analyzed using Jade v9.0 software and
compared against simulated PXRD patterns of known single crystal
structures.
Single Crystal X-ray Structure Determination. Crystal
structure determination was accomplished using a Siemans/Bruker
SMART or APEX II Platform CCD diffractometer (Mo Kα radiation
= 0.71073 Å) at 100 or 110 K in most cases. Intensity data was
corrected for absorption and decay in SADABS.32 Structures were
solved in SHELXS and refined using SHELXL.33 Non-hydrogen atoms
were solved using direct methods and refined with anisotropic
displacement parameters. Hydrogen treatment was mixed. Urea
hydrogen atom positions were typically determined from the residual
electron density, while most aromatic hydrogen atoms were placed in
ideal positions and refined with a riding model. Cif files for all nine
structures have been deposited in the CCDC 1504100−1504106 and
1504132−1504133.
Computational Methods. The rotational barrier about the amide
bond in oClPU and oClHPU were calculated using ab initio molecular
orbital calculations. Similar rotational barrier calculations for 1,3-
bis(m-chlorophenyl)urea (mClPU) were also performed to directly
compare ortho- and meta-substituent effects. Geometries at fixed
torsion angles were optimized in Gaussian09 with ModRedundant
constraints at the B3LYP/6-31G(d,p) level. Anti and syn refer to the
orientation of the substituent relative to the carbonyl group (syn =
−180°; anti = 180°). The planar anti−syn conformation was rotated in
increments of 10 degrees toward the anti−anti conformation.
Specifically, the phenyl ring bearing the syn substituent was rotated
around the C(O)−N−C−C torsion angle between the carbonyl
carbon and the aromatic carbon bound to the ortho-substituent. In the
case of mClPU, the aromatic carbon closest to the meta-substituent
β-1,3-Bis(o-nitrophenyl)urea (β-oNPU). Prepared from 2-nitro-
phenylisocyanate and 2-nitroaniline. Recrystallization in ethanol
yielded colorless crystals with mp = 210.2−215.9 °C (lit. 225−227
27
1
°C ). H NMR (DMSO-d6, ppm) δ: 9.21, (s, 2H); 7.20, (dd, 2H);
7.12, (dd, 2H); 6.87, (m, 2H); 6.46, (m, 2H). The β-oNPU structure
was determined from a plate grown from benzene.
1-(o-Nitrophenyl)-3-phenylurea (oNHPU). Prepared from phenyl-
isocyanate and 2-nitroaniline. Recrystallization in ethanol yielded
colorless needles (β-oNHPU) with mp = 163.0−166.6 °C (lit. 170
°C28). 1H NMR (DMSO-d6) δ: 9.82, (s, 1H); 9.58, (s, 1H); 8.29, (dd,
1H); 8.09, (m, 1H); 7.70, (m, 1H); 7.49, (m, 2H); 7.31, (m, 2H);
7.21, (m, 1H); 7.02, (m, 1H). Recrystallization in acetone yielded
yellow needles (α-oNHPU) with a mp = 171.0−173.4 °C.
1,3-Bis(o-chlorophenyl)urea (oClPU). Prepared from 2-chloroani-
line and 2-chlorophenylisocyanate. Recrystallization in ethanol yielded
colorless needles with mp = 240.0−241.7 °C (lit. 240.5−241.5 °C29).
1H NMR (DMSO-d6, ppm) δ: 9.02, (s, 2H); 8.07, (dd, 2H); 7.47, (dd,
2H); 7.30, (dd, 2H); 7.06, (dd, 2H).
1-(o-Chlorophenyl)-3-phenylurea (oClHPU). Prepared from 2-
chlorophenylisocyanate and aniline. Recrystallization in ethanol
yielded thin white needles with mp = 185.1−188.4 °C (lit. 180−182
°C30). 1H NMR (DMSO-d6) δ: 9.41, (s, 1H); 8.31, (s, 1H); 8.17, (dd,
1H); 7.47, (m, 3H); 7.31, (m, 3H); 7.02, (m, 2H).
