Co-crystals in the series of 4,5-dihydroxy- 4,5-diphenylimidazolidine-2-thiones

Article abstract of DOI:10.1016/j.mencom.2009.07.013

The synthesis of the first co-crystals among 4,5-dihydroxy-4,5-diphenylimidazolidin-2-ones (4,5-dihydroxyimidazolidine- 2-thione + 5-hydroxy-4-methoxy-4,5-diphenyl-1,3-diethylimidazolidine-2-thione) and of the cis isomer of 1,3-diethyl-4,5-dihydroxy- 4,5-

Full text of DOI:10.1016/j.mencom.2009.07.013

Mendeleev
Communications
Mendeleev Commun., 2009, 19, 211–213
Co-crystals in the series of 4,5-dihydroxy-
4,5-diphenylimidazolidine-2-thiones
Vladimir V. Baranov,a Yulia V. Nelyubina,b Aleksandr A. Korlyukovb and Angelina N. Kravchenko*a
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5328; e-mail: kani@server.ioc.ac.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation. Fax: +7 499 135 5085; e-mail: unelya@xrlab.ineos.ac.ru
DOI: 10.1016/j.mencom.2009.07.013
The synthesis of the first co-crystals among 4,5-dihydroxy-4,5-diphenylimidazolidin-2-ones (4,5-dihydroxyimidazolidine-
2-thione + 5-hydroxy-4-methoxy-4,5-diphenyl-1,3-diethylimidazolidine-2-thione) and of the cis isomer of 1,3-diethyl-4,5-dihydroxy-
4,5-diphenylimidazolidine-2-thione through the regiospecific condensation of 1,3-diethylthiourea with 1,2-dioxo-1,2-diphenylethane
was implemented; the structure was ascertained by single crystal X-ray diffraction and X-ray phase analysis.
An insight into the molecule self-assembly and self-organization
stands among the most exciting issues of supramolecular chemistry.
Therefore, the synthesis of objects capable of generating co-
crystals is a step to understanding the origination of these
processes. The problem of mixed crystals formation is very
timely and wide discussed in the recent chemical literature.1,2
No data on co-crystals among compounds with thiourea moieties
has been reported.
In addition, it is known that hydroxyl groups in 4,5-dihydroxy-
imidazolidine-2-thiones (DHITs) may have both trans and
cis orientations relative to the imidazolidine cycle.3–5 For the
first time, a regioselectivity of formation of DHIT trans (1a) and
cis (2a) isomers was observed for 4,5-dihydroxy-1,3-dimethyl-
4,5-diphenylimidazolidine-2-thione that is a mixture of trans
and cis isomers in the ratio 2:1.4 We have recently developed
methodologies for the DHIT synthesis and, basing on the
1H NMR spectra, identified that the generation of DHIT 1a–c
from corresponding thioureas, 1,3-dimethyl- and 1,3-diethyl-
thioureas, and glyoxal proceeds regioselectively.5 Note that
DHIT were isolated as a mixture of trans (1b,c) and cis (2b,c)
isomers with trans isomers 1b,c prevailing, whereas cis isomer
2d predominated over 1d. Maximal yields of those compounds
under the developed conditions were estimated at 45–78% and
no regiospecificity was marked. The structure of trans isomer
1b crystallized as a racemate was confirmed by X-ray analysis.
cis-Isomers were not isolated.
second product (mp 162–164 °C) precipitated as a fine-crystal
residue.†
In the 1H NMR spectra of the first product, along with proton
signals of the major substance, viz., 1,3-diethyl-4,5-diphenyl-
DHIT 3, signals from protons of the minor product were
detected. In the minor substance proton signals from Me, CH2
and Ph groups were present, which coincided with proton
signals from the major substance. In addition, at 3.53 ppm,
there was a singlet, which evidenced to a probable presence of
the OMe group and a singlet from OH group at 4.27 ppm. The data
indicated that the minor product could be 5-hydroxy-4-methoxy-
4,5-diphenyl-1,3-diethylimidazolidine-2-thione 4 (Scheme 1).
The 1H and 13C NMR spectra of the second reaction product
correspond to pure compound 3.
The X-ray diffraction study of the crystals obtained revealed
–
that the product is co-crystals (space group P1) of the DHIT
†
Commercially available compounds (benzil and diethylthioureas) from
ACROS were used in the syntheses. The solvents were used without
preliminary purification. The 1H and 13C NMR spectra were recorded on
a Bruker AM-300 (75.5 MHz) instrument. Chemical shifts were measured
with reference to the residual protons of CDCl3 as the solvent (d 7.26 ppm).
Mass spectra were recorded on a Kratos MS-30 mass spectrometer (70 eV).
