Supramolecular hydrogen-bonding patterns in 4′-substituted cyclohexane-5-spirohydantoin

Article abstract of DOI:10.1039/c2ce06560f

The preparation and single crystal structures of five derivatives of cyclohexane-5-spirohydantoin are described. A detailed analysis of Hirshfeld surfaces through the 2-D fingerprints has been carried out to facilitate comparison of the interactions established in the different structures. The derivatives of cyclohexane-5-spirohydantoin are characterized by the presence of cyclohexane-linked aromatic derivatives at position C4′, with this ring attached either directly or by different functional groups such as ethers or esters. The configuration of 1, 2, 4 and 5, as determined by X-ray diffraction, is cis while compound 3 is trans. All compounds have a Bucherer-Berg orientation of the hydantoin ring. In the Cambridge Structural Database (CSD) previous examples of 5-spirohydantoins with a trans configuration were not found. The crystal structures are compared with those previously described in the Cambridge Structural Database (CSD) and are classified according to the interactions between the hydantoin rings. Four types of structures are described, dimers and ribbons, which are common in hydantoin derivatives, and R₃ ³(10) and R₆⁶(26) supramolecular synthons, which are unprecedented in the literature.

Full text of DOI:10.1039/c2ce06560f

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PAPER
Supramolecular hydrogen-bonding patterns in 40-substituted
cyclohexane-5-spirohydantoin†
ab
bc
Sara Graus,ab Santiago Uriel
*
ꢀ
and Jose Luis Serrano
Received 22nd November 2011, Accepted 3rd February 2012
DOI: 10.1039/c2ce06560f
The preparation and single crystal structures of five derivatives of cyclohexane-5-spirohydantoin are
described. A detailed analysis of Hirshfeld surfaces through the 2-D fingerprints has been carried out to
facilitate comparison of the interactions established in the different structures. The derivatives of
cyclohexane-5-spirohydantoin are characterized by the presence of cyclohexane-linked aromatic
derivatives at position C40, with this ring attached either directly or by different functional groups such
as ethers or esters. The configuration of 1, 2, 4 and 5, as determined by X-ray diffraction, is cis while
compound 3 is trans. All compounds have a Bucherer–Berg orientation of the hydantoin ring. In the
Cambridge Structural Database (CSD) previous examples of 5-spirohydantoins with a trans
configuration were not found. The crystal structures are compared with those previously described in
the Cambridge Structural Database (CSD) and are classified according to the interactions between the
hydantoin rings. Four types of structures are described, dimers and ribbons, which are common in
3
6
hydantoin derivatives, and R3 (10) and R6 (26) supramolecular synthons, which are unprecedented in
the literature.
formation of a variety of one-, two- or three-dimensional
Introduction
supramolecular architectures.5,6 A good example of this type of
compound is the system that contains a hydantoin ring or imi-
dazoline-2,4-dione, which is easy to synthesize, rigid and has two
donor groups and two hydrogen bond acceptors.
Understanding the relationship between molecular structure and
crystal structure is a fundamental aspect in crystal engineering.1
In order to correlate the supramolecular structure with the
molecular structure it is necessary to have a broad range of
compounds of similar composition. This allows a detailed anal-
ysis of the influence of changes made to building blocks in the
supramolecular organization but requires the consideration of
the entire molecule, as stated by Desiraju.2 To achieve this
objective Hirshfeld surfaces and 2D fingerprints are helpful
because they contain information on all interactions and
contacts simultaneously and are very sensitive to the immediate
environment, thus providing an excellent visualization of close
intermolecular contacts.3,4
Hydantoin derivatives are biologically active compounds that
occur in nature and have been isolated from sources such as
sugar beets and butterfly wings.7 Synthetic analogues have found
widespread use as anticonvulsive, antiviral and antidepressant
drugs, bacteriocides, stabilizers in photographic films, and in the
preparation of high temperature epoxy resins. Recently a number
of hydantoin isomers, mainly 5,5-dimethylhydantoin, have been
detected and identified in coal gasification condensate water.8–10
In addition, the hydrolysis of hydantoin derivatives by acid or
enzymatic catalysis is a strategy for the synthesis of both natural
and synthetic amino acids.11 The properties outlined above have
led to the development of a large number of solution-phase and
solid-phase preparative methods.12,13
Recently, we described the structures of a series of 40-cyclo-
hexanespiro-5-hydantoin derivatives with small substituents
such as tert-butyl, ethoxy, carboxylic acid and methyl carboxy-
late.14 Solvent molecules are not present in these structures, a fact
that allowed us to study the influence of the nature of the
substituents on the supramolecular organization. We classified
the structures into two types according to the interactions
established between the hydantoin rings: those formed by dimers
(type I) and those consisting of infinite ribbons (type II).