1,3-Bis(o-cyanophenyl)urea (oCyPU). Prepared from 2-amino-
benzonitrile and 2-cyanophenylisocyanate. The reaction flask was left
undisturbed after a 96 h stirring period such that crystals suitable for
single crystal X-ray diffraction of the product could be obtained
directly from the reaction mixture. The colorless prisms obtained
undergo a phase change between mp = 154.9−178.8° and decompose
31
1
with continued heating (lit. 250 °C (decomp) ). H NMR (DMSO-
d6, ppm) δ: 9.44, (s, 2H); 8.03, (dd, 2H); 7.80, (dd, 2H); 7.63, (dd,
2H); 7.25, (dd, 2H).
1-(o-Cyanophenyl)-3-phenylurea (oCyHPU). Prepared from phe-
nylisocyanate and 2-aminobenzonitrile. Recrystallization in ethanol
yielded colorless prisms with a mp = 166.2−170.8 °C (lit. 163 °C
31
1
(decomp) ). H NMR (DMSO-d6) δ: 8.57, (s, 1H); 7.92, (s, 1H);
7.27, (d, 1H); 6.93, (dd, 1H); 6.83, (m, 1H); 6.65, (m, 2H); 6.49, (m,
2H); 6.36, (m, 1H); 6.19 (m, 1H).
Crystal Growth and Polymorph Characterization. Crystal-
lization by slow evaporation was attempted from a number of different
solvents, including but not limited to acetone, toluene, acetonitrile,
B
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Figure 1. Different types of hydrogen bonding identified in oPUs: (a) Type I, (b) Type II, and (c,d) Type III.
Table 2. Torsion Angles and Hydrogen Bond Distances in oPUs
urea chain axis
C(O)−N−C−C torsion angle (ortho substituent) (deg)
92.87 (A), −47.96 (H)
−138.40 (Br), −138.40 (Br)
O···H−N distance (O···N distance) (Å)
oAHPU
oBrPU
b (Type I)
2.126 (2.932), 1.942 (2.771)
2.104 (2.917), 2.104 (2.917)
2.159 (2.917), 2.029 (2.831)
2.074 (2.849), 2.272 (2.948)
2.056 (2.863), 2.056 (2.863)
2.081 (2.884), 2.065 (2.871)
N/A
c (Type I)
oCF3PU
oCF3HPU
oClPU
a (Type I)
116.52 (CF3), 126.91 (CF3)
c (Type I)
132.93 (CF3), −142.42 (H)
(mol 1) −43.68 (Cl), −43.68 (Cl); (mol 2) 47.88 (Cl), 47.88 (Cl)
43.94 (Cl), −36.08 (H)
−175.44 (Cy), 168.42 (Cy)
−178.60 (Cy), 178.99 (H)
−166.98 (E), −176.08 (E)
−124.61 (I), −130.62 (H)
−138.12 (Mo), −138.12 (Mo)
156.55 (Mo), 156.55 (Mo)
b (Type I)
oClHPU
oCyPU
a (Type II)
none (Type III)
none (Type III)
none (Type III)
b (Type I)
oCyHPU
oEPU
N/A
N/A
oIHPU
2.188 (2.925), 2.094 (2.866)
2.243 (2.996), 2.243 (2.996)
2.331 (3.144), 2.331 (3.144)
2.156 (2.915), 2.038 (2.844)
N/A
α-oMoPU
β-oMoPU
α-oNPU
β-oNPU
α-oNHPU
β-oNHPU
c (Type I)
c (Type II)
b (Type I)
−42.07 (N), −37.75 (N)
(mol 1) 174.65 (N), 176.95 (N); (mol 2) −153.32 (N), 167.86 (N)
138.08 (N), −136.79 (H)
none (Type III)
a (Type I)
2.240 (2.949), 2.118 (2.850)
2.116 (2.866), 2.133 (2.912)
a (Type I)
−51.64 (N), −55.57 (H)
was selected. In all cases, the anti−anti conformation was found to be
lowest in energy, and all energy optimizations were considered relative
to these minima.
categories based on their hydrogen bonding topologies (Figure
1). A majority of structures exhibit the classic one-dimensional
[C(4)R12(6)] bonding motif between urea groups. This motif
can form between molecules related by translation (Type I) or
between molecules that twist about the chain axis (Type II). In
some systems, hydrogen bonding between the ortho-
substituent and the urea group (Type III) is observed. For
the new compounds examined here, the crystallization into
either a needle or prismatic morphology proved to be a good
indicator for the presence or absence of the [C(4)R12(6)] motif,
respectively.
