A robust thiourea synthon for crystal engineering

Article abstract of DOI:10.1021/cg100589n

Crystallographic characterization of a series of bis-thiourea derivatives derived from N,N′-bis(3-aminopropyl)piperazine revealed a highly conserved intramolecular hydrogen bonding pattern, with intramolecular S(6) [or, in one case, S(8)] hydrogen bonding

Full text of DOI:10.1021/cg100589n

DOI: 10.1021/cg100589n
A Robust Thiourea Synthon for Crystal Engineering
2010, Vol. 10
3757–3762
Kathryn Paisner, Lev N. Zakharov, and Kenneth M. Doxsee*
Department of Chemistry, University of Oregon, Eugene, Oregon 97403
Received May 3, 2010; Revised Manuscript Received May 21, 2010
ABSTRACT: Crystallographic characterization of a series of bis-thiourea derivatives derived from N,N0-bis(3-aminopropyl)-
piperazine revealed a highly conserved intramolecular hydrogen bonding pattern, with intramolecular S(6) [or, in one case, S(8)]
hydrogen bonding interactions between each heterocyclic nitrogen atom and one proton of the adjacent propylthioureido substituent.
These intramolecular hydrogen-bonding interactions lend an overall spiral-like structure to the molecules, rather reminiscent of the
form of a spiral galaxy. These monomeric units assemble into infinite chains via the formation of intermolecular R22(8) cyclic thiourea
dimers, with the exception of a phenyl derivative, which crystallized as a monomeric bis(dimethyl sulfoxide) solvate. The S(6) intra-
molecular hydrogen bond motif was maintained in the phenylthioureido derivatives of both N-(3-aminopropyl)morpholine and 3,30-
diamino-N-methyl-dipropylamine. The robustness of the “spiral galaxy” motif and its apparent ability to direct intermolecular
interactions suggest its potential utility as a useful new synthon for solid-state design.
Scheme 1. Conformations of N,N0-Disubstituted Thioureas6
Introduction
While the solid-state behavior of urea derivatives is reason-
ably well-understood,1,2 allowing exploitation for a variety of
increasingly sophisticated chemical applications,3,4 develop-
ment of a comparable level of understanding of the factors dic-
tating the solid-state structures of substituted thioureas has
remained more elusive.5 As a likely consequence of the more
pronounced conformational pliability of the thioureas, for
which both s-cis and s-trans geometries are frequently encoun-
Scheme 2. Thioureas Derived from N,N0-Bis(3-amino-
propyl)piperazine
tered (Scheme 1),6 solid-state trends are more tenuous than for
the conformationally less adaptable ureas, and few reliable
solid-state “synthons” have been established.5,7 Nevertheless,
the strong hydrogen-bonding ability of thioureas has shown
utility in areas ranging from anion complexation8-11 and organo-
catalytic synthesis12-15 to nonlinear optics,16 and we believe that
improving our understanding of and control over the solid-
state behavior of thioureas will lend greater utility to this very
promising functional group in the development of new materials
with predictable, designed structures and properties.
The identification of reliable solid-state structural motifs is
central to our effort to establish control over the solid-state struc-
ture of substituted thioureas. In a crystallographic survey of tris-
thiourea derivatives derived from tris(2-aminoethyl)amine,17
through which we documented striking structural diversity
critically dependent on seemingly small changes in molecular
structure, a lead was established for a reliable, solid-state feature.
Amidst a highly variable set of molecular conformations and
inter- and intramolecular hydrogen-bonding interactions, dona-
tion of an intramolecular hydrogen bond from one of the
thiourea groups to the central, tertiary nitrogen, resulting in a
five-membered ring, was ubiquitous. While this S(5) motif18
appeared to contribute little to the overall solid-state organiza-
tion of this particular group of thioureas, its invariable presence
suggested further examination of compounds designed to facil-
itate this type of intramolecular interaction.
we felt that extension of the connecting “tether” could fur-
ther enhance this interaction by allowing for more optimal
orientation of the hydrogen-bond donating and accepting
groups. With this in mind, we chose to examine thio-
ureas prepared from N,N0-bis(3-aminopropyl)piperazine
(Scheme 2) as candidates for solid-state investigation, with
these bis-thiourea systems being of additional interest in that
the flexibility of the piperazine ring could, we felt, lead to the
formation of dimeric structures similar to those reported
earlier by us19 and others.20
While the tris(2-aminoethyl)amine derived thioureas al-
lowed for rather efficient intramolecular hydrogen-bonding,
*To whom correspondence should be addressed. Phone: (541) 346-2846.