In this article we describe the preparation and crystal struc-
tures of five 40-cyclohexane-5-spirohydantoin derivatives. The
In this context, compounds with simple synthesis routes that
allow the introduction of substituents of different natures and
have a rigid framework that includes multiple donor and
acceptor groups for non-covalent interactions are versatile
building blocks. This is because such compounds can lead to the
aDpto. de Quꢀımica Orgaꢀnica, Escuela de Ingenierꢀıa y Arquitectura,
Universidad de Zaragoza, 50015 Zaragoza, Spain. E-mail: suriel@
unizar.es
bInstituto de Nanociencia Aragoꢀn, Universidad de Zaragoza, 50015
Zaragoza, Spain
cDpto. de Quꢀımica Orgaꢀnica, Facultad de Ciencias, Universidad de
Zaragoza, 50009 Zaragoza, Spain
† CCDC reference numbers 855299–855303. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/c2ce06560f
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substituents are phenyl, phenyloxy and benzoate. The influence
of size, volume and nature of the substituents and configuration
(cis or trans) on the supramolecular organization are analyzed.
The Hirshfeld surfaces of the compounds were also analyzed in
order to gain a deeper understanding of the structures and to
highlight similarities and differences among them (Chart 1).
from CH3CN. The product was isolated as colourless crystal in
1
55% yield, m.p. 288–290 ꢀC. H-NMR (400 MHz, DMSO-d6):
d ¼ 1.59–1.73 (m, 8H), 2.41 (m, 1H), 6.66 (dd, 2H, HAr), 7.10 (d,
2H, HAr), 6.82 (s, 1H, OH), 9.13 (s, NH), 10.61 (s, NH). 13C-
NMR (100 MHz, DMSO-d6): d ¼ 28.3, 33.3, 41.5, 61.8, 114.9,
127.6, 137.1, 155.4, 156.4. IR (Nujol, NaCl) cmꢁ1: 3288–3180
(NH), 1751 (C]O), (CAr–C), (C–O). ESI+ (3000 plus) 282.9
(100% M + Na), 261.0 (M+).
Experimental section
Materials and methods
8-(4-(Methoxycarbonyl)phenoxy)-2,4-dioxo-1,3-diazaspiro[4,5]
decane (3). The general procedure using 4-(4-(methoxycarbonyl)-
phenoxy)-cyclohexanone (343 mg, 1.08 mmol) gave a white solid,
which was recrystallized from CH3CN. The product was isolated
as colourless crystals (224 mg) in 53% yield, m.p. 228–230 ꢀC. 1H-
NMR (400 MHz, DMSO-d6): d ¼ 1.67–1.68 (m, 4H), 1.80–1.85
(m, 2H), 2.03–2.07 (m, 2H), 3.88 (s, 3H), 4.45 (m, 1H), 7.09 (d,
2H, HAr), 7.87 (d, 2H, HAr), 8.49 (s, 1H, NH), 10.63 (s, 1H,
NH). 13C-NMR (100 MHz, DMSO-d6): d ¼ 179.5, 162.4, 159.1,
155.8, 131.7, 120.8, 115.3, 78.0, 63.8, 59.5, 35.1, 28.2. IR (Nujol,
NaCl) cmꢁ1: 3248–3067 (NH), 1777, 1734 (C]O), 1717 (C]O),
1508, 1458 (CAr–C), 1279, 1227 (C–O).
Cyclohexanone derivatives were prepared according to previ-
ously described methods.15–17 4-(4-Hydroxyphenyl)-cyclohexa-
none and 1,4-cyclohexadione-monoethylacetal were purchased
from Aldrich. All reagents and solvents were commercially
available and were used without further purification. FT-IR
spectra were recorded on a Nicolet Avatar FTIR spectropho-
1
tometer. H and 13C-NMR spectra were recorded on a Bruker
Avance 400 spectrometer (9.4 T, 400.13 MHz for 1H and
100.62 MHz for 13C). Melting points were measured on a Stuart
melting point apparatus. Elemental analyses were performed on
a Perkin-Elmer 240 analyzer. EI mass spectra were recorded on
a VG-Autospec spectrometer (VG Analytical), MALDI spectra
were obtained on a MICROFLEX (Bruker Daltonics) spec-
trometer and ESI spectra were obtained on an ESQUIRE
3000 plus (Bruker Daltonics) spectrometer.
8-(4-Butoxyphenoxy)-2,4-dioxo-1,3-diazaspiro[4,5]decane (4).