Structure Type I. Type I, the first and largest group,
consists of 10 structures. This includes (a) α-oNHPU, (b) β-
oNHPU, (c) oCF3PU, (d) oClPU, (e) α-oNPU (VIRVAV), (f)
oAHPU (LOYDAG), (g) α-oMoPU (SILTUC), (h) oBrPU
(AQASIV), and (i) oCF3HPU. In the classic [C(4)R12(6)]
bonding motif, the N−H···O distances range from 1.94 to 2.27
Å; N···O distances from 2.77 to 2.99 Å (Table 2). Molecules
within the chain are related by translation about a short axis
(4.56−4.75 Å); however, the short axis corresponds to the a-,
b-, or c-crystallographic axis in different structures. Type I
structures differ from one another in two key respects: the
relative orientation of urea chains (e.g., parallel vs antiparallel)
and/or the symmetry relationships between chains.
RESULTS AND DISCUSSION
■
The compounds in this study are named as oXPU and oXHPU,
depending on whether both or only one aromatic ring bears an
ortho-substituent. X represents the substituent with A = amino,
Br = bromo, CF3 = trifluoromethyl, Cl = chloro, Cy = cyano, E
= methylester, Mo = methoxy, and N = nitro. The X-ray data
for all new crystal forms obtained from our polymorph
screening of oNPU, oNHPU, oCF3PU, oCF3HPU, oClPU,
oClHPU, oCyPU, and oCyHPU appear in Table 1. The
previously reported structures include two polymorphs of
oMoPU (refcode: SILTUC, SILTUC01)25 and single struc-
tures of oBrPU (refcode: AQASIV),34 oEPU (refcode:
XULHUJ),35 oIHPU (refcode: AVADIM),36 oAHPU (refcode:
LOYDAG),37 and α-oNPU (refcode: VIRVAV).38 An entry for
oClPU (refcode: QQQAGD)39 lacked 3D coordinates and has
a different unit cell than the one obtained in our work. The X-
ray data for oMoPU, oBrPU, oEPU, oIHPU, oAHPU and α-
oNPU appear in Table S1.
Analysis of the 16 oXPU and oXHPU structures (Tables 1
and S1) reveals a variety of packing motifs, with only one pair
that is isostructural. In an effort to discuss the similarities and
differences across all structures, we sort them into three general
Packing diagrams for the Type I structures appear in Figure
2. All are viewed down the 1D hydrogen bonding axis.
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Figure 2. Type I oPU structures. All packing diagrams are viewed down the short hydrogen bonding axis. Molecules are color coded to reflect the
absolute orientation of the chain. Red chains are oriented with the carbonyl group up; chains colored by atom type are oriented with the amino end
up. View down a-axis: (a) α-oNHPU, (b) β-oNHPU, and (c) oCF3PU. View down b-axis: (d) oClPU, (e) α-oNPU, (f) oAHPU, and (g) oIHPU.
View down c-axis: (h) α-oMoPU, (i) oBrPU, and (j) oCF3HPU.
Molecules are colored to indicate the absolute direction of the
urea chain. Red chains are oriented with the carbonyl group up;
chains colored by atom type are oriented with the amino end
up. In eight of the oPU structures, urea chains adopt an
antiparallel alignment. However, in two cases, α-oNHPU and
oCF3HPU, urea chains align in parallel. A survey of all 1,3-
diphenylurea structures in the CSD shows this packing
arrangement is fairly rare, occurring in only ∼4 other entries.40
The orientation of molecules in these two structures differ
significantly, with the molecules mutually aligned (related by
translation) along one axis in the former and dimer units in the
latter.
