Crystal Engineering of N,N′-Diphenylurea Compounds Featuring Phenyl-Perfluorophenyl Interaction

Article abstract of DOI:10.1021/acs.cgd.7b00951

Here, aiming to adopt the phenyl-perfluorophenyl interaction to regulate molecular alignment and arrangement for crystal engineering, we examined and compared in detail the crystal structures of N,N′-diphenylurea compounds 1-6. We found that phenyl-perfluorophenyl interaction greatly influenced the intermolecular arrangement in the crystal, and we were able to prepare a cocrystal of 1 and 2, in which the molecules were alternately arranged under the control of the phenyl-perfluorophenyl interaction. This arrangement was driven by the asymmetric geometry of the hydrogen bonds in the cocrystal (1·2), in which 2, bearing two perfluorophenyl groups, worked as a better hydrogen bond donor. In contrast, NH connected to the phenyl group in 3 proved to be a better hydrogen bond donor due to the intramolecular resonance effect. N,N′-Dimethylated derivatives, 4-6, existed in cis-cis form in the crystal. Antiparallel carbonyl-carbonyl arrangements were observed in 4 and 6, while an unexpected carbonyl-perfluorophenyl interaction was observed in the crystal of 5. These findings will be helpful in the design of diphenylurea-based functional molecules, especially for solid-state application.

Full text of DOI:10.1021/acs.cgd.7b00951

Article
pubs.acs.org/crystal
Crystal Engineering of N,N′‑Diphenylurea Compounds Featuring
Phenyl−Perfluorophenyl Interaction
Ryu Yamasaki,*,† Mana Iida,† Ai Ito,† Kazuo Fukuda,† Aya Tanatani,‡ Hiroyuki Kagechika,§
Hyuma Masu,∥ and Iwao Okamoto†
†Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida, Tokyo 194-8543, Japan
‡Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan
§Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo
101-0062, Japan
∥Center for Analytical Instrumentation, Chiba University, 1-33 Yayoicho, Inage-ku, Chiba 263-8522, Japan
S
* Supporting Information
ABSTRACT: Here, aiming to adopt the phenyl−perfluorophen-
yl interaction to regulate molecular alignment and arrangement
for crystal engineering, we examined and compared in detail the
crystal structures of N,N′-diphenylurea compounds 1−6. We
found that phenyl−perfluorophenyl interaction greatly influenced
the intermolecular arrangement in the crystal, and we were able
to prepare a cocrystal of 1 and 2, in which the molecules were
alternately arranged under the control of the phenyl−perfluor-
ophenyl interaction. This arrangement was driven by the
asymmetric geometry of the hydrogen bonds in the cocrystal
(1·2), in which 2, bearing two perfluorophenyl groups, worked as
a better hydrogen bond donor. In contrast, NH connected to the
phenyl group in 3 proved to be a better hydrogen bond donor
due to the intramolecular resonance effect. N,N′-Dimethylated derivatives, 4−6, existed in cis-cis form in the crystal. Antiparallel
carbonyl−carbonyl arrangements were observed in 4 and 6, while an unexpected carbonyl−perfluorophenyl interaction was
observed in the crystal of 5. These findings will be helpful in the design of diphenylurea-based functional molecules, especially for
solid-state application.
conformation.44−46 This structural feature has been employed
INTRODUCTION
■
to design and create various new functional molecules.47,48
Phenyl−perfluorophenyl interaction is a useful design tool in
crystal engineering and related applications, such as top-
Supramolecular polymers have recently attracted enormous
interest as an emerging class of polymer materials for
ochemical polymerization.1−17 In the 1960s, benzene and
application to electronic and biomedical devices.49−51
A
hexafluorobenzene were found to form a stable complex and
could be cocrystallized in an alternating stacking manner,18 as
confirmed by a high-resolution powder X-ray diffraction
study.19 This interaction is not due to donor−acceptor
interaction, but is mainly due to electrostatic or quadrupole
moment interaction,20 although theoretical calculation indi-
cated that the dispersion energy also contributed.21,22 The
magnitude of interaction was dependent on the substitution of
the phenyl ring, and introduction of electron-donating
substituents on the phenyl ring favored the interaction.23
Compounds containing urea group(s) are important as
gelators,24−28 anion sensors,29−32 catalysts,33 and biologically
active compounds.34−37 Among them, N,N′-diphenylurea forms
a characteristic hydrogen-bond network in the crystal, which
was extensively studied by Etter et al.38−40 and other
groups.41−43 In addition, the N,N′-diphenylurea skeleton has
a unique structural feature, in that N,N′-dimethylation leads to
dramatic conformational switching from trans-trans to cis-cis
supramolecular polymer is defined as “polymeric arrays of
monomeric units that are brought together by reversible and
highly directional secondary interactions, resulting in polymeric
properties in dilute and concentrated solution as well as in the
bulk.”49 A number of compounds have been developed as
monomers for supramolecular polymers, and bis-urea com-
pounds form supramolecular polymers linked by hydrogen
bonds.52−56 However, supramolecular polymers consisting of
an alternating sequence of two different monomers have not yet
received much attention.
In this study, we aimed to investigate the utility of the
phenyl−perfluorophenyl interaction for crystal engineering, to
regulate molecular alignment and arrangement in crystals of a
Received: July 8, 2017
Revised: September 20, 2017
Published: September 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.cgd.7b00951
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Figure 1. Structures of N,N′-diarylurea compounds used in this study.
series of compounds with an N,N′-diphenylurea skeleton
(Figure 1). There has been some previous work on the crystal
structure of compounds bearing phenyl−perfluorophenyl
groups and hydrogen-bonding groups,57−60 but this did not
include compounds with a N,N′-diphenylurea skeleton. In
single crystals of N,N′-diphenylurea compounds, the molecular
arrangement and orientation are controlled by various
interactions. Here, we succeeded in cocrystallizing two different
N,N′-diphenylurea compounds, 1 and 2, with the aid of
hydrogen bonding and phenyl−perfluorophenyl interactions.
