Study of the sulfur atom as hydrogen bond acceptor in N(2)-pyridylmethyl- N′-arylthioureas

Article abstract of DOI:10.1023/B:JOCC.0000042022.16392.99

The hydrogen acceptor capability of the sulfur atom in the biologically relevant N-2-pyridylmethyl-N′-arilthioureas was explored. N-2-Pyridylmethyl thioreas were selected to avoid the formation of intramolecular six-membered hydrogen-bonded ring. The comp

Full text of DOI:10.1023/B:JOCC.0000042022.16392.99

Journal of Chemical Crystallography, Vol. 34, No. 8, August 2004 (ꢀC 2004)
Study of the sulfur atom as hydrogen bond acceptor
in N(2)-pyridylmethyl-Nꢀ-arylthioureas
Jesu´s Valde´s-Mart´ınez,(1),∗ Simo´n Herna´ndez-Ortega,(1) Manuel Rubio,(1)
Dung T. Li,(2) John K. Swearingen,(2) Werner Kaminsky,(3)
Diantha R. Kelman,(3) and Douglas X. West(3)
Received May 3, 2004
The hydrogen acceptor capability of the sulfur atom in the biologically relevant N-2-
pyridylmethyl-Nꢁ-arilthioureas was explored. N-2-Pyridylmethyl thioreas were selected
to avoid the formation of intramolecular six-membered hydrogen-bonded ring. The
compounds studied were N-2-pyridylmethyl-Nꢁ-phenylthiourea (1), N-2-pyridylmethyl-
Nꢁ-2-methoxythiourea (2), N-2-pyridylmethyl-Nꢁ-4-methoxyphenylthiourea (3), and
N-2-pyridylmethyl-Nꢁ-4-bromophenylthiourea (4). 1 crystallizes in the monoclinic space
◦
˚
˚
˚
group P21/c, with a = 7.419(1) A, b = 18.437(2) A, c = 9.656(1) A, β = 106.277(6) ,
3
˚
V = 1267.8(3) A , Z = 4. 2 crystallizes in the monoclinic space group P21/c, with
◦
3
˚
˚
˚
˚
a = 8.064(2) A, b = 18.382(7) A, c = 9.865(5) A, β = 97.81(3) , V = 1448.8(11) A ,
˚
Z = 4. 3 crystallizes in the monoclinic space group P21/c, with a = 11.472(1) A,
◦
3
˚
˚
˚
b = 13.520(1) A, c = 10.088(1) A, β = 112.60(1) , V = 1444.5(2) A , Z = 4. 4
˚
˚
crystallizes in the triclinic space group P-1, with a = 4.583(3) A, b = 10.263(3) A,
◦
◦
◦
3
˚
˚
c = 14.396(3) A, α = 77.92(2) , β = 88.55(4) , γ = 80.02(4) , V = 652.1(5) A ,
Z = 2. Both thiourea N H groups form intermolecular hydrogen bonds, one with the
thione sulfur atom and the other with the pyridine nitrogen atom but the H-bonding
schemes are not the same maybe due to the flexibility of the molecules.
KEY WORDS: S · · · H hydrogen bonding; thioureas; crystal engineering.
Introduction
rich acceptors, usually oxygen or nitrogen atoms.
However, the study of the S · · · H interaction
An important part of crystal engineering is
may have fundamental importance in biochem-
ical research due to the fact that living sys-
tems contain several important sulfur-containing
molecules, such as the amino acids cysteine and
methionine.2 Although S atoms are week ac-
ceptors, and for this reason less studied, a re-
cent report by Allen showed that the S atom
in R1R2C S systems is an effective acceptor
when R1 and R2 can form an extended delocal-
ized system with C S. Examples of molecules
showing this delocalization are thioureas and
thiosemicarbazones.3
the study of intermolecular interactions.1 These
studies have centered mainly in the interaction
between good hydrogen donors and electron-
(1) Instituto de Qu´ımica, Universidad Nacional Auto´noma de Me´xico,
Circuito Exterior s/n, Ciudad Universitaria, Coyoaca´n 04510,
Ciudad de Me´xico D.F., Me´xico.
(2) Department of Chemistry, Illinois State University, Normal,
Illinois.
(3) Department of Chemistry 351700, University of Washington,
Seattle, Washington.
∗ To whom correspondence should be addressed; e-mail: jvaldes@
servidor.unam.mx.
533
ꢀ
C
1074-1542/04/0800-0533/0 2004 Springer Science+Business Media, Inc.