None of the eight structures with antiparallel urea chains are
isostructural, though the differences between them are more
subtle and arise from differences in the symmetry elements with
respect to the chain direction (Figure S1). In cases where the
urea chain parallels the a-axis, glide planes and 2-fold rotation
axes run parallel to the chain. When the urea chain parallels the
b-axis, the urea chains intersect glide planes. The structures
with c-axis urea chains have perpendicular 2-fold axes and/or
glide planes that parallel the urea axis. Notably, the three Type I
(c-axis) structures (β-oMoPU, oBrPU, and oCF3HPU) do not
have inversion symmetry.
Structure Type II. The two members of class Type II, (k)
β-oOMePU (SILTUC01) and (l) oClHPU, also form 1D
[C(4)R12(6)] urea chains; however, in both cases, the molecules
rotate about the urea axis (Figures 3 and S2). The unusual
P42/n space group of β-oOMePU (SILTUC01) results in a 90°
rotation of adjacent molecules within the urea chain. Molecules
in the urea chain of oClHPU twist along a 21 screw axis. The
repeat distance along the twisted chain (9.18−9.83 Å) is
roughly double the repeat length observed in Type I oPUs, such
that the urea hydrogen bonding distances in Type I and Type II
are equivalent. In both Type II structures, the adjacent urea
chains are antiparallel for net centrosymmetry.
Structure Type III. The four structures shown in Figure 4,
(m) oEPU, (n) oCyHPU, (o) β-oNPU, and (p) oCyPU, are
classified as Type III. They share two features in common.
First, their torsion angles about the C(O)−N−C−C bonds are
significantly more planar than the other oPUs (see Table 2).
The more planar conformations allow for weak hydrogen C−
H···O interactions between the ortho hydrogen atoms and the
urea carbonyl group. The second common feature is the
D
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additional features of interest. Three of the four nitro groups
are twisted by ∼10° out of the plane of the aromatic ring, the
fourth is twisted out of the plane by ∼24°. This allows
molecules to assemble into nearly planar polar sheets in the
(110) plane, indicating that π−π interactions play an important
role in the overall lattice energy.
With nitrile substituents, the structures of oCyHPU (n) and
oCyPU (p) were unlike any others in this study. oCyHPU
adopts a unique cyclic R22(16) dimer motif formed from two
pairs of hydrogen bonds between the ortho-substituent of one
molecule and the urea NH group of the other. Both bonds
within the dimer have an N···H−N distance of 2.119 Å (N···N,
2.993 Å). The nearly planar dimer pairs form close packed π−π
assemblies in the (101) plane. The most unusual structure
across the entire series of compounds investigated was oCyPU.
Despite its multiple hydrogen bond donors and acceptors, none
are fulfilled. The π−π interactions appear to be dominant, with
face-to-face stacks aligned along the [101] axis. The ability for
both nitro and nitrile substituents to disrupt the formation of
1D urea chains is not entirely surprising, as it was also seen in
polymorphism studies of the meta-substituted diphenylurea
analogues.14,16,41 However, in these previous studies the
hydrogen bond donors and acceptors were satisfied either
partially or fully in all of the polymorphs identified. oCyPU is
truly unusual in that it does not.
Figure 3. Type II oPU structures. Red chains are oriented with the
carbonyl group up; chains colored by atom type are oriented with the
amino end up. (k) β-oMoPU is viewed down the c-axis. (l) oClHPU is
viewed down the a-axis.
Polymorphism. A recent review by Cruz-Cabeza and
Bernstein42 reported that 36% of all polymorphic molecules
exhibit conformational polymorphism. In our previous analyses
of meta-substituted diphenylureas, we were able to identify
conformational polymorphs in some systems16,17,43 but not
others.15 We assumed this would also be the case for oPUs.
Orthorhombic and monoclinic polymorphs of oMoPU were
previously reported by Etter et al.44 Both α- and β-forms exhibit
1D urea chains, though molecules can either be related by
translation (α, Type I) or twisted (β, Type II). A basic solvent
screen was applied to the new oPUs in this study. PXRD and
thermal analysis identified three polymorphic systems: oNPU,
oNHPU, and oCyHPU. This does not preclude the possibility
that other polymorphic systems might be found at some later
date through a more exhaustive survey of crystallization
conditions.