We show that phenyl−perfluorophenyl interaction enabled
alternating stacking in cocrystals of 1 and 2, although other
interactions, such as carbonyl−carbonyl and carbonyl−
perfluorophenyl interactions, also played a role.
Scheme 1. Synthesis of 2−6
RESULTS AND DISCUSSION
■
N,N′-Diphenylurea (1) was purchased, and compounds 2−6
were synthesized as shown in Scheme 1. Reaction of 2,3,4,5,6-
pentafluoroaniline with triphosgene afforded N,N′-bis-
(pentafluorophenyl)urea 2 in 91% yield. Unsymmetrical urea
compound, 3, with one phenyl group and one perfluorophenyl
group on the urea nitrogens, was synthesized by reaction of
2,3,4,5,6-pentafluorophenyl isocyanate and aniline. N,N′-
Dimethylation of 1−3 gave compounds 4−6, respectively, in
good yields.
The single-component crystal structures of 1 (CCDC
838624)61,62 and polymorphs of 2 (2a (CCDC 128559)63
and 2b (CCDC 935702)64), have been previously reported,
and the reported structures were used for comparison in this
work. Recrystallization of 3 afforded a suitable crystal for X-ray
crystallographic analysis, and the crystallographic parameters
and solved crystal structure are shown in Table S1 and Figure 2
(thermal ellipsoids in Figure S1). In the crystal structures of 1−
3, all clearly showed the typical 1D chain structure formed by
intermolecular hydrogen bonds between two NH proton
donors and the CO proton acceptor of the adjacent
molecule. The phenyl or perfluorophenyl groups were distorted
from the urea plane with dihedral angles of 27.7−61.8°, and the
two phenyl groups of adjacent molecules were also nonplanar
(Table 1 and Figure 3). Introduction of an N-perfluorophenyl
group, as in 2 (2a and 2b) and 3, resulted in larger dihedral
angles between the aromatic and urea planes (47.4−56.4°) than
those of 1 (27.7° and 41.9°) (Table 1). In particular,
intramolecular aromatic interaction was not apparent in the
crystal structures of 1−3 because of the trans-trans
conformation of the compounds. In the crystal structure of 1,
a T-shaped alignment of intermolecular phenyl groups (edge to
face) was observed with dihedral angles of 74.7° and 66.5°
(Table 2, see Figure 4 for the explanation of values shown in
Table 2). In contrast, the intermolecular interactions of the two
perfluorophenyl groups of 2 were different in the two types of
crystals; in the structure of 2a, one pair of perfluorophenyl
groups was in a face-to-face relationship (2.3°) with very close
contact (3.97 Å), while the groups of the other pair were
directed differently. However, in the structure of 2b, both pairs
of intermolecular perfluorophenyl groups were in parallel
relationships (0.0°) (Figure 3 and Table 2). It is noteworthy
that intermolecular phenyl and perfluorophenyl stacked
alternately and face-to-face (4.9 and 6.8°) at a moderate
centroid distance (4.52 and 4.54 Å) in the crystal of 3 (Figures
2 and 3). Although two independent molecules existed in the
asymmetric unit of the crystal of 3, the structures of the two
molecules are similar in terms of the dihedral angles between
urea and the aromatic planes. Overall, it appears that
B
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that from phenyl moiety, which means perfluorophenyl group
was tilted toward the phenyl moiety so that the F atoms are
directed to the phenyl plane. In addition, 3D assemblies in the
crystal of 3 and 1·2 were characteristic in that phenyl and
perfluorophenyl was separated along other axes, which might be
an interesting feature for further crystal design and engineering
(Figure S6).
The effect of hydrogen bonding and phenyl−perfluorophenyl
interaction was examined in detail by comparing bond lengths
and atom−atom distances related to intermolecular hydrogen
bonds (Table 3 and 4). The CO bond of 1 was lengthened
by hydrogen bond acceptance as a result of cocrystallization
with 2 (from 1.223 to1.239 Å, Table 3). This indicates that 1 in
1·2 is a better hydrogen bond acceptor than 1 in the crystal of 1
alone. Superior hydrogen-bonding ability of 1 in 1·2 is further
supported by the intermolecular hydrogen bond distance; the
distance of N(ArF(C6F5))−H···O(ArH(C6H5)) (2.760 and
2.770 Å) was shorter than that of N(ArH)−H···O(ArF)
(2.822 and 2.923 Å), suggesting that the former pair forms a
stronger hydrogen bond (Table 4). It is reasonable to think that
the urea compound 2 with the strongly electron-withdrawing
perfluorophenyl group would be more acidic and would be the
better hydrogen bond donor. On the other hand, the bonds in
3, especially the N(ArH)−C(O) bond, were unsymmetrical;
N(ArH)−C(O) (1.349 or 1.350 Å) was clearly shorter than
N(ArF)−C(O) (1.374 or 1.375 Å) or even than the
corresponding bond of 1 (1.369 or 1.365 Å) (Table 3). This
might be due to the unsymmetrical resonance structure of 3, as
depicted in Scheme 2; namely, the nitrogen atom attached to
C6H5 makes a larger contribution to the resonance structure
(III). Consequently, the NH proton attached to the phenyl
group seems to be a better hydrogen bond donor than that on
the perfluorophenyl group, and this was supported by the
shorter and more linear hydrogen bond of N(ArH)−H···O(Ar)
(156.2 and 157.1°), compared with N(ArF)−H···O(Ar) (154.0
and 149.5°) (Table 4). The ArH−N bond length was longer
than the ArF−N bond length, which implies the existence of
electron transfer from the nitrogen atom to the electron-
deficient perfluorophenyl group, reducing the contribution of
the resonance structure I in Scheme 2.