534 Valde´s-Mart´ınez, Herna´ndez-Ortega, Rubio, Li, Swearingen, Kaminsky, Kelman, and West
Related to the biological relevance of S · · · H
interactions, Uckum and coworkers reported re-
cently a structural study of a series of thiourea
compounds.4 The interest in the study of these
compounds respond to the identification, by ra-
tional drug design, of phenylyethylthioureas as
potent nucleoside inhibitors of human immun-
odeficiency virus-1 reverse transcriptase, and
the possibility to open, through solid-state stud-
ies, new doors for explaining the interaction of
biomolecules such as important proteins toward
small molecule drug candidates.5–10
A number of structural studies of N-2-
pyridyl-Nꢁ-arylthioureas have been reported.11–23
These compounds present an intramolecular
NꢁH · · · N hydrogen bond, as well as NH hydro-
gen bonding with a sulfur atom of a neighbor-
ing molecule to form centrosymmetric dimers, as
shown in Fig. 1. The lone exception to the latter
type of hydrogen bonding are the N-2-(3-picolyl)-
Nꢁ-arylthioureas, which have a very weak inter-
action, if any, due to the steric hindrance of the
methyl group in the pyridine ring.18,22
bond rules, which indicate that if six-membered
ring intramolecular hydrogen bonds can form,
they will usually do so in preference to form-
ing intermolecular hydrogen bonds.25 Another
rule states that the best proton donors and ac-
ceptors remaining after intramolecular hydrogen-
bond formation form intermolecular hydrogen
bonds to one another. In the N-2-pyridyl- and
N-2-pyridylethyl-Nꢁ-arylthioureas studied the re-
maining best proton donors and acceptors are
the N H and the sulfur atom, respectively. If
there were no intramolecular hydrogen bond the
best hydrogen-bond donor and the best hydrogen-
bond acceptor would preferentially form hydro-
gen bonds to one another, and the second-best
donor will form a hydrogen bond to the second-
best acceptor etc.,26 and if a repeating pattern
is observed, it would be possible to rank, as
a hydrogen acceptor, the thiourea S atom with
respect to the pyridine nitrogen atom or other
acceptors.
To contribute to the understanding of the
S · · · H interactions we decided to synthesize
compounds that will avoid the intramolecular
Inarecentreportofthecrystalstructureof N-
2-pyridylethyl-Nꢁ-arylthioureas a different inter-
molecular six-membered ring, between NꢁH and
the pyridyl nitrogenatom, wasobservedinthree of
the five structures studied. The expected N H in-
termolecular hydrogen bond to a sulfur atom was
also present.24
The intramolecular H-bond observed in these
compounds is in agreement with Etter’s hydrogen
Fig. 1. Intra- and intermolecular hydrogen bonding in
N-2-picolyl-Nꢁ-tolylthioureas.
Fig. 2. Representation of compounds 1–4.