Melting points were determined on a Gallenkamp instrument (Sanyo).
Procedure for the synthesis of co-crystals (3 + 4, 7:3) and DHIT 3.
A solution of potassium hydroxide (0.28 g, 0.005 mol) in H2O (1 ml) was
added to a solution of 1,3-diethylthiourea (0.76 g, 0.01 mol) and benzil
(2.1 g, 0.01 mol) in MeOH (10 ml). The reaction mixture was refluxed for
7 h, cooled to 20 °C and H2O (7 ml) was added. A precipitate of co-crystals
(3 + 4) was filtered off to give 0.24 g of crude product. Filtrate was
evaporated and residue of DHIT 3 (1.41g) was crystallized from MeOH.
Co-crystals of 1,3-diethyl-4,5-dihydroxy-4,5-diphenylimidazolidine-
2-thione 3 + 5-hydroxy-4-methoxy-4,5-diphenyl-1,3-diethylimidazolidine-
2-thione 4 (7:3): mp 152–154 °C. 1H NMR (CDCl3) d: 1.33 [t, 6H(3) +
R1
N
R1
N
R
R
R
R
OH
OH
OH
OH
S
S
a R = Ph, R1 = Me
b R = R1 = H
c R = H, R1 = Me
d R = H, R1 = Et
N
R1
N
R1
3
+ 6H(4), 2Me(3) + 2Me(4), J 7.1 Hz], 3.26–3.38 [m, 2H(3) + 2H(4),
1a–d
2a–d
CH2(3) + CH2(4)], 3.56 [s, 3H(4), OMe(4)], 3.85–3.97 [m, 2H(3) +
+ 2H(4), CH2(3) + CH2(4)], 4.24 [s, 2H(3), 2OH(3)], 4.27 [s, 2H(4),
2OH(4)], 6.89–6.93 [m, 4H(3) + 4H(4), Ph(3) + Ph(4)], 7.01–7.14 [m,
6H(3) + 6H(4), Ph(3) + Ph(4)].
To prepare the first co-crystals among DHIT series and cis
isomer of DHIT and to get a new insight into the crystalline
state of DHIT, we performed the regiospecific condensation of
1,3-diethylthiourea with 1,2-dioxo-1,2-diphenylethane (benzil),
previously non-described, in the alkaline medium for 7 h in a
boiling MeOH:H2O (10:1) mixture (similar to the described
procedure3 for preparing 1,3-dimethyl-4,5-diphenyl-DHIT). The
first precipitate from the reaction mass in the form of large
colourless crystals with mp 152–154 °C was filtered off. The
1,3-Diethyl-4,5-dihydroxy-4,5-diphenylimidazolidine-2-thione 3: yield
1
41%, mp 162–164 °C (MeOH). H NMR (CDCl3) d: 1.33 (t, 6H, 2Me,
3J 7.1 Hz), 3.26–3.38 (m, 2H, CH2), 3.85–3.97 (m, 2H, CH2), 4.24 (s,
2H, 2OH), 6.89–6.93 (m, 4H, Ph), 7.01–7.14 (m, 6H, Ph). 13C NMR
(CDCl3) d: 14.90 (Me), 39.83 (CH2), 96.45 (C, C–Ph), 127.12 (C, Ph),
127.84 (C, Ph), 128.52 (C, Ph), 136.12 (C, Ph), 183.51 (CS). MS, m/z (%):
342 (M+, 5), 324 (12.5), 194 (100), 166 (77), 165 (64), 104 (32).
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© 2009 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2009, 19, 211–213
Et
N
C(7)
Et
Et
C(7)
Ph
Ph
O
O
Ph
Ph
NH
NH
OH
O(1S)
C(2)
C(1S)
O(1)
S(1)
i
C(6)
N(2)
S(1)
C(6)
S
S
C(5)
C(5)
OH
N
C(2)
N(1)
N(2)
Et
O(2)
O(1)
O(2)
C(3)
C(3)
C(14)
C(16)
C(4)
3
N(1)
C(9)
C(4)
C(1)
C(1)
C(8)
C(15)
C(15)
C(8)
C(14)
C(19)
Et
Et
N
Ph
Ph
Ph
C(19)
C(16)
N
OH
OH
OH
C(13)
C(9)
C(13)
S
S
C(18)
C(12)
C(17)
OMe
N
N
C(18)
C(12)
C(17)
C(10)
Ph
C(10)
Et
Et
C(11)
C(11)
3
4
A
B
Scheme 1 Reagents and conditions: i, MeOH–H2O (10:1), KOH, reflux, 7 h.