The general procedure using 4-(4-butoxyphenoxy)-cyclohexa-
none (415 mg, 1.58 mmol), (NH4)2CO3 (9.48 mmol), and KCN
(3.16 mmol) in ethanol/water (3/2) (6 mL) gave a white solid,
which was recrystallized from CH3CN. The product was isolated
as colourless crystals (269 mg) in 53% yield, m.p. 226–228 ꢀC. 1H-
NMR (400 MHz, DMSO-d6): d ¼ 1.67–1.68 (m, 4H), 1.80–1.85
(m, 2H), 2.03–2.07 (m, 2H), 3.88 (s, 3H, COOCH3), 4.45 (m, 1H),
7.09 (dd, 2H, HAr), 7.87 (dd, 2H, HAr), 8.49 (s, 1H, NH), 10.63
(s, 1H, NH). 13C-NMR (100 MHz, DMSO-d6): d ¼ 14.3, 19.2,
27.1, 31.3, 31.8, 62.0, 68.1, 74.5, 115.9, 117.4, 118.1, 151.3, 153.3,
156.7, 178.5. IR (Nujol, NaCl) cmꢁ1: 3289–3044 (NH), 1752,
1717 (C]O), 1603, 1580, 1507 (CAr–C), 1286, 1252 (C–O).
General procedure for the preparation of 1, 3–5
A mixture of a solution of the appropriate ketone (1.33 mmol) in
ethanol/water (3/2) (4 mL), KCN (2.65 mmol) and (NH4)2CO3
(7.86 mmol) was stirred at 45 ꢀC for 24 h. The resulting solution
was cooled to 0 ꢀC. The precipitate was filtered off, washed with
ice-cold water and dried to yield the pure white product.
8-(4-Hydroxyphenyl)-2,4-dioxo-1,3-diazaspiro[4,5]decane (1).
The general procedure using 4-(4-hydroxyphenyl)-cyclohexa-
none (300 mg, 1.58 mmol) gave a solid, which was recrystallized
8-(3,4-Dimethoxybenzoate)-2,4-dioxo-1,3-diazaspiro[4,5]decane
(5). The general procedure using 4-(3,4-dimethoxybenzoate)-
cyclohexanone (342 mg, 1.23 mmol) gave a white solid, which was
recrystallized from CH3CN. The product was isolated as col-
ourless crystals (230 mg) in 54% yield, m.p. 276–278 ꢀC. 1H-NMR
(400 MHz, DMSO-d6): d ¼ 1.70–1.76 (m, 4H), 1.79–2.05 (m, 4H),
3.81 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 4.91 (m, 1H), 5.08 (s,
NH), 7.09 (dt, J ¼ 14.3, 7.1 Hz 1H HAr), 7.44 (dd, J ¼ 13.6, 1.9
Hz 1H HAr), 7.59 (ddd, J ¼ 10.6, 8.4, 1.9 Hz 1H HAr), 10.54 (s,
NH). 13C-NMR (100 MHz, DMSO-d6): d ¼ 26.9, 31.7, 55.9, 56.3,
61.7, 71.5, 111.6, 112.1, 122.8, 123.6, 149.0, 153.5, 156.9, 165.5,
178.9. IR (Nujol, NaCl) cmꢁ1: 3291–3185 (NH), 1765, 1728 (C]
O), 1702 (C]O), 1599, 1511 (CAr–C), 1250, 1225 (C–O). ESI+
(3000 plus) 371.0 (100% M + Na), 348.9 (5% M).
Procedure for the preparation of 8-(4-methoxyphenyl)-2,4-
dioxo-1,3-diazaspiro[4,5]decane (2). 4-(4-Methoxyphenyl)cyclo-
hexanone (1 g, 4.90 mmol), KCN (1.274 g, 19.6 mmol) and
(NH4)2CO3 (4.70 g, 49.0 mmol) were mixed in ethanol/water
(3/2) (20 mL) and the mixture was loaded into a Teflon-lined
stainless steel autoclave. The sealed autoclave was heated under
autogenous pressure at 75 ꢀC for 3 h. The mixture was cooled to
ambient temperature and colourless crystals were obtained
Chart 1
3760 | CrystEngComm, 2012, 14, 3759–3766
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ꢀ
1
ꢁ
(1.166 g) in 87% yield, m.p. 274–276 C. H-NMR (400 MHz,
DMSO-d6): d ¼ 1.56–1.74 (m, 8H), 2.49–2.50 (m, 1H), 3.71 (s,
3H, OCH3), 6.85 (d, 2H, HAr), 7.24 (d, 2H, HAr), 8.67 (s, 1H,
NH), 10.57 (s, 1H, NH). 13C-NMR (100 MHz, DMSO-d6): d ¼
28.8, 33.4, 41.5, 54.9, 61.8, 113.6, 127.8, 138.7, 156.4, 157.5,
178.6. IR (Nujol, NaCl) cmꢁ1: 3176–3067 (NH), 1766 (C]O),
1732 (C]O), 1508, 1458 (CAr–C), 1279, 1227 (C–O). Elemental
analysis calcd (%) for C15H18O3N2: C 65.41, H 6.60, N 10.19;
found: C 65.44, H 6.96, N 10.17.
and O–H ¼ 0.983 A). In the 2D histograms (or fingerprints) the
distance external to the surface (de) (i.e. the distance from the
surface to the nearest nucleus in another molecule) is plotted
against the distance internal to the surface (di) (i.e. the distance
from the surface to the nearest atom in the molecule itself).