Infrared (IR) spectra and melting points of crystal 1, 2, and
1·2 were also measured, and no marked difference was found
between the individual components (1 and 2) and the cocrystal
(1·2). The cocrystal 1·2 exhibited a morphological change at
240 °C (mp of 1) and melted at 270.5 °C (mp of 2). The IR
spectrum (KBr tablet) of 1·2 was not distinguishable from the
superposition of those of the two components (1 and 2).
Overall, the hydrogen bonds governed structure and molecular
coordination, but alignment and bond length were affected by
the introduction of the phenyl−perfluorophenyl pair.
The structures of N,N′-dimethylated N,N′-diphenyl urea
derivatives, compounds 4−6, were also analyzed by crystallog-
raphy and views of the crystal packing are shown in Figure 5. In
the crystal structures of those compounds, the cis-cis conformer,
with two intramolecular aromatic groups located at the face-to-
face position, was observed even for compounds 5 and 6
bearing perfluorophenyl group(s) with two unsymmetrical
molecules in a single unit. Unfortunately, attempts to
cocrystallize 4 and 5 have not been successful to date,
indicating a key role of hydrogen bonding in cocrystallization
of urea compounds. The dihedral angles of the urea plane N−
C(O)−N and the phenyl or perfluorophenyl moiety of 4−6
lay in a narrow range, 67.8−73.1°, but were larger than those of
Figure 2. Views of the structures in crystals 1, 2, 3, and cocrystal (1·2).
Two polymorphs, 2a (CCDC 128559)63 and 2b (CCDC 935702),64
of 2 are shown.
Table 1. Dihedral Angle (deg) of Urea Plane and Phenyl (or
a
Perfluorophenyl) Group Observed in Crystals of 1−3
b
1
2a
2b
3
1(1·2) 2(1•2)
ArH−urea
ArF−urea
41.9
27.7
54.6
56.4
55.8
38.8
47.8
33.5
56.5
58.2
61.8
47.4
37.0
50.5
54.8
30.1
56.2
c
Ar−Ar
35.5
43.9
51.6
39.0
a
b
ArH = phenyl (C6H5), ArF = perfluorophenyl (C6F5). Two
c
asymmetric molecules exist in a single unit. Dihedral angle of two
closely located intramolecular phenyl groups.
introduction of the perfluorophenyl group favored intermo-
lecular aromatic−aromatic interaction, which resulted in
twisting of the urea plane and aromatic ring (vide supra) to
optimize the geometry of the aromatic moiety.
To our delight, cocrystallization of 1 and 2 was successful by
slow evaporation from a 1:1 molar ratio in DMF solution, and
the molecular alignment in this cocrystal, denoted as 1·2, was as
expected from the phenyl−perfluorophenyl interaction;1−23
molecules 1 and 2 in 1·2 were aligned alternately via hydrogen
bonds and phenyl−perfluorophenyl interaction (Figure 2). The
intermolecular phenyl−perfluorophenyl dihedral angle was in
the range of 7.1−7.6°, and the centroid distance was 4.51−4.60
Å, similar to that of 3. These values were close to those of a
benzanilide derivative bearing phenyl and perfluorophenyl
groups in the same molecule (4.54 and 4.78 Å),57 but larger
than those of a cocrystal of C6H5COOH and C6F5COOH
(3.81−3.97 Å).58 The presence of linker moieties (amide or
urea) between the two aromatic groups (phenyl or
perfluorophenyl) and hydrogen bonds would prevent close
contact of the aromatic groups. In fact, phenyl and
perfluorophenyl were displaced by 2.91−3.31 Å for 3 and
2.74−3.44 Å for 1·2, evaluated by the value of r, respectively,
and those values were close to twice that of cocrystal of C6F6−
C6D6 (1.49−1.71 Å) (see Table 2).19 It is noteworthy that in all
phenyl−perfluorophenyl interaction observed 3 and 1·2, the
distance from perfluorophenyl centroid (D) was larger than
C
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Figure 3. Views of hydrogen-bond networks in the crystal structures of 1, 2, 3, and 1·2. (a) Front views. (b) Vertical views.
1−3 (Table 5). Introduction of the methyl groups on urea
nitrogen would tend to tilt the phenyl moiety from the urea
plane. Dihedral angles and centroid distances of the intra-
molecular aromatic group pairs in 4−6 were similar, though a
small decrease in the dihedral angle of 6 was observed, due to
the intramolecular phenyl−perfluorophenyl interaction. It is
noteworthy that intermolecular phenyl−perfluorophenyl stack-
ing was observed in the crystal structure of 6, and the
intermolecular centroid distance of 6 (3.79 and 3.85 Å) was
smaller than that of 3 (4.52 and 4.56 Å) (Figure 6). Absence of
hydrogen bonds in 6 manifested the intermolecular phenyl−
perfluorophenyl interaction, and displacement of phenyl−
perfluorophenyl (r, 0.53−1.67 Å) was close to that of C6F6−
C6D6 rather than that of 3 (Figure 6 and Table 2). In addition,
the phenyl and perfluorophenyl group of 6 in the crystal
assembled separately in 3D images, similarly to that of 3 and 1·
2 (Figure S6). The bond lengths in the crystal structures of 4−
6 are summarized in Table 6. The CO bond was shortened
in 4−6 compared to 1−3 as a result of the lack of hydrogen
bonding. The unsymmetrical resonance effect of the urea bond
observed in 3 was retained in 6, albeit to a lesser extent.
The crystal structures of 4−6 showed characteristic arrange-
ments of the carbonyl group. In the crystal structures of 4 and
6, the carbonyl group of the urea moiety formed an anti-parallel
type dimer. Raines et al. recently suggested that carbonyl-
carbonyl n−π* interaction serves to stabilize protein secondary
structures, such as helix and turn, and protein−ligand
interactions.65−67 The orthogonal geometry that would enable
the n−π* interaction seen in amide or peptide compounds was
not observed in the crystal structures of 4 and 6. The geometry
observed in the crystal structures of ureas 4 and 6 showed
values typical of antiparallel dimers, as judged from a database
study (Figure 7);68 the intermolecular O···C distance was
around 3.5−3.6 Å, and the angle (∠C−O−C) was around 90°.