The structure of oNPU, which we now refer to as α, had
been previously reported (refcode: VIRVAV).38 In our
polymorph screen, we obtained this yellow form from multiple
growth solutions, as well as colorless crystals of β-oNPU from
recrystallization in benzene. Not only do α- and β-oNPU have
different hydrogen boding motifs (Type I and III), they have
very different amide torsion angles (see Table 2) and torsions
between the nitro groups and the plane of the aromatic ring. In
α, the nitro out-of-plane torsion angles are 15.8−17.8° and in β
they range from 3.6 to 23.8°. The α- and β-oNHPU forms were
identified by the presence of two endotherms in the DSC of the
initially precipitated material, indicating these crystallize
concomitantly. Recrystallization from assorted solvents yielded
yellow α-needles from acetone and colorless β-needles from
ethanol. Though both α and β adopt Type I motifs, the former
is a polar phase and the latter centrosymmetric. Differences also
exist in both the amide and nitro torsion angles.
Figure 4. Type III oPU structures include (m) oEPU, (n) oCyHPU,
(o) β-oNPU, and (p) oCyPU. The carbonyl group of the urea is
oriented up in molecules colored in red and down in molecules
colored by atom type.
absence of a 1D hydrogen-bonded urea chain. Beyond that, the
four structures differ significantly. Two exhibit intramolecular
bonding between the ortho-substituent and the urea (scheme
(d) in Figure 1), one exhibits intermolecular hydrogen bonding
between ortho-substituents and urea (scheme (c) in Figure 1),
and the fourth oddly exhibits no strong hydrogen bonding at
all.
Intramolecular S(6) bonds between the ortho-substituent
and urea are seen in (m) oEPU and (o) β-oNPU. In oEPU, O···
H−N bonds are 1.918 and 1.961 Å (O···N, 2.659 and 2.677 Å).
β-oNPU has two molecules in the asymmetric unit, and the O···
H−N contacts range between 1.835 and 2.015 Å (O···N,
2.603−2.676 Å). Neither structure exhibits strong intermo-
lecular hydrogen bonding, either between urea groups or
between urea and ortho-substituents. β-oNPU has some
Evidence suggested that oCyHPU is also polymorphic
(Figures 5 and S3). Clear prisms obtained from ethanol melt
at approximately 181 °C. The yellow melt rapidly solidifies to a
polycrystalline material, which begins to melt at 195 °C.
Comparison of the oCyHPU PXRD patterns of the colorless
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Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Article
Figure 5. HSM of oCyHPU prisms showing a phase transition to a second, unidentified polymorph from melt recrystallization.
Figure 6. Overlays of oPU molecular conformations obtained from single crystal structures. Monosubstitued systems are shown in (a): oCyHPU
(purple), oClHPU (green), oCF3HPU (yellow), α-oNHPU (red), and β-oNHPU (blue). Disubstitued systems are shown in (b): β-oNPU (blue),
oCF3PU (orange), oClPU (magenta), and oCyPU (green).
prism and the melt-recrystallized phase show they are clearly
different, though we have so far been unable to obtain high-
quality single crystals of the latter.
anti−anti conformation. The second aromatic ring in the
disubstituted systems was then rotated to achieve a planar syn−
anti conformation (identical to the original anti−syn).
Molecular Conformation. Rotation about the amide bond
allows PUs to adopt multiple conformations. For disubstituted
compounds, these can broadly be described as anti−anti, anti−
syn, and syn−syn based on the relative orientation of the ortho-
substituents with respect to the carbonyl group. Monosub-
stituted compounds can similarly adopt anti or syn
conformations. All the oPU structures were found to adopt
anti−anti or anti conformations, though a range of C(O)−N−
C−C torsion angles is seen. Many have torsions >100°, twisting
the phenyl rings nearly perpendicular to the urea groups. Figure
6 overlays the conformations of oXHPU and oXPUs observed
in single crystals (for specific angles see Table 2).
The crystal structures of PUs bearing meta-substituents show
a much greater range of torsion angles about the urea bond.