E-mail: doxsee@uoregon.edu.
r
2010 American Chemical Society
Published on Web 06/10/2010
pubs.acs.org/crystal

3758 Crystal Growth & Design, Vol. 10, No. 8, 2010
Paisner et al.
In contrast to the great diversity of solid-state structures
found for the tris-thiourea derivatives, these bis-thiourea deri-
vatives derived from N,N0-bis(3-aminopropyl)piperazine dis-
played startlingly similar structures, seemingly regardless of the
nature of the pendant “R” groups. As we discuss below, the bis-
thiourea derivatives (1a-f) adopt conformations allowing both
“arms” to form hydrogen bonds to the central piperazine
moiety, leading to molecular structures reminiscent of a “spiral
galaxy.” Herein, we report the synthesis and solid-state struc-
tural analysis of these thioureas, and, for comparison, an
acyclic version and a single-armed morpholine analogue. Given
the predictable formation of solid-state structures in these
systems, and in the face of the current dearth of reliable thiourea
synthons, we believe that this “spiral galaxy” motif will provide
significant assistance to the efforts of those engaged in crystal
engineering with these intriguing and useful molecules.
the crude product as a powdery-white solid (crude yield 100%). An
analytical sample was prepared by crystallization from hot acetone,
yielding colorless, octahedral crystals with an average diameter
of 2.5-5.0 mm, which were washed with acetone and air-dried.
Recrystallization from either acetone or a mixture of acetonitrile
and water afforded crystals suitable for single crystal X-ray diffrac-
tion analysis, mp 126-127 °C. IR (KBr): νmax 3162 (NH), 1529
1
(CdS) cm-1; H NMR (CDCl3, 300 MHz): δ 7.62 (bs, 1H, NH),
7.44 (t, 2H, CH), 7.30 (t, 1H, CH), 7.23 (d, 2H, CH), 3.81 (bs, 2H),
3.24 (bs, 4H), 2.39 (m, 2H), 2.27 (bs, 4H), 1.75 (m, 2H); 13C NMR
(CDCl3, 75.156 MHz): δ 180.7 (CdS), 137.5 (CH), 130.6 (CH),
127.3 (CH), 125.3 (CH), 66.8 (O-CH2), 59.8 (N-CH2), 54.2
(N-CH2), 46.6 (N-CH2), 24.9 (CH2). Anal. Calcd for C14H21
-
N3OS: C, 60.18; H, 7.58; N, 15.04; O, 5.73; S, 11.48; found: C, 60.35;
H, 7.46; N, 15.02; S, 11.28; O, 5.89 (by difference).
Preparation ofN,N0-Bis[3-(N-phenylthioureido)propyl]-N00-methyl-
amine (3). Following the procedure used for 2, treatment of N,N0-
bis(3-aminopropyl)methylamine with phenyl isothiocyanate pro-
vided 3 in quantitative yield. Colorless crystals, suitable for single
crystal X-ray diffraction analysis, were grown from dichloroethane/
hexanes. An analytical sample was prepared by recrystallization from
acetone; the powdery-white solid was washed with acetone and
allowed to air-dry overnight, mp 138-140 °C. IR (KBr): νmax 3391,
3161 (NH), 1534 (CdS) cm-1; 1H NMR (CDCl3, 300 MHz): δ 8.10
(bs, 2H, NH), 7.38 (t, 4H), 7.21 (m, 8H), 3.55 (q, 4H), 2.18 (t, 4H), 1.44
(m, 4H); 13C NMR (CDCl3, 75.156 MHz): δ 180.2 (CdS), 136.7 (CH),
130.0 (CH), 126.9 (CH), 125.4 (CH), 56.3 (N-CH2), 45.5 (N-CH2),
41.9 (N-CH3), 25.4 (CH2). Anal. Calcd for C21H29N5S2: C, 60.69; H,
7.03; N, 16.85; S, 15.43; found: C, 60.56; H, 6.84; N, 16.67; S, 15.15.
Structure Determination. X-ray diffraction data were collected on
a Bruker Smart Apex diffractometer at 173(2) K using MoKR
Experimental Section
General. All reagents were used as purchased, from Aldrich or
TCI, without further purification. Tetrahydrofuran (THF) was
dried with molecular sieves before use; all other solvents were
technical-grade and used as received. Representative procedures
and partial characterizations are presented here; full experimental
details and characterization for all new compounds are provided as
Supporting Information.