The carbonyl−carbonyl interaction is weak (ca. ∼5 kcal/mol
based on the calculation),68 and may have been masked in the
crystal structures of 1−3 due to the existence of the dominant
hydrogen bonds. Carbonyl−carbonyl interaction was also not
observed in the crystal structure of 5, which has two
perfluorophenyl groups. On the other hand, an interesting
feature that the carbonyl group was sandwiched by the two
perfluorophenyl groups connected by cis−cis urea architecture
was observed (Figure 8). The feature might manifest the
existence of carbonyl−perfluorophenyl interaction, presumably
derived from the electrostatic interaction similar to n−π*
interaction between hexafluorobenzene and water which was
estimated to stabilize the complex ca. 2−3 kcal/mol based on
the calculation.69−72
D
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Table 2. Dihedral Angles and Distances of Intermolecular
Aromatic−Aromatic Stacking Observed in Crystals 1−3 and
Cocrystal 1·2
Table 4. Distance and Angles Relevant to Hydrogen Bonds
in crystals 1−3 and Cocrystal 1·2
a
b
crystal
H-bond
D/Å
θ/°
N(ArH)−H···O(ArH)
2.772
2.896
2.798
2.929
2.850
2.825
2.811
2.813
2.829
2.833
2.822
2.923
2.760
2.770
155.4
145.3
154.0
146.8
152.2
154.1
156.2
157.1
154.0
149.5
156.5
148.5
152.3
153.8
planar angle
(deg)
centroid distance
1
b
b
(D) (Å)
d (Å)
r (Å)
N(ArF)−H···O(ArF)
N(ArF)−H···O(ArF)
N(ArH)−H···O(Ar)
N(ArF)−H···O(Ar)
N(ArH)−H···O(ArF)
1
74.7
66.5
2.3
5.38
5.12
3.97
6.84
4.58
4.58
4.52
2a
2b
3
2a
2b
2.3
0.0
0.0
c
3
4.9
3.46,
3.21
2.91,
3.19
6.8
4.9
6.8
7.6
7.1
7.6
7.1
4.7
4.54
4.57
4.55
4.59
4.51
4.52
4.60
3.76
3.45,
3.14
2.95,
3.28
1·2
3.45,
3.19
2.99,
3.27
N(ArF)−H···O(ArH)
3.43,
3.12
2.99,
3.31
a
b
Distance between N−O. θ = ∠N−H−O.
1·2
3.52,
3.11
2.95,
3.38
Scheme 2. Resonance Structures of Urea Bond in 3
3.53,
3.19
2.85,
3.19
3.59,
3.21
2.74,
3.18
3.43,
3.05
3.07,
3.44
a
C6F6−C6D6
3.45,
3.35
1.49,
1.71
a
Calculated with the structure reported in ref 19 (CCDC 1110270).
D, d, and r indicate the distance as in the Figure 4. Two values were
b
carbonyl, and carbonyl−perfluorophenyl interactions. Phenyl−
perfluorophenyl interaction was particularly important for the
control of the molecular arrangement of these diphenylurea
derivatives. However, the stronger intermolecular interaction,
hydrogen bonds, played the major role to decide the geometry
of the urea compounds. The hydrogen bonds of cocrystal of 1
and 2 (1·2) were characteristic: urea worked as a hydrogen
bond donor with perfluorophenyl compound 2, but as a
hydrogen bond acceptor with phenyl compound 1. In contrast,
the NH proton attached phenyl nitrogen seemed to be a
stronger hydrogen bond donor than the NH proton attached to
perfluorophenyl, due to the unsymmetrical resonance structure.
In the crystal structures of 4−6, where no hydrogen bond is
involved and cis-cis conformation of the urea skeleton is
observed, antiparallel type carbonyl-carbonyl interaction was
seen in 4 and 6, and carbonyl−perfluorophenyl interaction in 5.
This new type of carbonyl−perfluorophenyl interaction
resembles the anion−π interaction in catalytic systems,73,74
and might be applicable for the design of novel catalysts for
asymmetrical reactions as a new oxyanion hole motif. Even
though, these interactions, phenyl−perfluorophenyl, carbonyl-
carbonyl, and carbonyl−perfluorophenyl interactions, contrib-
shown for distances from the centroid of C6F5 and C6H5, in this order.
Two asymmetric molecules exist in a single unit.
c
Figure 4. Schematic presentation of planar angle, centroid distance
(D), and d.
CONCLUSION
■
We examined and compared the crystal structures of N,N′-
diphenylurea compounds 1−6 in detail in order to acquire
insight into the relative importance of the various interactions,
such as hydrogen bonding, phenyl−perfluorophenyl, carbonyl−
Table 3. Bond Lengths (Å) Observed in Crystals 1−3 and Cocrystal 1·2
1
2a
2b
3
1(1·2)
2(1·2)
ArH−N
1.419(6)
1.426(2)
1.429(2)
1.350(2)
1.421(2)
ArF−N
1.405(3)
1.406(2)
1.401(2)
N(ArH)−C(O)
N(ArF)−C(O)
CO
1.369(5)
1.223(4)
1.365(6)
1.418(6)
1.349(2)
1.358(2)
1.239(2)
1.357(2)
1.424(2)
1.359(3)
1.225(3)
1.357(3)
1.365(2)
1.232(3)
1.368(3)
1.365(2)
1.225(2)
1.371(2)
1.237(2)
1.374(2)
1.236(2)
1.375(2)
N(ArF)−C(O)
N(ArH)−C(O)
ArF−N
1.390(3)
1.406(2)
1.404(2)
1.405(2)
1.407(2)
ArH−N
E
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Figure 5. Views of the crystal structures of 4−6.