Results and discussion
Synthesis and spectroscopic properties
The 40-substituted cyclohexane-5-spirohydantoins were prepared
using a Bucherer–Bergs reaction, in which an aldehyde (or
ketone) is converted into the corresponding hydantoin in a 4-
component reaction involving an NH imine. Reactions were
carried out in two ways, using the classical method of synthesis
for compounds 1, 3–5 and also in a Teflon-lined stainless steel
autoclave for compound 2, with better performance obtained
using the latter technique.
X-Ray crystallographic analysis
X-Ray quality single crystals were obtained by slow evaporation
of solutions of compounds 1–5 in CH3CN. The crystals are air
stable and were mounted on the tip of a glass fibre using epoxy
cement. X-Ray diffraction experiments were carried out on an
Oxford-diffraction Xcalibur
S diffractometer. Data were
collected at 293(2) K with Mo-Ka radiation. Software packages
XSCANS18 and CrysAlis19 were used to process data.
The IR spectra of the compounds all show a medium-intensity
band at around 3100 cmꢁ1, which is typical of the NH group, and
Final cell parameters were obtained by global refinement of
reflections obtained from integration of all the frame data. The
structures were solved by direct methods and refined by the full-
matrix method based on F2 using the SHELXTL program.20 The
non-hydrogen atoms of structures 1–5 were refined anisotropi-
cally, whereas the hydrogen atoms of structures 1–5 were
observed in difference electron density maps and refined iso-
tropically. The crystal parameters and basic information relating
data collection and structure refinement for compounds 1–5 are
summarized in Table 1.
two very strong C]O bands at around 1770 and 1730 cmꢁ1
,
corresponding to the C]O groups of the hydantoin ring. The
spectra of 3 and 5 also show a strong C]O band at 1702 and
1717 cmꢁ1, respectively, due to the ester group.
The 1H-NMR spectra are characterized by chemical shift
differences of NH protons (N(1)H ¼ 10.5 ppm and N(2)H ¼
5.08–8.67 ppm). The displacement of N(2)–H (5.08 ppm) of
compound 5 may be related to the formation of intermolecular
hydrogen bonds in solution. This is supported by the presence in
the mass spectra of charge/mass peaks corresponding to dimers,
trimers and tetramers. As described above, the proton signal for
the proton on C40 is very sensitive to the electron-withdrawing
character of the substituent. For example, the signal varies from
0.95 ppm with tert-butyl, to 2.3 ppm with a carboxylic acid or
carboxylate, to 2.5 ppm with a phenyl, to 4.3 ppm with a phenoxy
and to 4.9 ppm with a benzoate group.
Hirshfeld surface analyses
Hirshfeld surfaces and the associated fingerprint plots were
calculated using CrystalExplorer,21 which accepts a structure
input file in the CIF format. Bond lengths to hydrogen atoms were
ꢁ
ꢁ
set to typical neutron values (C–H ¼ 1.083 A, N–H ¼ 1.009 A,
Table 1 Crystallographic data for 1, 2, 3, 4 and 5
Compound
1
2
3
4
5
Empirical formula
Formula weight
Crystal system
C14H16N2O3
260.29
Monoclinic
7.0111(4)
10.3913(3)
17.7538(11)
C15H18N2O3
274.31
Monoclinic
36.189(5)
7.5131(5)
10.3712(16)
C16H19N2O5.5
327.33
Monoclinic
20.003(4)
13.847(3)
12.636(3)
C18H24N2O4
332.39
C17H20N2O6
348.35
Triclinic
7.823(3)
9.608(5)
12.6865(15)
102.052(7)
90.957(17)
113.86(2)
847.3(6)
293(2)
ꢂ
P1
2
0.104
2.86 to 26.37
15 532
34 01/0.0721
0.0396/0.0506
0.1358/0.0594
0.002
Triclinic
6.047(2)
6.272(3)
26.102(8)
89.21(4)
85.21(3)
66.67(4)
906.7(6)
293(2)
ꢁ
a/A
ꢁ
b/A
ꢁ
c/A
a/deg
b/deg
g/deg
94.186(6)
102.949(13)
113.540(10)
3
ꢁ
V/A
T/K
1289.99(11)
150(2)
Cc
4
0.095
3.51 to 26.37
6677
2475/0.0283
0.0283/0.0521
0.0364/0.0537
0.002
2748.2(6)
150(2)
C2/c
8
0.093
2.77 to 26.37
23 495
2798/0.0280
0.0321/0.0837
0.0439/0.0874
0.002
3208.7(11)
293(2)
C2/c
8
0.103
1.84 to 25.01
2643
2358/0.0202
0.0533/0.1216
0.0823/0.1391
0.001
ꢂ
Space group
Z
P1
2
0.086
m (Mo Ka)/mm
q Range/deg
Refl. collected
Uniq. reflect/Rint
R1a/wR2b (I > 2s)
R1a/wR2b (all data)
Max. shift/esd
3.13 to 23.23
15 453
2525/0.0382
0.0594/0.1783
0.0848/0.1911
0.001
ꢁ3
ꢁ
Residual r/e A
P
0.130 and ꢁ0.168
0.219 and ꢁ0.150
0.303 and ꢁ0.546
0.366 and ꢁ0.216
0.121 and ꢁ0.161
P
P
P
a
b