Study of the NNꢀC S · · · H hydrogen bond
535
groups. Through this paper N and Nꢁ will be
used to differentiate the two nitrogen atoms in the
thiourea moiety according to the N-2-pyridyl-Nꢁ-
arylthioureas nomenclature, as shown in Fig. 2.
six-memberedhydrogenbondedringandfavorthe
formation of intermolecular H-bonds, allowing in
this way the competition of the two H-donors
(NH and NꢁH) for the two acceptor (S and N). To
do so, we propose the use of N-2-pyridylmethyl-
Nꢁ-arilthiourea instead of the N-2-pyridy- or N-
2-pyridylethyl-Nꢁ-arilthiourea. In this paper we
report a structural study of four such thioureas:
N-2-pyridylmethyl-Nꢁ-phenylthiourea, 1; N-2-
pyridylmethyl-Nꢁ-2-methoxythiourea, 2; N-2-
pyridylmethyl-Nꢁ-4-methoxyphenylthiourea, 3;
and 2-pyridylmethyl-Nꢁ-4-bromophenylthiourea,
4. Theoretical calculations were done to evalu-
ate, through their partial charges, the H-acceptor
capability of the S and pyridine N atoms and
Experimental
The isothiocyanates and 2-aminomethyl-
pyridine were purchased from Aldrich and
used as received. The desired aryl isothio-
cyanate was mixed in a 1:1 molar ratio with 2-
aminomethylpyridine in anhydrous EtOH, and the
resulting mixture gently refluxed for a minimum
of 1 hr. The thioureas precipitate from solution
on cooling and slowly evaporating the reactant
mixture. The solids were filtered, washed with
the H-donor capability of the N H and Nꢁ
H
Table 1. Crystallographic Data and Methods of Data Collection, Solution, and Refinement for 1–4
Crystal data
1
2
3
4
Empirical formula
Color, habit
Crystal size (mm)
Crystal system
Space group
C13H13N3S
Colorless, prism
0.40 × 0.26 × 0.24
Monoclinic
P21/c
C14H15N3OS
Colorless, prism
0.25 × 0.20 × 0.12
Monoclinic
P21/c
C14H15N3OS
Colorless, prism
0.29 × 0.26 × 0.24
Monoclinic
P21/c
C13H12BrN3S
Colorless, prism
0.30 × 0.20 × 0.12
Triclinic
P-1
˚
a, A
7.419(1)
18.437(2)
9.656(1)
8.064(2)
18.382(7)
9.865(5)
90
97.81(3)
90(0)
11.472(1)
13.520(1)
10.088(1)
90
112.60(1)
90
4.583(3)
˚
b, A
10.263(3)
14.396(3)
77.92(2)
88.55(4)
80.02(4)
˚
c, A
α,◦
β,◦
γ ,◦
90
106.277(6)
90
1267.8(3)
4
3
˚
Volume, A
1448.8(11)
4
1444.5(2)
4
652.1(5)
2
Z
Formula weight
d (calcd.), g/cm3
Abs. coeff., mm−1
F(000)
243.32
1.275
0.236
512
273.36
1.253
0.219
576
273.56
1.257
0.220
576
322.2
1.641
0.330
324
Index ranges
−1 ≤ h ≤ 10
−1 ≤ k ≤ 25
−13 ≤ l ≤ 13
2.21–30.0
4733
3701, 0.0464
analytical
0.9455 & 0.9115
3701/161
0.865
0 ≤ h ≤ 10
0 ≤ k ≤ 23
−12 ≤ l ≤ 12
2.21–27.39
2417
2104, 0.0240
ψ-scan
1.000 & 0.822
2417/221
1.063
−14 ≤ h ≤ 14
−16 ≤ k ≤ 15
−12 ≤ l ≤ 12
3.72–24.71
2412
1428, 0.0414
HKL-SCALEPACK
0.9491 & 0.9390
2412/179
1.037
0 ≤ h ≤ 5
−13 ≤ k ≤ 13
−18 ≤ l ≤ 18
1.44–27.41
2957
2367, 0.0084
ψ-scan
1.000 & 0.924
2957/211
1.213
θ range,◦
Refls. collected
Ind. refls., Rint
Abs. correct.
Max. & min. trans.
Data/parameters
Goodness-of-fit
−3
˚
˚
Lgst. diff. peak, e A−3
0.230
0.353
0.233
0.524
Lgst. diff. hole, e A
−0.224
−0.339
−0.190
−0.455
R, wR
R, wR (all refls.)
0.0456, 0.1019
0.0824, 0.1153
0.0400, 0.1074
0.0483, 0.1182
0.0539, 0.1129
0.1095, 0.1322
0.0322, 0.0684
0.0502, 0.0890

536 Valde´s-Mart´ınez, Herna´ndez-Ortega, Rubio, Li, Swearingen, Kaminsky, Kelman, and West
coldisopropanolfollowedbyanhydrousether, and
dried.
1 were taken from International Tables for X-ray
Crystallography (1974, Vol. IV), and all calcula-
tions were done with the SHELXTL PCTM pro-
gram package.27 Scattering factors for the other
thioureas of this study are from Wassmaire and
Kirfel,28 calculations were done by maXus, ver-
sion 2.0,29 refinement by SHELX97,30 the mate-
rial for publication done with PLATON.31
Crystals of the thioureas were grown by slow
evaporation of 1:1 acetone–anhydrous ethanol so-
lutions at room temperature. The crystals were
mounted in random orientation on a glass fiber
on a Siemens P4 Four Circle Diffractometer (1),
a Nonius Mach 3 Diffractometer (2 and 4) and a
Nonius Kappa CCD Diffractometer (3). The struc-
tures were solved with direct methods and miss-
ing atoms were found by difference Fourier syn-
thesis. All non-hydrogen atoms were refined with
anisotropic temperature factors and all hydrogen
atoms were found on the difference Fourier map.
The H atoms of CH2 and CH3 were allowed to
ride on the C atoms and assigned a fixed isotropic
Method of calculations
The initial geometries used were from the
X-ray studies, ab initio geometries were calcu-
lated at a restricted Hartree–Fock (RHF) level,
using 6-31G∗∗ basis, with the Gaussian 98
Revision-A.11.4 package.32
The crystallographic data and methods of
data collection, solution, and refinement are given
in Table 1.
2
˚
temperature factor, U = 0.05 A . The coordinates
of the H atoms attached to nitrogen atoms and aro-
matic carbons were refined. Scattering factors for
Fig. 3. Thermal ellipsoid plot (50% probability) of 1–4 with atom numbering scheme.

