Annular desmotropy of three pairs of seven-membered heterocycles confirmed by X-ray crystallography

Article abstract of DOI:10.1039/b925635k

The tautomers of 3-ethoxycarbonyl-2-phenyl-4,1-benzothiazepine and its 2-(4-methylphenyl) and 2-(4-chlorophenyl) derivatives, identified in solution by spectroscopic means, could be separated in the form of single-crystals suitable for X-ray diffraction. This is at present a unique situation in the literature on desmotropy. For the three desmotropic pairs, the bond lengths and angles present in the puckered seven-membered rings are fairly consistent within each group of desmotropes, but differ between the imines and the enamines. The structural similarity within the imines is revealed best by the isostructurality of the methyl and chloro derivatives, while the puckering differences between the heterorings of the desmotropic groups are reminiscent of conformational polymorphism. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/b925635k

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COMMUNICATION
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Annular desmotropy of three pairs of seven-membered heterocycles
confirmed by X-ray crystallography†‡
a
a
bc
a
Tamas Holczbauer, Laszlo Fabian, Peter Csomos, Lajos Fodorbc and Alajos Kalman
*
ꢀ
ꢀ
ꢀ
ꢀ ꢀ ꢀ
ꢀ
ꢀ
ꢀ
Received 7th December 2009, Accepted 29th January 2010
First published as an Advance Article on the web 16th February 2010
DOI: 10.1039/b925635k
tautomerism in general has a vast literature.5 This disparity
highlights the importance of structure determinations of tautomers
in the solid state. Katritzky5b considered that ‘it is impossible to
correctly interpret the detailed mechanism of reaction of tauto-
meric heterocycles without knowing the dominant tautomeric
structures.’
A study of the items listed in Table 1x of Holczer et al.4 reveals
that the pioneering work was the determination6e of the crystal
structures of a pair of 1H,3H desmotropes{ (I) which had been
predicted on the basis of IR spectra.6a Subsequently, however, the
characterization of desmotropy has remained hindered by the fact
that, in general, only one of the tautomers can be crystallized in
a form suitable for single-crystal studies. The second desmotrope
can usually be obtained only as polycrystals e.g. for irbesartan.7 In
another form of desmotropy both tautomers are present in the same
crystals.8c
The tautomers of 3-ethoxycarbonyl-2-phenyl-4,1-benzothiazepine
and its 2-(4-methylphenyl) and 2-(4-chlorophenyl) derivatives,
identified in solution by spectroscopic means, could be separated in
the form of single-crystals suitable for X-ray diffraction. This is at
present a unique situation in the literature on desmotropy. For the
three desmotropic pairs, the bond lengths and angles present in the
puckered seven-membered rings are fairly consistent within each
group of desmotropes, but differ between the imines and the
enamines. The structural similarity within the imines is revealed
best by the isostructurality of the methyl and chloro derivatives,
while the puckering differences between the heterorings of the
desmotropic groups are reminiscent of conformational poly-
morphism.
The majority of isolated desmotropes involve co-planar five-
membered rings. Occasionally, the co-planar rings are six-member-
ed,k as in phenylazopyridines9 (OH/NH desmotropes). The first
reported evidence for the desmotropy of condensed seven-membered
heterocycles was observed in the course of the preparation of new
isomers of 4,1-benzothiazepines.11 The structures of prototropic
annular desmotropes 2 and 3 (Scheme 1), which were separated by
column chromatography, were established by means of NMR and
mass spectrometry. After a few days, both NMR samples were found
to display the same equilibrium in which the ratio of 2 and 3 was 3 : 1,
as in the crude reaction production. In the present paper we report
seven crystal structures characterized previously by spectroscopic
means. The fine structure, conformation (stereoisomerism) and close
packing of three desmotropic pairs of 4,1-benzothiazepines, 2a/3a, 2b/
3b and 2c/3c (Scheme 1), are compared with each other and with 1,4-
benzothiazepine 5 (Scheme 2) where desmotropy could not be
obtained.