R1 ¼ ||Fo| ꢁ |Fc||/ |Fo| wR2 ¼ [ {(Fo ꢁ Fc )2}/ {w(Fo2)2}]1/2
2
2
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Molecular and crystal structures
the structure of compound 5 is type I, which is characterized
by the formation of dimers, the structures of 2 and 4 are of type
II, characterized by the presence of tape-like polymers of
hydantoin rings, and finally the structure of 1 is type III, char-
acterized by infinite chains (Fig. 1). These relationships
between hydantoin rings have been described for other
cycloalkane-5-spirohydantoin derivatives such as 8-methoxy-
2,4-dioxo-1,3-diazaspiro-[4.5]decane (type I) and 8-tert-butyl-
2,4-dioxo-1,3-diazaspiro-[4.5]decane (type II). A search of the
Cambridge Structural Database did not show any type III
structures formed by hydantoin derivatives alone. However,
similar interactions between hydantoin rings are found in
structures in which water molecules are present.26 The structure
of 3 with a trans configuration and a water molecule of crystal-
lization is described separately and we did not assign a type of
structure to this system due to the differences found with the
structures of other compounds.
The cyclohexane rings in the crystal structures of compounds 1–5
adopt a stable chair conformation with the N–H group (N1) in
an axial position (Bucherer–Berg orientation). Meanwhile, in the
structures of 1, 2, 4 and 5 the substituent occupies an equatorial
position leading to a cis configuration whereas in the structure of
3 the substituent occupies an axial position, which gives rise to
a trans configuration. None of the structures of cyclohexane-5-
spirohydantoins described to date has a trans configuration.
The bond lengths and angles of the hydantoin fragments of
structures 2–5 are very similar to those observed in other 5-spi-
rohydantoins.22,23 The data for 4 were not considered due to the
low quality of the crystal. Selected bond distances and angles
from the crystal structures of 1–5 and cyclohexane-5-spi-
rohydantoin22 are gathered in Table 2.
Hydantoin ring bonds, which involve the C(3) carbon atom, are
the longest due to their higher s character. The N(1)–C(1) (average
In comparison with structures of cyclohexane-5-spi-
rohydantoin derivatives described previously, we have observed
that functional groups attached directly to the cyclohexane ring
are not involved in strong interactions.14 This is due to the steric
effect of the benzene ring attached to these groups. Moreover,
the most accessible groups attached to the benzene ring also have
a minor influence and need to be able to form strong interactions,
as in the case of 1, or be capable of forming multiple interactions,
as in 5, to determine the type of structure that a particular
compound has.
ꢁ
1.341[0.005] A) and C(2)–N(2) (average 1.364[0.012] A) bonds
ꢁ
are shorter than the C(1)–N(2) bond (average 1.416[0.055] A).
ꢁ
In the hydantoin structure of compounds 1–3 and 5, both
carbonyl groups are bent towards the N(2) atom. The O(1)–C(1)–
N(1) angle (average 128.3[0.92]) is greater than the O(1)–C(1)–
N(2) angle (average 124.5[0.85]) by 3.8ꢀ. This difference may be
due to the fact that the N(2) atom shares its lone pair between the
C(1) and C(2) atoms, while the N(1) atom is involved in a p-
resonance with C(1)–O(1) only. In 4, the O(1)–C(1)–N(1) angle
[125.3(3)] is smaller than the O(1)–C(1)–N(2) angle [126.3(3)].
The hydantoin unit is nearly planar in all five structures, with
Type I structures. The structure of compound 5 shows infinite
ꢁ
maximum deviations from planarity ranging from 0.015 A C(3) in
ꢁ
4 to 0.047 A C(3) in 2. The planes defined by the hydantoin ring
head-to-tail-type intermolecular hydrogen bonding and these
2
chains are joined by non-planar dimers of hydantoin (R2 (8)).
and cyclohexane are almost perpendicular and the angles range
from 82.1ꢀ in 4 to 89.4ꢀ in 5. These findings are in good agreement
with values described for other hydantoin derivatives24 and those
obtained by ab initio molecular orbital calculations.23,25 In addi-
tion, the trans configuration does not affect the relationship
between angles and bond distances (Table 2).
The fragments of hydantoin that form a dimer are located in
ꢁ
parallel planes separated by 0.698 A.