Figure 1 General view of compound 3 + 4, which is a superposition of
DHIT monohydrate A and its ether derivative B in a 7:3 ratio. Hydrogen
atoms except for those of OH groups and water molecules are omitted for
clarity.
monohydrate 3 with 5-hydroxy-4-methoxy-4,5-diphenyl-1,3-
diethylimidazolidine-2-thione 4 in a 7:3 ratio (Figure 1). The
pattern in the 1H NMR spectrum did not change even after
double recrystallization from methanol. This phenomenon,
observed for this class of compounds for the first time, was
unambiguously proven by X-ray phase analysis of product
3 + 4.‡ Its results indicated the identity of the experimental
powder pattern to that obtained on a basis of the single crystal
X-ray diffraction data.
According to the analysis of co-crystals molecular geometry,
the conformation of the imidazolidine ring is twist with the
C(4) and C(5) atoms deviated from the plane of the others by
0.18(1) and 0.31(1) Å. Both the nitrogen atoms are slightly
piramidalized; the sum of the bond angles is 357.1(2) and
358.0(1)° for N(1) and N(2), respectively. Such a distortion of
the heterocycle leads to the variation of C–C and C–O bond
lengths for the substituents at C(4) and C(5) atoms, i.e., the
hydroxyl or methoxy groups in a cisoid configuration with
the dihedral angle O(1)–C(4)–C(5)–O(2) of 27.3(2)°. Thus, the
C(4)–O(1) [1.421(2) Å] and C(5)–C(14) [1.520(2) Å] bonds are
slightly longer than the C(5)–O(2) [1.399(2) Å] and C(4)–C(8)
[1.511(2) Å] ones. This is, apparently, due to the anomeric
interactions between lone pairs (Lp) of nitrogen atoms and σ*
orbitals of C–O and C–C bonds [the Lp–N(1)–C(4)–O(1) and
Lp–N(2)–C(5)–C(14) angles are close to the linear and are
equal to 169.4(2) and 166.9(2)°]. The latter can be responsible
for the stabilization of cisoid mutual disposition of OH and/or
OMe groups.
Note that the diol 3 component of co-crystals 3 + 4 displays
the intermolecular H-bonds O(2)–H(2O)···O(1) of the inter-
mediate strength [O···O 2.622(1) Å, O–H···O 127(1)°]. The
second OH group of the diol binds only to the water molecule
[O···O 2.608(1) Å, O–H···O 159(1)°]. The latter links the diol
moiety with its two neighbours via O–H···O [O···O 2.936(1) Å,
O–H···O 147(1)°] and O–H···S [O···S 3.204(1) Å, O–H···S 171(1)°]
interactions of the similar strength, thus resulting in the forma-
tion of double chain. These associates are assembled into 3D
framework by means of weaker C–H···O, H···π and H···H
contacts. In the case of the ether molecule, all the above
interactions, except for those involving the water molecule, are
also present. As a result, instead of the double chain there are
dimers formed though the unusual O···O [2.964(1) Å] contacts
between the neighbouring O(2)H groups accompanied by the
occurrence of very weak C–H···S ones.
‡
Crystallographic data: crystals of 3 + 4 (C19.3H24.9N2O2.7S, M = 360.17)
–
are triclinic, space group P1, at 120 K: a = 8.1594(7), b = 9.2364(7) and
c = 13.0904(11) Å, a = 104.354(5)°, b = 103.535(5)° and g = 97.904(5)°,
V = 908.95(13) Å3, Z = 2 (Z' = 1), dcalc = 1.316 g cm–3, m(MoKα) =
= 1.97 cm–1, F(000) = 385. Intensities of 9456 reflections were measured
on a Bruker SMART 1000 CCD diffractometer [l(MoKα) = 0.71072 Å,
w-scans, 2q < 56°] and 4369 independent reflections (Rint = 0.0258) were
used in further refinement.
Crystals of 3 (C19H22N2O2S, M = 342.45) are triclinic, space group
–
P1, at 120 K: a = 8.2532(8), b = 9.8748(10) and c = 12.0858(12) Å,
a = 99.724(3)°, b = 106.271(3)° and g = 106.861(3)°, V = 870.68(15) Å3,
Z = 2 (Z' = 1), dcalc = 1.306 g cm–3, m(MoKα) = 1.99 cm–1, F(000) = 364.
Intensities of 10610 reflections were measured with a Bruker SMART
1000 CCD diffractometer [l(MoKα) = 0.71072 Å, w-scans, 2q < 58°]
and 4615 independent reflections (Rint = 0.0190) were used in further
refinement.