Introduction
ꢀ
The term desmotropy or desmotropism (Gr. d3smo2 bond,
1
ꢀ
sropo2 change) was introduced by Jacobson in an attempt to
improve the hypothesis deduced by Laar2 from the dualistic
behaviour of acetoacetic ester in the chemical reactions studied at
that time in different laboratories. It was found that with certain
reagents it acts as if it contained a hydroxyl group, while with
other substances it behaves as if it were a pure ketonic compound.
ꢀ ꢀ
Laar proposed to call this phenomenon tautomerism (sayso the
ꢀ
same, mero2 part). To differentiate between tautomerism and
desmotropy, Hantzsch and Herrmann3 suggested that if
a substance could be isolated in two stable forms it should be
called desmotropic, while if it could not be isolated it should be
termed tautomeric. Although reports of the occurrence of des-
motropy are still rather rare, this classification is still the most
appropriate, as underscored recently by Holczer et al.4 who
emphasized that ‘desmotropy is intimately linked with crystallog-
raphy’. The association of desmotropy with the solid state explains
why only 12 desmotropic pairs (excluding pyrazolinones) could be
listed in Table 1 of Holczer et al.4 whereas the study of
Experimental
Synthesis
Preparation of single-crystals of (R*)-3-ethoxycarbonyl-2-aryl-
3,5-dihydro-4,1-benzothiazepines (2a–c: 4-H, Cl, Me) and
3-ethoxycarbonyl-2-aryl-1,5-dihydro-4,1-benzo thiazepines (3a–c:
4-H, Cl, Me) and 2-ethoxycarbonyl-3-(4-chlorophenyl)-
4,5-dihydro-7,8-dimethoxy-1,4-benzothiazepine (5) for X-ray
crystallography. The various reaction intermediates, i.e. azeto-3,1-
benzothiazines (Scheme 1) 1a–c,11c azeto-1,3-benzothiazine
(Scheme 2) 4,11a 4,1-benzothiazepines 2a and 3a,11b 4,1-benzothiaze-
pines 2b–c and 3b–c11d (Scheme 1) and 1,4-benzothiazepine
511d (Scheme 2) were synthesized by literature methods.
aInstitute of Structural Chemistry, Chemical Research Center, Hungarian
Academy of Sciences, P. O. Box 17, H-1525 Budapest, Hungary
bCentral Laboratory, County Hospital, P. O. Box 46, H-5701 Gyula,
Hungary
cInstitute of Pharmaceutical Chemistry, University of Szeged, Research
Group of Stereochemistry, Hungarian Academy of Sciences, Eo€tvo€s u. 6.,
H-6701 Szeged, Hungary
† CCDC reference numbers 756120–756126. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b925635k
ꢀ
‡ Dedicated to the memory of Prof. Gabor Bernath PhD, DSc,
University of Szeged, who died on 1st October 2009.
ꢀ
1712 | CrystEngComm, 2010, 12, 1712–1717
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Table 1 Crystallographic data on 2a–c, 3a–c and 5
Compound
2a
2b
2c
3a
3b
3c
5
Chemical formula C18H17NO2S
Molecular weight 311.39
C19H19NO2S
325.41
C18H16ClNO2S C18H17NO2S
345.83 311.39
C19H19NO2S
325.41
C18H16ClNO2S
345.83
C20H20ClNO4S
405.88
Colourless, chunk Colourless, block Colourless, plate Colourless, block Yellow, chunk Colourless, chunk Yellow, chunk
Color, habit
Crystal system
Space group
Z
Triclinic
Monoclinic
P21/n
4
12.9550(4)
7.1696(2)
18.6157(8)
90.00
109.082(2)
90.00
1634.06(10)
1.323
100(2)
0.71070
0.207
2.32
Monoclinic
P21/n
Monoclinic
P21
Orthorhombic Orthorhombic
P212121
4