The fact that all oPU structures adopted anti−anti/anti
conformations suggested the barrier to free rotation was higher
than in the corresponding meta-substituted PUs. To test this
hypothesis, the conformations of oClPU, oClHPU, and mClPU
monomers with fixed torsion angles were subjected to
geometric optimizations in Gaussian09. The aromatic rings
were initially fixed with C(O)−N−C−C torsion angles of 180/
−180° or an anti−syn conformation. The substituent-bearing
ring was then rotated sequentially in 10° increments toward the
The planar anti−anti/anti conformations of each compound
were found to be lowest in energy, though there are clear
differences in the rotational barrier of the three. All optimized
energies plotted in Figure 7 are relative to the anti−anti/anti
conformation. For oClPU, the planar anti−syn conformation
was highest in energy. Rotation of the ortho-chlorophenyl ring
in oClHPU resulted in a similar trend, yielding an approximate
rotational barrier of ∼15 kcal/mol for each ring. The rotational
barrier in mClPU, initially reported in a previous work,15 was
recalculated here with an improved basis set. The rotational
barrier in mClPU was only one-third that of oClPU and
oClHPU, or ∼5 kcal/mol. Figure 7 also illustrates that while the
anti−anti and anti−syn conformations of mClPU are energeti-
cally similar, this is not the case with oPUs, whose anti−syn
conformations are the highest in energy. The significantly larger
energy difference between syn and anti oPU conformations
affects their relative population in solution and helps to explain
why only anti−anti/anti molecular conformations were
observed in structural studies. Given the wide range of low
energy conformations that is covered by our definition of anti
geometries, it is not clear to what extent, if any, restricted
rotations limit the ability of oPUs to crystallize as conforma-
tional polymorphs.
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Article
Figure 7. Rotational barrier about the amide bond of oClPU, oClHPU, and mClPU. Syn conformations were the highest in energy in oClPU and
oClHPU, which may explain why they are typically not observed in oPUs. In oClPU and oClHPU, syn conformations were the highest in energy,
which may explain why they are typically not observed in oPU systems.
CONCLUSIONS
ASSOCIATED CONTENT
■
■
S
* Supporting Information
The 16 total (nine new) oPU structures analyzed in this study
exhibit an interesting diversity of hydrogen bonding motifs
(urea chains, intramolecular and dimeric motifs), as well as
packing arrangements (polar, nonpolar, and symmetry
relations). All of the molecular conformations observed were
anti−anti/anti, which is consistent with the calculated barrier
for rotation about the amide bond. Four of the 13 systems
analyzed were shown to exhibit polymorphism. Though 13
systems are a relatively small data set, and additional
polymorphs may be found with an expanded screen, it seems
that when substituents can compete with urea as a hydrogen
bond acceptor, oPUs may be generally more likely to crystallize
in multiple forms. It is less clear whether diphenylurea
structures with H-bond donors in ortho-positions are likely
to exhibit polymorphism since so few have been reported. Any
intramolecular hydrogen bonds would require a syn con-
formation, which seems less likely in view of their higher
conformational energies. Intermolecular H-bonding between
substituent H-bond donors and urea acceptors is still possible
with an anti conformation, as is the case for oAPU (LOYDAG).
Restricted amide bond rotation has been suggested to confer
specific advantages in other fields such as in drug binding45,46
and/or stereochemical recognition (atropisomerism).47−49
Notably, a relatively high proportion of oPU structures are
noncentrosymmetric. This observation hints that restricted
conformations, which lock the PUs into a chiral conformation,
may provide a helpful bias toward crystallization in acentric
space groups.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.cgd.7b00757.
Additional PXRD data for oCyHPU (PDF)
Accession Codes
CCDC 1504100−1504106 and 1504132−1504133 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jas2@georgetown.edu.
ORCID
Jennifer A. Swift: 0000-0002-8011-781X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support provided by the
National Science Foundation under awards CHE-1156788
(REU), CHE-0959546 (MRI), and CHE-1337975 (MRI).
M.A.S. thanks the ARCS Foundation for a predoctoral
fellowship. We additionally thank Jeffery Bertke for assistance
with the refinement of oCF3HPU and Maxime Siegler (Johns
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Article
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