Preparation of N,N0-Bis[3-(N00-isopropylthioureido)propyl]pipera-
zine (1c). Isopropyl isothiocyanate (0.52 mL, 0.0048 mol) was added
to a solution of N,N0-bis(3-aminopropyl)piperazine (0.50 mL, 0.0024
mol) in THF (10 mL) at room temperature. The mixture was stirred
overnight, and then the solvent was removed on a rotary evaporator,
providing the crude product as a powdery-white solid (crude yield
radiation (λ = 0.71073 A).21 Absorption corrections were applied
˚
by SADABS.22 Structures were solved using direct methods com-
pleted by subsequent difference Fourier syntheses, and refined by
full matrix least-squares procedures on F2. All non-H atoms were
refined with anisotropic thermal parameters. For all compounds
except 1a, the H atoms were found on the residual density maps and
refined with isotropic thermal parameters. For compound 1a, the H
atoms involved in H-bonds were found on the residual density map
and refined with isotropic thermal parameters, while the other H
atoms were treated in calculated positions. The crystallographic
data and some details of data collection, solution, and refinement of
the crystal structures are given in Table 1. All calculations were
performed using the SHELXTL 6.10 package.23
1
100%). H NMR analysis revealed no impurities other than residual
solvent, and an analytical sample was prepared simply by triturating a
small amount of the crude product with methylene chloride (in which it
has only limited solubility), isolation of the solid by filtration, and
drying in vacuo for approximately 96 h. Recrystallization from a
mixture of ethanol and hexanes afforded crystals suitable for single
crystal X-ray diffraction analysis, mp 151-153 °C. IR (KBr): νmax 3224
(NH), 1558 (CdS) cm-1; 1H NMR (DMSO-d6, 300 MHz): δ 7.38 (bs,
2H, NH), 7.29 (d, 2H, NH), 4.35 (bs, 2H), 3.47 (bs, 4H), 2.46 (m, 12H),
1.75 (m, 4H), 1.24 (d, 12H); 13C NMR (DMSO-d6, 75.156 MHz): δ
180.8 (CdS), 55.4 (N-CH2), 52.7 (N-CH2), 44.8 (N-CH2), 41.8
(N-CH2), 25.9 (CH), 22.3 (CH3). Anal. Calcd for C18H38N6S2: C,
53.69; H, 9.51; N, 20.87; S, 15.93; found: C, 53.79; H, 9.19; N, 20.68; S,
16.34 (by difference).
Preparation of N,N0-Bis[3-(N-benzylthioureido)propyl]piperazine
(1f). Benzyl isothiocyanate (1.29 mL, 0.0096 mol) was added to a
solution of N,N0-bis(3-aminopropyl)piperazine (1.00 mL, 0.0048 mol)
in THF (15 mL), at room temperature. The mixture was stirred
overnight, and then the solvent was removed on a rotary evaporator,
providing the crude product as a powdery-white solid (crude yield
100%). 1H NMR analysis revealed no impurities other than residual
solvent, and an analytical sample was prepared simply by triturating a
small amount of the crude product with methylene chloride (in which it
has only limited solubility), isolation of the solid by filtration, and
drying in vacuo for approximately 96 h. Recrystallization from a
mixture of ethanol and water afforded crystals suitable for single
crystal X-ray diffraction analysis, mp 147-148 °C. IR (KBr): νmax
3238 (NH), 1527 (CdS) cm-1;1HNMR(DMSO-d6, 300 MHz): δ7.85
(bs, 2H, NH), 7.48 (bs, 2H, NH), 7.29 (m, 10H), 4.65 (bs, 4H), 3.35 (bs,
4H), 2.25 (m, 12H), 1.61 (m, 4H); 13C NMR (DMSO-d6, 75.156 MHz):
δ 183.0 (CdS), 140.2 (C), 128.9 (CH), 127.9 (CH), 127.5 (CH), 55.9
(N-CH2), 53.4 (N-CH2), 47.7 (N-CH2), 42.6 (N-CH2), 26.7
(CH2). Anal. Calcd for C26H38N6S2: C, 62.61; H, 7.68; N, 16.85; S,
12.86; found: C, 62.77; H, 7.65; N, 16.82; S, 12.76 (by difference).