Hydantoin rings in the chains are in parallel planes that are
ꢁ
separated by a distance of 1.859 A. This differs from other type I
structures, in which the planes containing hydantoin rings form
angles of about 85ꢀ. This difference could be due to the bifur-
cated hydrogen bond between N(2)–H and oxygen atoms of both
methoxy groups (O(5) and O(6)) and also because of steric
hindrance (Fig. 2).
Structures of compounds 1, 2, 4 and 5 with a cis configuration
and without solvent molecules have been classified on the basis of
the interactions established between the hydantoin rings. Thus,
ꢀ
ꢁ
Table 2 Selected bond lengths (A) and angles ( ) in the hydantoin fragments
1
2
3
4
5
Ref. 22
N(1)–C(1)
N(1)–C(3)
O(1)–C(1)
C(1)–N(2)
N(2)–C(2)
O(2)–C(2)
C(2)–C(3)
C(1)–N(1)–C(3)
O(1)–C(1)–N(1)
O(1)–C(1)–N(2)
N(1)–C(1)–N(2)
C(2)–N(2)–C(1)
O(2)–C(2)–N(2)
O(2)–C(2)–C(3)
N(2)–C(2)–C(3)
N(1)–C(2)–C(3)
1.337(2)
1.457(19)
1.221(18)
1.391(2)
1.348(2)
1.213(17)
1.529(2)
112(1)
129(1)
123(1)
107(1)
112(1)
1.339(14)
1.459(14)
1.224(13)
1.396(14)
1.362(14)
1.220(13)
1.522(15)
113.3(1)
128(1)
1.351(3)
1.469(3)
1.235(3)
1.400(4)
1.369(4)
1.224(3)
1.527(4)
112.5(2)
127.6(3)
125.0(2)
107.4(2)
111.7(2)
127.0(3)
125.7(3)
107.2(2)
100.9(2)
1.339(1)
1.539(4)
1.251(3)
1.515(4)
1.382(4)
1.316(3)
1.604(4)
110.4(3)
125.3(3)
126.3(3)
108.0(3)
113.9(3)
126.4(3)
130.4(3)
103.2(2)
104.6(2)
1.340(2)
1.451(2)
1.217(2)
1.381(2)
1.361(2)
1.203(2)
1.516(2)
112(1)
127(2)
125(2)
108(2)
112(2)
1.326
1.460
1.218
1.397
1.344
1.221
1.518
113.38
129.45
123.31
107.24
111.37
126.56
125.32
108.12
124(1)
107.0(9)
111.6(9)
126(1)
126(1)
107.4(9)
100.3(8)
127(1)
125(1)
107(1)
100(1)
126(2)
126(2)
107(2)
100.8(2)
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2
Fig. 1 (a) Type I structure, (dimers) R2 (8) synthon; (b) type II structure, tape-like polymer and (c) type III structure, infinite chains.
chains. The 2-D assembly is stacked along the b axis to form
ꢁ
columns and the distance between the ribbons is 3.267 A, which
is slightly shorter than that in the 40-tert-butylcyclohexanespiro-
ꢁ
5-hydantoin (3.382 A).
In the crystal structure of 2 the hydantoin rings that form the
2
supramolecular synthon R2 (8) are not coplanar and nor are they
in parallel planes but are twisted by 6.69ꢀ relative to one another.
Fig. 2 Compound 5: (a) head-to-tail interaction through N(2)–H/O
2
hydrogen bonds and chain dimerization through R2 (8) interactions and
This causes the polymeric tapes, which propagate along the c
axis, to bend. When these tapes stack along the b axis through an
inversion centre, two types of alternate distances are generated
(b) perpendicular view of dimerized chains.
ꢁ
between tapes (4.11 and 3.40 A).
Type II structure. 8-(4-Butoxyphenoxy)-2,4-dioxo-1,3-dia-
zaspiro[4,5]decane (4) and 8-methoxy-benzene-2,4-dioxo-1,3-
diazaspiro[4,5]decano-8-phenoxy (2) are tape-like polymers that
arise through the formation of four intermolecular hydrogen
Voids are generated in the area of greatest separation between
tapes, but these are not large enough to form channels (Fig. 3).
2
2
bonds between hydantoin rings with graph-set C2 (9)[R2 (8)]
2
[R2 (8)] (Fig. 3). The angle between the hydantoin ring and the
Type III structure. The structure of 1 is different from types I
and II. This structure has a three dimensional network. The
interactions between the hydantoin rings can be described as
chains formed by N(1)–HN1/O(2) hydrogen bonds and the
hydantoin rings are coplanar. The hydrogen bonding donor and
acceptor groups remaining in the hydantoin ring form hydrogen
benzene ring in 4 is 47.43ꢀ (cf. 12.27ꢀ in 2). In the structures
described in this article we did not find any correlation between
this angle and the features of the compound or its supramolec-
ular organization. In fact, the two type II structures are those
that have the extreme values for this angle.