Study of the NNꢀC S · · · H hydrogen bond
537
◦
Table 4. Thiourea Mean Plane Deviation and Angles Between
˚
Table 2. Selected Bond Distances (A) and Angles ( ) for 1–4
Planes
1
2
3
4
ꢂ
ꢂ
ꢂ
A
B
C
A/B
B/C
A/C
Bond distances
S1 C8
N1 C2
N1 C6
N2 C7
N2 C8
N3 C8
N3 C9
1
2
3
4
0.0174 0.0047 0.0042 76.2(1)
0.0075 0.0014 0.0048 89.62(7) 61.70(8) 57.16(8)
0.0037 0.0049 0.0064 88.3(1) 46.90(6) 57.20(8)
0.0066 0.0069 0.0045 77.90(9) 48.3(1) 81.3(1)
52.1(1)
55.0(1)
1.699(2)
1.334(2)
1.334(3)
1.457(2)
1.327(2)
1.348(2)
1.428(2)
1.705(2)
1.342(2)
1.338(3)
1.458(2)
1.325(2)
1.352(2)
1.435(2)
1.695(1)
1.343(3)
1.363(4)
1.459(2)
1.348(3)
1.358(3)
1.425(3)
1.688(3)
1.330(4)
1.345(4)
1.454(4)
1.334(3)
1.363(4)
1.420(4)
Note. Plane A = mean plane of pyridine ring, B = mean plane of the
thiourea moiety, N C(S) Nꢁ, and plane C = mean plane of the six
carbon atoms of the aromatic ring.
Bond angles
N1 C2 C7 114.3(2)
C2 C7 N2 114.1(2)
C7 N2 C8 123.9(2)
C8 N3 C9 128.5(2)
S1 C8 N2 122.5(1)
S1 C8 N3 118.7(1)
N2 C8 N3 118.8(2)
114.2(2)
114.1(2)
117.1(3)
114.4(2)
123.0(2)
129.0(2)
122.4(1)
118.8(1)
118.9(2)
115.6(2)
124.7(2)
130.6(2)
123.2(1)
119.5(1)
117.3(2)
111.7(2)
125.2(3)
128.4(2)
123.8(2)
119.7(2)
116.5(2)
Compounds 1, 2, and 4 have similar inter-
molecular H-bonding patterns, they present R22(8)
N H · · · S H-bonds that generate centrosymmet-
ric dimers, and C(5) N H · · · N chains, as shown
in Fig. 4. The combination of these two motifs
produce waving 2D structures as exemplify with
the structure of 1 in Fig. 5.
Results
In compound 3 the N H forms a C(4) motif
with the S atom and the Nꢁ H forms a C(7) motif
with the N atom of the pyridine ring, Fig. 4. These
two motifs produce a 2D structure that pack as
shown in Fig. 6.
The theoretical calculations show that in all
the molecules the py is the best acceptor than the
S atom. Having average partial charges of −0.396
and −0.586 for the S and pyridine N atoms, re-
spectively. ThepartialchargeontheHatomsofthe
donors have average values of +0.333 and +0.346
for NH and NꢁH, respectively.
The thermal ellipsoid plots of 1–4 are shown
in Fig. 3. Selected bond distances and angles are
in Table 2. Hydrogen-bonding geometries are in
Table 3. The conformation of 1 is such that the
C9 of the phenyl ring and the S atom are anti
with respect to the N3 C7, and C7 and the S
atom are syn with respect to C8 N2. The angles
between the mean planes of the thiourea moi-
ety the phenyl and pyridine rings are shown in
Table 4.
◦
˚
Table 3. Intramolecular and Intermolecular Hydrogen Bond Distances (A) and Angles ( ) for 1–4
(D H · · · A) (◦)
Symmetry code
˚
˚
˚
ꢂ
D
H · · · A
D
H (A)
H · · · A (A)
D
H · · · A (A)
1
N2 H · · · S1
N3 H · · · N1
0.86(2)
0.81(3)
2.48(2)
2.31(2)
3.312(2)
3.051(3)
163(2)
153(2)
−x, 1 − y, 1 − z
x, 0.5 − y, −0.5 + z
2
3
N2 H · · · N1
N3 H · · · S1
0.79(3)
0.84(2)
2.30(3)
2.52(2)
3.032(3)
3.319(2)
154(2)
160(2)
x, 0.5 − y, −0.5 + z
1 − x, −y, 1 − z
N2 H · · · O1
N2 H · · · S1
N3 H · · · N1
0.79(3)
0.83(3)
0.76(3)
2.65(2)
2.62(3)
2,26(3)
3.025(2)
3.331(3)
2.989(4)
111.2(19)
145(3)
162(3)
x, 0.5 − y, −0.5 + z
1 − x, 0.5 + y, 0.5 − z
4
N2 H · · · N1
N3 H · · · S1
0.80(3)
0.89(4)
2.43(3)
2.63(4)
3.153(4)
3.465(2)
150(3)
157(3)
1 + x, y, z
1 − x, 1 − y, 2 − z