Preparation of N-[3-(N0-Phenylthioureido)propyl]morpholine (2).
Phenyl isothiocyanate (0.84 mL, 0.0071 mol) was added to a
solution of N-(3-aminopropyl)morpholine (1.00 mL, 0.0071 mol)
in THF, at room temperature. The mixture was stirred overnight,
and then the solvent was removed on a rotary evaporator, providing
Results and Discussion
The piperazine-derived bis-thioureas are prepared by treat-
ment of N,N0-bis(3-aminopropyl)piperazine with two equiva-
lents of the desired isothocyanate and may be obtained in
quantitative yield and high purity simply by evaporation of
the reaction solvent. Each of the bis-thioureas is highly
crystalline, and recrystallization easily affords samples suita-
ble for single crystal X-ray structural analysis.
Despite the propensity of thioureas to display significant
solid-state conformational variability, N,N0-bis(3-aminopropyl)-
piperazine derivatives (1a-e) uniformly form essentially iden-
tical S(6) intramolecular hydrogen bonds,18 illustrated by the
representative molecular structures of 1a and 1b (Figure 1).
The six-membered rings formed through these intramole-
cular hydrogen bonds, roughly perpendicular to the plane
defined by the piperazine ring (Figure 2 and Table 2), appear
relatively strain-free, as evidenced by the three nicely stag-
gered methylene units, which are essentially superimposable
on a portion of a chair-form cyclohexane ring.
The length of the intramolecular N H contact increases
3 3 3
in proportion to the relative size of the substituent (Table 2),
while no obvious trend is apparent in either the N-H bond
length or in the N H-N angle. Interestingly, even the
3 3 3
tert-butyl-substituted thiourea 1d forms this intramolecular

Article
Crystal Growth & Design, Vol. 10, No. 8, 2010 3759
Table 1. Crystal Data and Details of Structure Determination for Bisthioureas 1a-f, 2, and 3
parameter
1a
1b
1c
1d
1e
1f
2
3
formula
formula wt
habit
C18H38N6S2
402.665
plate
C22H46N6S2
458.771
block
C18H38N6S2
402.665
block
C20H42N6S2
430.718
plate
C28H46N6O2S4 C26H38N6S2
C14H21N3OS C21H29N5S2
279.40
block
626.964
needle
0.42 ꢀ
498.750
block
415.61
block
size (mm)
0.38 ꢀ
0.28 ꢀ
0.38 ꢀ
0.35 ꢀ
0.34 ꢀ
0.40 ꢀ
0.32 ꢀ
0.16 ꢀ 0.02
0.23 ꢀ 0.08
0.35 ꢀ 0.24
0.18 ꢀ 0.06
0.06 ꢀ 0.05
0.17 ꢀ 0.08
0.29 ꢀ 0.18
0.26 ꢀ 0.17
T (K)
Xtl system
space grp
173(2)
triclinic
P1
173(2)
triclinic
P1
173(2)
monoclinic
P21/n
173(2)
triclinic
P1
173(2)
monoclinic
P21/c
173(2)
triclinic
P1
173(2)
monoclinic
P21/n
173(2)
monoclinic
P21/c
˚
a (A)
7.9711(6)
8.9324(6)
9.7837(7)
69.193(1)
66.872(1)
65.622(1)
567.79(7)
1, 0.5
7.5087(9)
9.4482(12)
9.4581(12)
85.891(2)
76.883(2)
82.603(2)
647.42(14)
1, 0.5
11.6092(12)
14.2683(15)
13.8136(15)
90
102.133(1)
90
2237.0(4)
4, 1
0.253
8.5296(9)
8.9162(10)
9.0911(10)
64.991(1)
88.749(2)
71.490(1)
589.05(11)
1, 0.5
6.3651(4)
27.4003(17)
9.8447(6)
90
108.800(1)
90
1625.37(17)
2, 0.5
0.327
7.8621(8)
8.9516(9)
10.6574(11)
71.844(2)
75.928(2)
68.330(2)
655.33(12)
1, 0.5
9.4941(8)
15.9450(13)
10.5815(8)
90
7.5140(7)
16.7692(15)
18.0518(17)
90
˚
b (A)
˚
c (A)
R (deg)
β (deg)
γ (deg)
110.839(1)
90
92.693(1)
90
3
˚
volume (A )
0
1497.1(2)
4, 1
0.213
2272.1(4)
4, 1
0.250
Z, Zh
μ (mm-1
)
0.249
0.226
0.244
0.230
reflections
measured
ind reflns
5522 [Rint
0.0198]
2000
=
7305 [Rint
0.0230]
2800
=
24732 [Rint
0.0337]
4886
=
6814 [Rint
0.0295]
2549
=
10083 [Rint
0.0345]
3498
=
7381 [Rint
0.0202]
2842
=
17175 [Rint
0.0310]
3275
=
26099 [Rint
0.0361]
4971
=
reflns/restraints/
parameters
R, wR (%)
(I > 2σ(I))
GOF
2000/0/126
5.57, 14.42
1.07
2800/0/228
3.88, 9.64
1.05
4886/0/387
2549/0/211
3.99, 9.85
1.01
3498/0/273
2842/0/230
3275/0/256