The structures were solved by direct method and refined by the full-
matrix least-squares technique against F2 in the anisotropic–isotropic
approximation. The hydrogen atoms of OH group in 4 and those of
OH groups and water molecules in 3 + 4 were located from the Fourier
density synthesis and refined in isotropic approximation. The H(C)
atom positions were calculated. All hydrogen atoms were refined in the
isotropic approximation in riding model with the Uiso(H) parameters
equal to 1.2Ueq(Ci), for methyl groups equal to 1.5Ueq(Cii), where U(Ci)
and U(Cii) are respectively the equivalent thermal parameters of the
carbon atoms to which corresponding H atoms are bonded. For 3 + 4
the refinement converged to wR2 = 0.1278 and GOF = 1.002 for all
independent reflections [R1 = 0.0515 was calculated against F for 3302
observed reflections with I > 2s(I)]. For 3 the refinement converged to
wR2 = 0.0873 and GOF = 1.001 for all independent reflections [R1 = 0.0345
was calculated against F for 4055 observed reflections with I > 2s(I)].
All calculations were performed using SHELXTL PLUS 5.0.8
Quantum chemical calculations of the cis and trans isomers of 3 were
performed with the Gaussian 03 program.9 The standard threshold limits
of 4.5×10–4 and 1.8×10–3 a.u. were applied for the maximum force and
displacement, respectively. After optimization the analysis of vibration
frequencies was carried out.
According to published data5–7 on the structural features of
DHIT and 4,5-dihydroxyimidazolidin-2-one (DHI) containing
no phenyl substituents at C(4) and C(5) atoms, for instance, 1b,
the isomers with the transoid disposition of OH groups prevail.
As a result, we do not expect the components of co-crystals
3 + 4 to be the cis isomers. The found single cis orientation of
hydroxyl groups in the co-crystals 3 + 4 had appeared surprising,
which is why we prepared crystals of the second condensation
product, pure DHIT 3, via the crystallization from methanol.
According to the X-ray diffraction analysis, the latter gives
the solvent-free crystals of pure DHIT 3. As a result, the
supramolecular organization in the crystal of pure 3 differs
XRD powder patterns for 3 + 4 were measured with a Bruker D8
Advance diffractometer (T = 298 K, l(CuKα) = 1.5418 Å, q/2q-scans
with a 0.02° step; angle range of 2–60°).
CCDC 735643 and 735644 contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2009.
– 212 –

Mendeleev Commun., 2009, 19, 211–213
dramatically. The O(1)–H(1O)···S(1) bonds [O···S 3.190(2) Å,
This work was supported by the Russian Academy of Sciences
(programme OKh-9).
O–H···O 146(1)°] assemble the molecular moieties into the
centrosymmetric dimers. The second OH group in the crystal
of 3 exhibits the unusual O···O [O···O 2.656(1) Å] contacts close
to those for the component 4, which leads to the ‘double chain’
type of binding. A number of weaker C–H···S and H···π contacts
complete the formation of the 3D framework of 3.
However, the overall geometrical parameters of DHIT mole-
cule, including the mutual disposition of OH groups, remain
practically the same. The sum of the CNC bond angles is 352.2(1)
and 359.2(1)° for N(1) and N(2) atoms. The corresponding
torsion angle Lp–N(1)–C(4)–O(1) is equal to 168.1(2)°, while
the second nitrogen atom is planar. The dihedral angle O(1)–
C(4)–C(5)–O(2) is 26.9(1)°.
To find out the reason of cis isomer stabilization in the case
of the above DHIT derivative with phenyl substituents at carbon
atoms of heterocycle we performed the quantum chemical
calculation (B3LYP/6-311+G**) of the molecule 3 in both its
cis and trans forms. The geometry of the former is close to
the experimental one; the sum of bond angles at nitrogen
N(1) and N(2) sites was 354.0 and 358.2° with the value of
Lp–N(1)–C(4)–O(3) angle equal to 170.5°. Although the corre-
sponding geometrical parameters in the case of the trans isomer
vary only in a minor way [the sum of the CN(1)C and CN(2)C
angles is 352 and 355.6°; the anomeric interactions involve just the
C–O bonds with the pseudo-torsion angles Lp–N(1)–C(4)–O(3)
and Lp–N(2)–C(5)–O(2) being 163.1 and 166.7°], it is less
energetically stable than its cis analogue by 2.41 kcal mol–1.
Thus, the study on the interaction of 1,3-diethylthiourea
with benzil resulted in identifying regiospecificity of the DHIT
generation with cis-positioning of hydroxyl groups and preparing
the first co-crystals within this class of compounds. The data
were ascertained by single crystal X-ray diffraction and X-ray
phase analyses. The results obtained are of high promise in
terms of attaining a deeper insight into the DHIT synthesis and
structure, including their crystalline state, and contribute to
understanding of molecule self-assembly and self-arrangement
processes such as co-crystallization.
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Received: 3rd December 2008; Com. 08/3247
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