Table 5. Dihedral Angle (deg) of Urea Plane (N−C(O)−
N) and Phenyl (or Perfluorophenyl) Group and
Intramolecular Phenyl−Phenyl (or Perfluorophenyl)
Centroid Distance (Å) Observed in Crystals of 4−6
4
5a
5b
6a
6b
ArH−Urea
ArF−Urea
71.6
67.5
67.3
67.8
70.3
70.3
73.1
73.1
71.7
70.7
Figure 7. Carbonyl−carbonyl interactions observed in the crystal
structures of 4 and 6.
Ar−Ar
angle (deg)
34.6
35.9
36.0
26.7
31.4
distance (Å)
3.87
3.52
3.74
3.69
3.76
Figure 6. Views of intermolecular stacking structures of phenyl−
perfluorophenyl rings in the crystal structure of 6. Dihedral angle and
centroid distance are shown. Hydrogen atoms are omitted for clarity.
For explanation of D and r values (Å), see Figure 4.
ute subtly in energy, it would be nonnegligible to predict
molecular arraignment in crystalline state.
Figure 8. Carbonyl−perfluorophenyl interactions observed in the
crystal structure of 5.
Table 6. Bond Length (Å) Observed in Crystals of 4−6
4
5a
5b
6a
6b
ArH−N
1.431(2)
1.435(2)
1.436(2)
ArF−N
1.418(2)
1.474(2)
1.415(2)
1.474(2)
N−CH3
1.466(2)
1.376(2)
1.463(2)
1.372(2)
1.467(2)
1.380(2)
N(ArH)−C(O)
N(ArF)−C(O)
CO
1.379(2)
1.220(2)
1.379(2)
1.383(2)
1.219(2)
1.383(2)
1.227(1)
1.219(2)
1.392(2)
1.219(2)
1.385(2)
N(ArF)−C(O)
N(ArH)−C(O)
N−CH3
1.383(1)
1.464(2)
1.474(2)
1.418(2)
1.474(2)
1.415(2)
1.466(2)
1.413(2)
1.465(2)
1.410(2)
ArF−N
ArH−N
1.433(1)
F
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General Procedure for N-Methylation of Ureas 1−3 to
Afford N,N′-Dimethylated Ureas (4−6). To a suspension of NaH
(60% oil suspension, 450 mg, 11.3 mmol; washed twice with n-hexane
and dried) in DMF (5 mL) was added 1 (955 mg, 4.50 mmol) in
DMF (6 mL) in an ice bath. The reaction mixture was stirred for 15
min, then CH3I (0.84 mL, 13.5 mmol) was added on the ice bath.
After additional stirring for 24 h, the mixture was diluted with diethyl
ether (250 mL), washed with sat. NH4Cl aq. (700 mL) and brine (20
mL), dried over Na2SO4, filtered, and evaporated in vacuo to afford a
colorless powder (867 mg, 80%). The crude product was further
purified by recrystallization from diethyl ether to afford colorless
prisms. Analytical data were in good accordance with reported
values.77
Our findings here should be helpful to predict and control
the molecular arrangement of urea compounds, and to create
new functional molecules in the context of supramolecular
polymers consisting of alternating sequences of two different
monomers.
EXPERIMENTAL SECTION
■
General Information. All reagents and solvents were obtained
from commercial suppliers and were used as received. Melting points
were determined by using a Yanaco melting point apparatus MP-S3
and are uncorrected. FT-IR spectra were recorded on a Horiba FT-
710. 1H, 13C, and 19F NMR spectra were recorded on a JEOL AL-300
or BRUKER AV-300, or AV-600, and chemical shifts are expressed in
parts per million relative to benzotrifluoride (C6H5CF3 at −63.72 ppm
for 19F) or residual solvent peak (2.49 ppm (1H), 39.5 ppm (13C) for
DMSO-d6 and 7.26 ppm (1H), 77.0 ppm (13C) for CDCl3). Mass
spectra were measured on a JEOL MS700 V or HX110. Silica gel
[silica gel 40−50 μm neutral (Kanto Chemical Co., Inc.)] was used for
all chromatographic procedures.
N,N′-Dimethyl-N,N′-bis(pentafluorophenyl)urea (5). Synthesized
according to the general procedure. mp 107.5−108.0 °C; IR (KBr)
2952, 1672, 1529, 1495, 1439, 1352, 1227, 1147, 1107, 1053, 1014,
1
989, 930, 837, 783, 739, 707, 660, 548 cm−1; H NMR (300 MHz,
CDCl3) δ 3.16 (3H, s); 13C NMR (150 MHz, CDCl3) δ 158.5, 143.3
(m), 140.3 (m), 137.6 (m), 119.1 (m), 38.0; 19F NMR (282 MHz,
CDCl3) δ −147.3, −155.5, −161.9; HRMS (EI+) m/z: [M]+ Calcd for
C15H6F10N2O 420.0315; Found 420.0312.
Single Crystal X-ray Diffraction. Variable-temperature single-
crystal X-ray diffraction experiments were carried out on an Rigaku R-
AXIS Rapid II (graphite-monochromated Cu Kα radiation, λ = 1.541
Å). Crystals were mounted on MiTeGen dual-thickness MicroMounts
using parabar oil. Data collections were carried out at low temperature
(93−102 K) using liquid nitrogen. The crystal structures were solved
by direct methods using SHELXS-201375 (for crystals of 3, 5, and 1·2)
or SIR201176 (for crystals of 4 and 6). All non-hydrogen atoms were
refined with anisotropic displacement parameters. Some hydrogen
atoms of urea groups (in crystals of 3 and 1·2) were refined
isotropically. Other hydrogen atoms were included at their calculated
positions. Crystallographic refinement details are summarized in Table
S1 (CCDC 1560994−1560998). Structure analysis was performed
with Mercury ver. 3.9 (CCDC) programs.