4971/0/369
3.36, 9.07
1.05
3.97, 8.76
1.05
3.59, 9.51
1.01
4.10, 10.89
1.027
3.67, 9.34
1.046
max/min resid
˚
density (e A
0.698/-0.247 0.284/-0.152 0.310/-0.185 0.347/-0.178 0.335/-0.232
0.363/-0.156 0.518/-0.292 0.292/-0.181
-3
)
Figure 1. Molecular structures of 1a and 1b, showing intramolecular hydrogen bonds.
N,N0-dialkylthioureas could be controlled by the bulkiness of
the two alkyl substituents. In that work, an N-tert-butyl-N0-
ethylthiourea adopted the trans, trans conformation;as
did all other N-tert-butyl thioureas, if the N0 substituent was
bulkier than a simple methyl group;and not the trans, cis
conformation found in thiourea 1d.
The benzyl derivative (1f) displays a solid-state structure
that superficially closely resembles that of compounds 1a-e
(Figure 3). However, closer examination reveals a funda-
mental difference - it is the more remote thiourea NH group
that donates the hydrogen bond to the piperazine nitrogen in
this derivative, forming an eight-membered S(8) ring rather
than the six-membered S(6) ring seen for each of the other
derivatives. Interestingly, this variation in intramolecular
hydrogen bonding is accommodated with surprisingly little
perturbation of the gross molecular structure, as compari-
son of Figures 1 and 3 attests. More quantitatively, the
intramolecular hydrogen-bonding data for 1f presented in
Table 2 largely parallel the data for compounds 1a-e,
differing primarily in a slightly shorter hydrogen bond and,
Figure 2. Least-squares planes through the piperazine ring and one
of the hydrogen-bonded ring in 1a.
˚
hydrogen-bond, although it is considerably longer (2.32 A).
This can be contrasted to the observations of Custelcean et al.,7
who reported that the solid-state conformation of certain
more noticeably, in the N H-N angle, which, given the
3 3 3

3760 Crystal Growth & Design, Vol. 10, No. 8, 2010
Paisner et al.
larger hydrogen-bonding ring size, is able to more closely
approach linearity (164°).
distances leading to the average of 2.62 reported in Table 2) to
˚
2.73 A, and demonstrates no apparent correlation with sub-
stituent size (Table 2).
Interchain interactions are limited to rather long aliphatic
Equally independent of significant substituent effects, the
intermolecular contacts of thioureas 1a-d and 1f are also
surprisingly similar. (The phenyl derivative, 1e, crystallized as
a DMSO solvate, thus changing dramatically the nature of the
solid-state packing. This derivative is discussed separately
below.) Because the formation of the “spiral galaxy” motif
forces both thiourea moieties into the trans,cis conformation,
withthetransN-H participatinginintramolecularhydrogen-
bonding, the sulfur atom and the cis N-H are ideally located
to form an eight-membered cyclic R22(8) dimer18 with a
neighboring molecule, a common solid-state thiourea struc-
tural motif. In thioureas 1a-d and 1f, the formation of this
cyclic dimer on each face of the molecule results in long chains
of identically configured molecules (Figure 4a), which pack in
H-H and H-S contacts (e.g., the S atom of n-pentyl deriva-
tive 1b is 3.00 A from one of the piperazine H atoms) and
˚
appeartobecompletelyabsent in the t-butyl derivative, 1d, for
˚
which the closest H-H “contact,” at 2.50 A, is between a t-Bu
methyl group and the central methylene of one of the tethering
C3 groups. The Kitaigorodski packing indices24,25 for these
compounds (Table 2), calculated using the PLATON pro-
gram, also appear to highlight the great overall structural
similarity among the various derivatives, increasing slightly
with increasing size of the R group.