3
bonds with the hydroxyl group, which gives rise to an R3 (10)
Although there are some differences (as detailed below), the
two structures of type II—as well as those described previously—
have a stack of tapes rotated 180ꢀ relative to each other. These
stacks are slightly shifted and run in the opposite direction with
respect to the next tape.
supramolecular synthon (see Fig. 1 and Table 3). This synthon
has been described previously in the structure of (50S)-hydroxy-
methyl-50-[methyl
(4R)-2,3-O-isopropylidene-L-erythrofur-
anosid-4-C-yl]-imidazolidin-20,40-dione27 and structures of
spirohydantoins to crystallize with water molecules.28,29
3
The hydantoin rings that participate in the R3 (10) synthon
2
In the structure of 4 the R2 (8) (CONH)2 rings are flat and
form an angle of 49.95ꢀ. This leads to an intermolecular orga-
adjacent hydantoin moieties are coplanar. The substituents of
the hydantoin rings are disposed toward the outside of the
nization characterized by 3D hydrogen-bonding connectivity
2
Fig. 3 (a) 8-Methoxybenzene-2,4-dioxo-1,3-diazaspiro[4,5]decano-8-phenoxy structure (2) along the c axis and (b) detail of the C2 (9)[R2 (8)]
2
2
[R2 (8)] motif.
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Table 3 Hydrogen bonds in 40-substituted cyclohexane-5-spirohydantoins
D–H/A
d(D–H)
d(H/A)
d(D/A)
<(DHA)
Symmetry equivalence
1
N(1)–HN1/O(2)
N(2)–HN2/O(3)
O(3)–HO3/O(1)
2
0.862(16)
0.842(19)
0.850(2)
2.029(17)
1.990(2)
1.810(2)
2.890(17)
2.828(18)
2.650(16)
179.6(16)
171.3(18)
175(2)
x + 1/2, y ꢁ 1/2, z
x ꢁ 3/2, ꢁy + 3/2, z ꢁ 1/2
x + 1, ꢁy + 1, z + 1/2
N(1)–HN1/O(1)
N(2)–HN2/O(2)
3
0.911(16)
0.877(15)
1.965(16)
2.011(16)
2.863(14)
2.970(13)
168.4(13)
165.8(14)
ꢁx, y, ꢁz + 3/2
ꢁx, y, ꢁz + 5/2
N(1)–HN1/O(2)
N(2)–HN2/O(1)
O(10)–HO1/O(4)
4
0.85(4)
0.88(4)
0.98
2.12(4)
1.98(4)
2.02
2.963(3)
2.839(3)
2.979(4)
175(4)
167(4)
166.4
x, ꢁy, z ꢁ 1/2
ꢁx + 1/2, ꢁy + 1/2, ꢁz + 1
ꢁx + 1/2, ꢁy ꢁ 3/2, ꢁz + 1
N(1)–HN1/O(1)
N(2)–HN2/O(2)
5
0.900(3)
0.920(3)
2.260(3)
2.100(4)
3.142(4)
3.025(4)
168(3)
179(3)
ꢁx, ꢁy + 1, ꢁz + 1
ꢁx ꢁ 2, ꢁy + 2, ꢁz + 1
N(1)–HN1/O(1)
N(2)–HN2/O(5)
0.900(17)
0.860(2)
1.999(18)
2.240(2)
2.890(2)
3.026(2)
168.4(16)
151.7(19)
ꢁx + 2, ꢁy + 1, ꢁz + 1
x ꢁ 1, y, z + 1
3
patterns. The parallel molecular sheets of hydantoin R3 (10)
ꢁ
show an interlayer separation of 4.48 A and they are not stacked
the aromatic rings and an interior zigzag layer formed by
cyclohexane-5-spirohydantoin moieties (Fig. 5(c)). These planes
are linked through water molecules that form hydrogen bonds
with the carbonyl oxygen of ester groups.
(Fig. 4).
Structure of 8-(4-(methoxycarbonyl)phenoxy)-2,4-dioxo-1,3-
diazaspiro[4,5]decane (3). This structure differs from those
described so far in that the compound has a trans configuration
and it also contains a water molecule. In the bibliographic review
we did not find any structures of hydantoins with a trans
configuration. It is also noteworthy that the water molecule does
not interfere with interactions between the hydantoin rings. Each
hydantoin ring interacts with three rings of adjacent molecules.
Two interact through N(1)–HN1/O(2) interactions and the third
Hirshfeld surface analysis
Hirshfeld surfaces provide a three-dimensional picture of close
contacts in a crystal and these contacts can be summarized in
a bidimensional fingerprint plot. The Hirshfeld surfaces of
hydantoin derivatives were analyzed and, as expected, they
reveal the close contacts of hydrogen bond donors and acceptors.