N,N′-Dimethyl-N-(pentafluorophenyl)-N′-phenylurea (6). Synthe-
sized according to the general procedure, except that THF was used as
the reaction solvent instead of DMF. Recrystallization from diethyl
ether afforded colorless prisms. mp 94.5−95.0 °C; IR (KBr) 2941,
1678, 1595, 1518, 1498, 1429, 1352, 1302, 1209, 1117, 1078, 1049,
989, 891, 773, 748, 700, 658, 579 cm−1; 1H NMR (300 MHz, CDCl3)
δ 7.17 (2H, t, J = 7.5 Hz), 7.06 (1H, t, J = 7.5 Hz), 6.89 (2H, d, J = 7.5
Hz), 3.26 (3H, s), 3.14 (3H, s); 13C NMR (150 MHz, CDCl3) δ
158.9, 143.5 (m), 139.6 (m), 137.4 (m), 129.2, 126.0, 124.9, 120.1
(m), 39.7, 37.8; 19F NMR (282 MHz, CDCl3) δ −146.9, −158.3, −
164.7; HRMS (EI+) m/z: [M]+ Calcd for C15H11F5N2O 330.0786;
Found 330.0768.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.cgd.7b00951.
■
Synthesis of 1,3-Bis(pentafluorophenyl)urea (2). To 2,3,4,5,6-
pentafluoroaniline (1.83 g, 10.0 mmol) in a 100 mL two-necked flask
filled with argon was added triphosgene (0.53 g, 1.7 mmol) in 1,2-
dichloroethane (20 mL) and triethylamine (2.8 mL, 20 mmol). The
mixture was refluxed for 2 h at 98 °C, then cooled to rt, diluted with
CH2Cl2 (130 mL), and washed with 10% HCl (60 mL) and brine. A
colorless precipitate formed on standing for 12 h, and was collected by
suction. The crude product was recrystallized from CH3OH afforded a
colorless powder (1.79 g, 91%). mp 270.0−270.5 °C; IR (KBr) 3342,
3022, 2924, 1648, 1587, 1533, 1498, 1466, 1329, 1273, 1236, 1190,
S
1
ORTEP drawing images of 3D assemblies; copies of H,
13C and 19F NMR spectra of the compounds (PDF)
Accession Codes
CCDC 1560994−1560998 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing 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.
1
1155, 1076, 1030, 976, 739, 710 cm−1; H NMR (300 MHz, DMSO-
d6) δ 9.04 (2H, brs, -NH); 13C NMR (150 MHz, DMSO-d6) δ 152.0,
143.1 (m), 138.8 (m), 137.2 (m), 113.6; 19F NMR (282 MHz,
DMSO-d6) δ −148.9, −161.2, −166.4; HRMS (EI+) m/z: [M]+ Calcd
for C13H2F10N2O 392.0002; Found 391.9997.
Synthesis of N-(Pentafluorophenyl)-N′-phenylurea (3). To a
solution of aniline (300 μL, 3.29 mmol) in diethyl ether (3 mL) was
added pentafluorophenyl isocyanate (0.43 mL, 3.29 mmol) in diethyl
ether in an ice bath. The reaction mixture was warmed to room
temperature and stirred for 2 h. The resulting colorless precipitate was
collected by suction to afford the title compound (741 mg, 74%). This
compound was purified by recrystallization from CH3OH to afford
colorless needles. mp 225.0−230.0 °C; IR (KBr) 3293, 1645, 1595,
1570, 1525, 1502, 1327, 1292, 1265, 1228, 1059, 1012, 978, 858, 825,
756, 694, 551 cm−1; 1H NMR (300 MHz, DMSO-d6) δ 9.07 (1H, brs,
-NH), 8.48 (1H, brs, -NH), 7.43 (2H, dd, J = 8.1, 1.2 Hz), 7.28 (2H, t,
J = 8.1 Hz), 6.99 (2H, tt, J = 8.1, 1.2 Hz); 13C NMR (150 MHz,
DMSO-d6) δ 151.9, 142.9 (m), 139.2, 138.6 (m), 137.2 (m), 128.8,
122.4, 118.4, 114.0 (m); 19F NMR (282 MHz, DMSO-d6) δ −149.0, −
162.3, −166.7; HRMS (EI+) m/z: [M]+ Calcd for C13H7F5N2O
302.0473; Found 302.0476.
AUTHOR INFORMATION
Corresponding Author
*Tel: (+81)-42-721-1570. Fax: (+81)-42-721-1570. E-mail:
yamaryu@ac.shoyaku.ac.jp.
■
ORCID
Ryu Yamasaki: 0000-0002-8976-2962
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank Mr. Chiba (Showa Pharmaceutical University) for
HR-MS measurement.
■
REFERENCES
Cocrystallization of 1 and 2. A solution of 1 in DMF was added
to a solution of 2 in DMF to give a 1:1 molar ratio. The precipitate
after slow evaporation was collected by suction to afford the cocrystals
as colorless needles.
■
(1) Pace, C. J.; Gao, J. Acc. Chem. Res. 2013, 46, 907−915.
(2) Reichenbacher, K.; Suss, H. I.; Hulliger, J. Chem. Soc. Rev. 2005,
̈
̈
34, 22−30.
G
DOI: 10.1021/acs.cgd.7b00951
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
(3) Sharber, S. A.; Baral, R. N.; Frausto, F.; Haas, T. E.; Muller, P.;
(36) Drewe, W. C.; Nanjunda, R.; Gunaratnam, M.; Beltran, M.;
Parkinson, G. N.; Reszka, A. P.; Wilson, W. D.; Neidle, S. J. Med.
Chem. 2008, 51, 7751−7767.
̈
Thomas, S. W., III J. Am. Chem. Soc. 2017, 139, 5164−5174.
(4) Pawle, R. H.; Haas, T. E.; Muller, P.; Thomas, S. W., III Chem.
̈
(37) Shantz, E. M.; Steward, F. C. J. Am. Chem. Soc. 1955, 77, 6351−
6353.
Sci. 2014, 5, 4184−4188.
(5) Hsu, S.-M.; Lin, Y.-C.; Chang, J.-W.; Liu, Y.-H.; Lin, H.-C. Angew.