The phenyl derivative, compound 1e, crystallized from a
mixture of DMSO and ethyl acetate as a bis(DMSO) solvate,
in which molecules of 1e are present not as hydrogen-bonded
chains, but rather as isolated individual molecules, with the
two s-cis thiourea groups each “capped” by a hydrogen-
bonded DMSO molecule (Figure 5). The contact between
the DMSO oxygen atom and the thiourea hydrogen atom is
a parallel arrangement (Figure 4b,c). The S H(N) contact
3 3 3
˚
in these structures ranges from 2.61 A (the lowest of the two
˚
quite short, at 2.01 A, and the thiourea sulfur atom and a rela-
tively acidic R-proton on the DMSO molecule, at a distance of
2.98 A, also appear to be engaged in a somewhat weaker
˚
hydrogen-bonding interaction.26,27
Although not depicted in Figure 5, each DMSO oxygen
atomalso interactswiththe modestly acidic28 aromatic hydro-
gen ortho to the thiourea moiety on a neighboring molecule of
˚
1e (distance 2.58 A), a type of hydrogen bonding that has been
observed in both proteins and small organic molecules.28-30
Each thiourea sulfur atom also falls within weak hydrogen-
bonding distance of the para hydrogen on an adjacent mole-
˚
cule (distance 2.94 A). Compound 1e displays negligible solu-
bility in all solvents examinedexcept the polar aprotic DMSO,
DMF, and N-methylpyrrolidinone, and even in these, it dis-
plays only sparing solubility at elevated temperatures. Should
it prove possible to crystallize 1e from a less strongly hydro-
gen-bonding solvent, we would anticipate it to adopt the
general structure displayed by 1a-d (Figure 4), and we are
continuing our efforts to confirm this expectation.
Figure 3. Molecular structures of 1f, showing intramolecular
hydrogen bonds.
Table 2. Selected Structural Data for Bisthioureas 1a-f, 2, and 3
parameter
substituent
1a
1b
1ca
1d
1e
1f
2
3
n-propyl
n-pentyl
i-propyl
t-butyl
phenyl
benzyl
Intramolecular H-Bonding
˚
N
N
N (A)
2.911(3)
2.18(3)
0.87(3)
142(3)
88.37
2.929(2)
2.22(2)
0.83(2)
143(2)
87.81
2.94(1)
2.25(3)
0.83(1)
141(3)
89.30
3.009(2)
2.32(2)
0.88(2)
135(2)
87.23
3.011(2)
2.49(2)
0.79(2)
125(2)
71.72
2.946(2)
2.14(2)
0.82(2)
164(2)
73.43
2.925(2)
2.27(2)
0.82(2)
138(2)
87.45
2.813(2)
2.08(2)
0.86(2)
142(2)
3 3 3
3 3 3
˚
H (A)
N-H (A)
N H-N (deg)
interplanar angle (deg)
˚
3 3 3
Intermolecular R22(8) H-Bonding
2.48(5)a
0.86(2)a
165(2)a
163.28a
8.52a
˚
H (A)
N-H (A)
S
2.65(3)
0.83(3)
163(3)
145.10
21.57
2.69(2)
0.81(2)
164(2)
126.82
42.16
2.62(1)
0.83(2)
163(2)
156.70
19.42
2.73(2)
0.80(2)
170(2)
174.51
7.49
2.65(2)
0.81(2)
165(2)
158.51
31.31
2.54(2)
0.80(2)
166(2)
169.88
13.42
3 3 3
˚
S
S
S
H-N (deg)
3 3 3
3 3 3
3 3 3
H-N-CS (deg)
H-N-C (deg)
Thiourea Unit
2.42
179.00
H-N-CdS (deg) (cis)
11.84
13.81
9.62
175.85
5.13
3.63
8.77
12.68/9.93b
H-N-CdS (deg) (trans)
CdS (A)
173.28
1.692(3)
1.340(3)
1.340(3)
66.2
166.22
1.700(2)
1.337(2)
1.340(2)
67.5
176.52
1.696(2)
1.355(2)
1.336(2)
67.9
171.93
1.703(2)
1.345(2)
1.338(2)
68.6
166.37
1.698(2)
1.348(2)
1.330(2)
66.6
170.49/178.51b
1.703(2)/1.688(2)b
1.360(2)/1.352(2)b
1.319(2)/1.330(2)b
65.0
˚
1.702(3)
1.34(1)
1.34(1)
66.9
1.702(2)
1.350(2)
1.342(2)
69.0
˚
C-N (A) (cis)
˚
C-N (A) (trans)
packing index
a Average of values for the two symmetry-inequivalent functional groups. b Thiourea unit engaged in intramolecular H-bonding/thiourea unit
engaged only in intermolecular H-bonding.