However, other close contacts are evident. In the fingerprint
plots (Fig. 6) one can observe a lack of symmetry across the
diagonal and this indicates the presence of voids between the
Hirshfeld surfaces. This fact is related to the cis configuration of
all cyclohexane-5-spirohydantoins, with the exception of
compound 3. This is the only compound with a trans configu-
ration and a very symmetric fingerprint is observed despite the
2
one through an R2 (8) ring. The interaction N(1)–HN1/O(2)
gives rise to a chain similar to that described for the type III
structure. There are, however, some differences between these
two systems, e.g. the chain molecules are generated by a glide
plane perpendicular to the b axis and with a glide component [0,
0, ½] versus a centring vector [½, ½, ½] in the type III structure.
This causes the molecules in the chains to have opposite direc-
tions or the same direction, respectively, and the planes con-
taining adjacent hydantoin rings form an angle of 41.3ꢀ from the
coplanar rings present in the chains of the type III structure.
As mentioned above, two adjacent chains are linked by
hydantoin dimers and in these dimers hydantoin rings are in
ꢁ
peak at de 0.78, di 1.22, A. This spike is due to hydrogen bonding
6
ꢁ
parallel planes separated by 0.430 A. This gives rise to an R6 (26)
supramolecular synthon (Fig. 5(a) and (b)) and the structure is
formed by planes perpendicular to the a axis. Each plane consists
of three layers—two outer layers formed by the interdigitation of
6
Fig. 5 Structure of compound 3 (a); (b) detail of R6 (26) supramolecular
Fig. 4 (a) 2,4-Dioxo-1,3-diazaspiro[4,5]decano-8-phenol (1), view of 3D
3
lattice. (b) Detail of R3 (10) supramolecular synthon.
synthon; (c) zigzag layers formed by cyclohexane-5-spirohydantoin
moieties; and (d) view of the 3D network.
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Fig. 7 Relative contributions of various intermolecular contacts to the
Hirshfeld surface area for 1, 2, 3, and 5 and some cyclohexane-5-spi-
rohydantoins retrieved from CSD (QOPYO28, XAFWAE, XAFWEI,
and XAFWIM14).
We did not find any correlation between the type of structure
and distribution of the Hirshfeld surface, although in general the
O/H interactions in structures of type I show a greater contri-
bution to the surface.
Conclusions
In conclusion, it is clear that derivatives of cyclohexane-5-spi-
rohydantoin give rise to a variety of supramolecular organiza-
tions. The series of compounds studied and compared with other
structures described above allow us to highlight variations
depending on the nature of the substituents present on the
cyclohexane ring. The presence of a benzene ring prevents the
functional group bound to cyclohexane from participating in
the supramolecular organization. The nature of groups attached
to the benzene ring and even crystallization water molecules have
little tendency to interfere in the interactions of hydantoins
unless they can form additional effective interactions.
Fig. 6 Fingerprint plots of compounds 1 (a), 2 (b), 3 (c), and 5 (d).
between the carbonyl oxygen and the crystallization water
molecule.
However, all of the charts have a number of common char-
acteristics regardless of the crystal structure. For example, a pair
of sharp spikes is observed in the lower left and these are related
to the hydrogen bonds, the upper peak with the donor atoms and
the lower with the acceptor. The differences between the
hydrogen bonds are reflected in the narrowness of these spikes, as
well as in the presence of scattered points between these spikes.
These diffuse points in the fingerprints of 1, 3 and 5 are char-
acteristic of a cyclic hydrogen bonded dimer (H/H distance of
hydrogen atoms across the ring).3,4
Acknowledgements
ꢀ
This work was supported by the Ministerio de Educacion y
The fingerprint plot of 5 shows several distinct differences from
those of the other spirohydantoins, including a sharp point due to
Ciencia (CTQ2007-62245). S. Graus thanks the Instituto de
ꢀ
Nanociencia de Aragon for a grant. Thanks are given to Crys-
ꢁ
short H/H contacts (2.032 A). This kind of interaction has been
tallography Service from the University of Zaragoza (Spain).
described previously for aromatic derivatives such as pyrene and
perylene, which have a sandwich herringbone structure, and
diperinaphthyleneanthracene, which has a b structure. The
fingerprint also contains wings, which are characteristic of the C–
H/p interactions, as can be seen in the histogram (Fig. 7) by
a larger contribution of C/H to the Hirshfeld surface (17.1%).
The relative contributions of the different interactions to the
Hirshfeld surface were calculated for the spirohydantoin deriv-
atives. Due to the varying compositions of the molecules, the
values are not directly comparable across the compounds, but
they do offer an insight into the effect of different substituents on
the hydantoin backbone. Comparison of the hydantoin deriva-
tives shows that for all nine molecules weak H/H dispersion
forces and hydrogen bonding interactions contribute between
80 and 95% of the surface area.
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