Chem., Int. Ed. 2014, 53, 1921−1927.
(38) Etter, M. C. Acc. Chem. Res. 1990, 23, 120−126.
(39) Etter, M. C.; Urbanczyk-Lipkowska, Z.; Zia-Ebrahimi, M.;
Panunto, T. W. J. Am. Chem. Soc. 1990, 112, 8415−8426.
(40) Etter, M. C.; Panunto, T. W. J. Am. Chem. Soc. 1988, 110,
5896−5897.
(41) Politzer, P.; Murray, J. S. Cryst. Growth Des. 2015, 15, 3767−
3774.
(42) Custelcean, R. Chem. Commun. 2008, 295−307.
(43) Chang, Y.-L.; West, M.-A.; Fowler, F. W.; Lauher, J. W. J. Am.
Chem. Soc. 1993, 115, 5991−6000.
(44) Galan, J. F.; Germany, E.; Pawlowski, A.; Strickland, L.;
Galinato, M. G. J. Phys. Chem. A 2014, 118, 5304−5315.
(45) Clayden, J.; Hennecke, U.; Vincent, M. A.; Hillier, I. H.;
Helliwell, M. Phys. Chem. Chem. Phys. 2010, 12, 15056−15064.
(46) Yamaguchi, K.; Matsumura, G.; Kagechika, H.; Azumaya, I.; Ito,
Y.; Itai, A.; Shudo, K. J. Am. Chem. Soc. 1991, 113, 5474−5475.
(47) Kagechika, H.; Azumaya, I.; Tanatani, A.; Yamaguchi, K.; Shudo,
K. Tetrahedron Lett. 1999, 40, 3423−3426.
(48) Fukutomi, R.; Tanatani, A.; Kakuta, H.; Tomioka, N.; Itai, A.;
Hashimoto, Y.; Shudo, K.; Kagechika, H. Tetrahedron Lett. 1998, 39,
6475−6478.
(49) Yang, L.; Tan, X.; Wang, Z.; Zhang, X. Chem. Rev. 2015, 115,
7196−7239.
(6) Ryan, D. M.; Doran, T. M.; Nilsson, B. L. Langmuir 2011, 27,
11145−11156.
(7) Xu, R.; Schweizer, W. B.; Frauenrath, H. Chem. - Eur. J. 2009, 15,
9105−9116.
(8) Xu, R.; Schweizer, W. B.; Frauenrath, H. J. Am. Chem. Soc. 2008,
130, 11437−11445.
(9) Rasmusson, T.; Martyn, L. J. P.; Chen, G.; Lough, A.; Oh, M.;
Yudin, A. K. Angew. Chem., Int. Ed. 2008, 47, 7009−7012.
(10) Mu, Z.; Shu, L.; Fuchs, H.; Mayor, M.; Chi, L. J. Am. Chem. Soc.
2008, 130, 10840−10841.
(11) Kishikawa, K.; Oda, K.; Aikyo, S.; Kohmoto, S. Angew. Chem.,
Int. Ed. 2007, 46, 764−768.
(12) Shu, L.; Mu, Z.; Fuchs, H.; Chi, L.; Mayor, M. Chem. Commun.
2006, 1862−1863.
(13) Watt, S. W.; Dai, C.; Scott, A. J.; Burke, J. M.; Thomas, R. L.;
Collings, J. C.; Viney, C.; Clegg, W.; Marder, T. B. Angew. Chem., Int.
Ed. 2004, 43, 3061−3063.
(14) Vangala, V. R.; Nangia, A.; Lynch, V. M. Chem. Commun. 2002,
1304−1305.
(15) Ponzini, F.; Zagha, R.; Hardcastle, K.; Siegel, J. S. Angew. Chem.,
Int. Ed. 2000, 39, 2323−2325.
(16) Blanchard, M. D.; Hughes, R. P.; Concolino, T. E.; Rheingold,
A. L. Chem. Mater. 2000, 12, 1604−1610.
(50) Aida, T.; Meijer, E. W.; Stupp, S. I. Science 2012, 335, 813−817.
(51) De Greef, T. F. A.; Smulders, M. M. J.; Wolffs, M.; Schenning,
A. P. H. J.; Sijbesma, R. P.; Meijer, E. W. Chem. Rev. 2009, 109, 5687−
5754.
(52) Brocorens, P.; Linares, M.; Guyard-Duhayon, C.; Guillot, R.;
Andrioletti, B.; Suhr, D.; Isare, B.; Lazzaroni, R.; Bouteiller, L. J. Phys.
Chem. B 2013, 117, 5379−5386.
(17) Coates, G. W.; Dunn, A. R.; Henling, L. M.; Ziller, J. W.;
Lobkovsky, E. B.; Grubbs, R. H. J. Am. Chem. Soc. 1998, 120, 3641−
3649.
(18) Patrick, C. R.; Prosser, G. S. Nature 1960, 187, 1021.
(19) Williams, J. H.; Cockcroft, J. K.; Fitch, A. N. Angew. Chem., Int.
Ed. Engl. 1992, 31, 1655−1657.
(20) Williams, J. H. Acc. Chem. Res. 1993, 26, 593−598.
(21) Ehrlich, S.; Moellmann, J.; Grimme, S. Acc. Chem. Res. 2013, 46,
916−926.
(22) Tsuzuki, S.; Uchimaru, T.; Mikami, M. J. Phys. Chem. A 2006,
110, 2027−2033.
(23) Adams, H.; Jimenez Blanco, J.-L.; Chessari, G.; Hunter, C. A.;
Low, C. M. R.; Sanderson, J. M.; Vinter, J. G. Chem. - Eur. J. 2001, 7,
3494−3503.
(24) Yamanaka, M.; Fujii, H. J. Org. Chem. 2009, 74, 5390−5394.
(25) Schoonbeek, F. S.; van Esch, J. H.; Hulst, R.; Kellogg, R. M.;
Feringa, B. L. Chem. - Eur. J. 2000, 6, 2633−2643.