Article
Crystal Growth & Design, Vol. 10, No. 8, 2010 3761
Figure 4. (a) Infinite chain of cyclic dimers of 1a; (b) side view of infinite chains (three individual hydrogen-bonded chains in red, blue, and
green for clarity); (c) end view of rows of infinite chains (two individual hydrogen-bonded chains in red and blue for clarity).
Figure 7. (a) Molecular and (b) crystal structure of 3, showing
Figure 5. Molecular structures of 1e, showing intramolecular hy-
drogen bonds and hydrogen-bonded DMSO solvates.
intra- and intermolecular hydrogen bonds.
bond was highly “conserved,” we extended our investigation to
other compounds offering the potential for formation of a six-
membered, intramolecular hydrogen-bonding contact. Most
generally, this simply requires a tertiary amine31 separated from
the thiourea by a three-carbon alkyl chain.
Compound 2 (Figure 6a) was prepared from N-(3-amino-
propyl)morpholine and phenyl isothiocyanate. Unlike 1e,
morpholine derivative 2 was reasonably soluble in conven-
tional organic solvents and was easily recrystallized from
acetone or aqueous acetonitrile. Single crystal X-ray diffrac-
tion analysis revealed that 2 behaved exactly as expected
(Figure 6b), displaying both the six-membered, intramolecu-
lar contact and the eight-membered intermolecular cyclic
dimer seen in compounds 1a-d and 1f.
Figure 6. (a) Molecular and (b) crystal structure of 2, showing
intra- and intermolecular hydrogen bonds.
˚
The intramolecular N H contact in 2, at 2.27 A, is
3 3 3
˚
significantly shorter than that observed in 1e, 2.49 A, despite
the similar structure of these compounds. This shorter con-
tact may either be allowed by or result from a twisting of the
Given the overwhelming consistency of the “spiral galaxy”
motif among the bis-thiourea derivatives of N,N0-bis(3-amino-
propyl)piperazine, in which the intramolecular S(6) hydrogen

3762 Crystal Growth & Design, Vol. 10, No. 8, 2010
Paisner et al.
phenyl substituent in 2 away from the face of the morpholine
ring (19.4° angle between two least-squares planes), whereas
in 1e, the phenyl substituent is almost perfectly parallel to the
face ofthepiperazine ring, witha torsion angle of only4.1°. As
in 1a-d and 1f, 2 forms an eight-membered cyclic R22(8) dimer
with an adjacent thiourea (Figure 6b and Table 2). Because the
morpholine ring possesses only a single thiourea-containing
“arm,” only discrete dimers are formed rather than the infinite
chains depicted in Figure 4. However, relatively short inter-
molecular contacts are evident between the morpholine oxy-
gen and two methylene hydrogen atoms on a neighboring
Supporting Information Available: Additional experimental de-
tails, full characterization, and X-ray crystallographic information
files (CIF) are available for compounds 1a-f, 2, and 3. This
information is available free of charge via the Internet at http://
pubs.acs.org.
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Conclusion
We have discovered a new, solid-state structural motif, the
“spiral galaxy,” common among all reported thioureas de-
rived from N,N0-bis(3-aminopropyl)piperazine. We have also
demonstrated that the robustness of this synthon extends to
other thioureas that possess the requisite structural character-
istics: a three-carbon chain, separating an N-substituted
thiourea moiety and a tertiary amine. The “spiral galaxy”
motif alsoappears todirect intermolecularhydrogenbonding,
at least in the N,N0-bis[3-(N00-substitutedthioureido)propyl]-
piperazine compounds examined in this paper. We are con-
tinuing to examine the generality of the “spiral galaxy” motif
in directing intermolecular hydrogen bonding and, conse-
quently, crystal packing in a diverse array of thioureas, in
order to explore its use as a synthetic building block in solid-
state design.