538 Valde´s-Mart´ınez, Herna´ndez-Ortega, Rubio, Li, Swearingen, Kaminsky, Kelman, and West
Fig. 4. Representation of the different H-bonding motifs in 1–4.
Fig. 5. 2D structure of 1 seen along the a (a) and c axis (b).

Study of the NNꢀC S · · · H hydrogen bond
539
Fig. 6. Packing of molecules in 3, along c axis.
Discussion
Theoretical calculations clearly indicate that
the pyridine N atom is the best acceptor and
that there is no significative effect due to the
sustituents on the phenyl ring. With respect to the
H-donor the charge on the hydrogen atom in NꢁH
is consistently higher than the charge on the NH,
but the difference is small.
The approach used to avoid the intramolec-
ular H-bonds was successful, so we can analyze
the results with the best donor–best acceptor
approach. In three of the four structures, 1 , 2, and
4, the pyridine N atom hydrogen bonds with the
NH but in one, 3, it H-bonds with NꢁH. The last
result is the expected one according to theoretical
calculations, but the others are not; this may
reflect that the difference between the two donors
is not significative specially when we consider
that the solid-state assembly is an enormously
complex process governed by a subtle balance
between relatively weak and often ill-defined
intermolecular forces. The molecules chosen
in this study may be too flexible introducing
factors that result more important than the small
difference between the donors to decide the
preferred molecular interactions. This flexibility
may also be affecting the N H · · · S patterns and
for this reason the usual dimmers are not observed
in 3.
Conclusions
The strategy of using one C atom between
the thiourea N atom and the py ring to avoid
the formation of intramolecular H-bonds and al-
low a competition between the two acceptor
for the donor atoms was successful; unfortu-
nately this “unlocks” the molecules, introducing
a flexibility that complicates the analysis of the
structures. A better approach for the solid-state
study of the S atom in the biologically relevant

540 Valde´s-Mart´ınez, Herna´ndez-Ortega, Rubio, Li, Swearingen, Kaminsky, Kelman, and West
NNꢁ C S systems can be envisioned; we can
see at least two strategies, one is the synthesis
9. Uckun, F.M.; Pendergrass, S.; Maher, D.; Zhu, D.; Tuel-
Ahlgren, L.; Mao, C.; Venkatachalam, T.K. Bioorg. Med. Chem.
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of co-crystals with different donor–acceptor sys-
tems (carboxylic acids, amides, oximes, etcetera),
another is the solid-state study of molecules hav-
ing only one donor atom and two acceptors (one
of which will be the S atom). In both cases it is
convenient to select less flexible molecules than
the ones used in this study. Work in both di-
rections are in progress and will be published
elsewhere.
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Acknowledgments
We acknowledge the Universidad Nacional
Auto´noma de Me´xico and the Consejo Nacional de
Ciencia y Tecnolog´ıa (40332-Q) for partial support of
this research.
Supplementry material
CCDC-206927 (1), CCDC-
206928 (2), CCDC-206929 (3), and CCDC-206930 (4)
contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44(0)1223-336033; e-mail: deposit@
ccdc.cam.ac.uk).
22. Kaminsky, W.; Goldberg, K.I.; West, D.X. J. Mol. Struct. 2002,
605, 9.
23. Valde´s-Mart´ınez, J.; Herna´ndez-Ortega, S.; Hermetet, A.K.;
Ackerman, L.J.; Presto, C.A.; Swearingen, J.K.; Kelman, D.R.;
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