(26) van Gorp, J. J.; Vekemans, J. A. J. M.; Meijer, E. W. J. Am. Chem.
Soc. 2002, 124, 14759−14769.
(53) Isare, B.; Pembouong, G.; Boue,
2012, 28, 7535−7541.
́
F.; Bouteiller, L. Langmuir
(54) Simic, V.; Bouteiller, L.; Jalabert, M. J. Am. Chem. Soc. 2003,
125, 13148−13154.
(55) Lortie, F.; Boileau, S.; Bouteiller, L. Chem. - Eur. J. 2003, 9,
3008−3014.
(56) Boileau, S.; Bouteiller, L.; Laupret
2000, 24, 845−848.
̂
re, F.; Lortie, F. New J. Chem.
(57) Wang, J. L.; Xu, J. S.; Wang, D. Y.; Wang, H.; Li, Z. T.; Zhang,
D.-W. CrystEngComm 2014, 16, 2078−2084.
(58) Reddy, L. S.; Nangia, A.; Lynch, V. M. Cryst. Growth Des. 2004,
4, 89−94.
(59) Meejoo, S.; Kariuki, B. M.; Harris, K. D. M. ChemPhysChem
2003, 4, 766−769.
(60) Gdaniec, M.; Jankowski, W.; Milewska, M. J.; Połonski, T.
̃
(27) Schoonbeek, F. S.; van Esch, J. H.; Wegewijs, B.; Rep, D. B. A.;
de Haas, M. P.; Klapwijk, T. M.; Kellogg, R. M.; Feringa, B. L. Angew.
Chem., Int. Ed. 1999, 38, 1393−1397.
Angew. Chem., Int. Ed. 2003, 42, 3903−3906.
(61) Uehara, K.; Mizuno, N. J. Am. Chem. Soc. 2011, 133, 1622−
1625.
(28) van Esch, J.; De Feyter, S.; Kellogg, R. M.; De Schryver, F.;
Feringa, B. L. Chem. - Eur. J. 1997, 3, 1238−1243.
(29) Diemer, V.; Fischer, L.; Kauffmann, B.; Guichard, G. Chem. -
Eur. J. 2016, 22, 15684−15692.
(62) Dinesh, R.; Deshmukh, M. B.; Kamni; Rajnikant. Bull. Mater. Sci.
2006, 29, 239−242.
(63) Jai-nhuknan, J.; Karipides, A. G.; Hughes, J. M.; Cantrell, J. S.
Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 1997, 53, 455−457.
(64) Okuno, T. Acta Crystallogr., Sect. E: Struct. Rep. Online 2013, 69,
o608.
(30) Custelcean, R.; Jiang, D.; Hay, B. P.; Luo, W.; Gu, B. Cryst.
Growth Des. 2008, 8, 1909−1915.
(31) Caltagirone, C.; Hiscock, J. R.; Hursthouse, M. B.; Light, M. E.;
Gale, P. A. Chem. - Eur. J. 2008, 14, 10236−10243.
(65) Bartlett, G. J.; Choudhary, A.; Raines, R. T.; Woolfson, D. N.
Nat. Chem. Biol. 2010, 6, 615−620.
(66) Choudhary, A.; Gandla, D.; Krow, G. R.; Raines, R. T. J. Am.
Chem. Soc. 2009, 131, 7244−7246.
(67) Bretscher, L. E.; Jenkins, C. L.; Taylor, K. M.; DeRider, M. L.;
Raines, R. T. J. Am. Chem. Soc. 2001, 123, 777−778.
(68) Allen, F. H.; Baalham, C. A.; Lommerse, J. P. M.; Raithby, P. R.
Acta Crystallogr., Sect. B: Struct. Sci. 1998, 54, 320−329.
(69) Singh, S. K.; Das, A. Phys. Chem. Chem. Phys. 2015, 17, 9596−
9612.
́
(32) Boiocchi, M.; Del Boca, L.; Gomez, D. E.; Fabbrizzi, L.;
Licchelli, M.; Monzani, E. J. Am. Chem. Soc. 2004, 126, 16507−16514.
(33) Connon, S. J. Synlett 2009, 2009, 354−376.
(34) Solinas, A.; Faure, H.; Roudaut, H.; Traiffort, E.; Schoenfelder,
A.; Mann, A.; Manetti, F.; Taddei, M.; Ruat, M. J. Med. Chem. 2012,
55, 1559−1571.
(35) Muller, S.; Pantos,
Chem. Commun. 2009, 80−82.
̧
G. D.; Rodriguez, R.; Balasubramanian, S.
̈
H
DOI: 10.1021/acs.cgd.7b00951
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
Article
(70) Egli, M.; Sarkhel, S. Acc. Chem. Res. 2007, 40, 197−205.
(71) Jain, A.; Purohit, C. S.; Verma, S.; Sankararamakrishnan, R. J.
Phys. Chem. B 2007, 111, 8680−8683.
(72) Gallivan, J. P.; Dougherty, D. A. Org. Lett. 1999, 1, 103−105.
(73) Zhao, Y.; Cotelle, Y.; Sakai, N.; Matile, S. J. Am. Chem. Soc.
2016, 138, 4270−4277.
(74) Zhao, Y.; Cotelle, Y.; Avestro, A.-J.; Sakai, N.; Matile, S. J. Am.
Chem. Soc. 2015, 137, 11582−11585.
(75) Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr.
2008, 64, 112−122.
(76) Camalli, M.; Carrozzini, B.; Cascarano, G. L.; Giacovazzo, C. J.
Appl. Crystallogr. 2012, 45, 351−356.
(77) Wakita, Y.; Kobayashi, Y.; Maeda, M.; Kojima, M. Chem. Pharm.
Bull. 1982, 30, 3395−3398.
I
DOI: 10.1021/acs.cgd.7b00951
Cryst. Growth Des. XXXX, XXX, XXX−XXX