7.75740(10)
11.3316(2)
17.9221(3)
90.00
90.00
90.00
1575.42(4)
1.372
93(2)
Monoclinic
P21/c
4
15.2508(4)
9.1719(3)
14.8923(4)
90.00
115.920(2)
90.00
1873.57(10)
1.439
98(2)
1.54187
3.077
6.60
ꢂ
P1
P212121
4
8.005(4)
10.923(3)
18.797(7)
90.00
90.00
90.00
1643.5(11)
1.398
99(2)
2
4
2
ꢁ
a/A
8.5761(11)
9.7540(11)
10.7880(14)
65.345(3)
73.471(3)
72.509(3)
768.95(16)
1.345
12.699(2)
7.2028(9)
18.542(3)
90.00
5.905(2)
7.947(4)
16.797(9)
90.00
ꢁ
b/A
ꢁ
c/A
a/ꢀ
b/ꢀ
g/ꢀ
108.578(6)
90.00
97.611(15)
90.00
3
ꢁ
V/A
1607.6(4)
1.429
293(2)
0.71070
0.376
3.06
781.3(6)
1.324
295(2)
0.71070
0.214
D/g cmꢁ3
T/K
140(2)
ꢁ
X-Ray l/A
0.56089
0.120
2.43
1.54187
1.897
6.9
0.71070
0.368
3.16
m/mmꢁ1
qmin
qmax
3.48
27.51
24.75
26.35
27.48
71.63
27.51
71.75
Reflections
Collected
Independent
Observed
24 226
2710
2577
32 297
3324
2637
59 115
3690
3325
12 443
3040
2443
12 715
2748
2707
13 178
3758
3543
12 566
3194
1795
Threshold expression
R1 observed
wR2 (all)
>2s(I)
0.0294
0.0751
>2s(I)
0.0444
0.0919
>2s(I)
0.0313
0.0769
>2s(I)
0.0454
0.0874
>2s(I)
0.0270
0.0699
>2s(I)
0.0496
0.1162
>2s(I)
0.0729
0.2473
subjected to column chromatography [Merck Silica gel 60 (0.063–
0.100)], using n-hexane–EtOAc 9 : 1, followed by n-hexane–EtOAc
4 : 1 as eluent (for separation of 2b and 3b, n-hexane: EtOAc–
MeCN–CH2Cl2 85 : 5 : 6 : 4 was used as eluent). After evaporation
of the corresponding fractions, the oily residues (2a–c and 3a–c)
crystallized on trituration with n-hexane (3 mL). The single-crystals of
2a–c and 3a–c were obtained by crystallization from n-hexane (for the
crystallization of 3b EtOAc and for 5 EtOH was used as solvent). The
corresponding analytical and NMR data are reported in ref. 11.
Scheme 1
X-Ray crystallography
Intensity data were collected on a Rigaku R-axis Rapid diffractom-
ꢁ
Scheme 2
eter with graphite monochromated Ag Ka radiation (l ¼ 0.56089 A)
ꢁ
for 2a, with Mo Ka radiation (l ¼ 0.71070 A) for 2b, 2c, 3a and 3c,
2a ¼ (R*)-3-ethoxycarbonyl-2-phenyl-3,5-dihydro-4,1-benzothiaze-
pine. 2b ¼ (R*)-3-ethoxycarbonyl-2-(4-chlorophenyl)-3,5-dihydro-
and with Cu Ka radiation (l ¼ 1.54187 A) for 3b and 5. No des-
ꢁ
motropic phase transition occurred during the measurement in any
case. Lorentz and polarization and absorption corrections were
performed. The structures were solved by direct methods and
refined12 by an anisotropic least squares method against F2 for the
non-hydrogen atoms. The desmotropic protons could be located in
difference Fourier maps. Other hydrogen atoms were assigned to
idealized positions and were refined in riding mode. Due to chirality,
generated by the flopping protons in the imines (see below), the
4,1-benzothiazepine. 2c
¼
(R*)-3-ethoxycarbonyl-2-(4-methyl-
phenyl)-3,5-dihydro-4,1-benzothiazepine. 3a ¼ 3-ethoxycarbonyl-2-
phenyl-1,5-dihydro-4,1-benzothiazepine. 3b ¼ 3-ethoxycarbonyl-2-(4-
chlorophenyl)-1,5-dihydro-4,1-benzothiazepine. 3c
¼
3-ethoxy
carbonyl-2-(4-methylphenyl)-1,5-dihydro-4,1-benzothiazepine. 5 ¼ 2-
ethoxycarbonyl-3-(4-chlorophenyl)-4,5-dihydro-7,8-dimethoxy-
1,4-benzothiazepine.
ꢂ
crystals of 2a–c are racemic (space groups P1 and P21/n), whereas the
The single-crystals of 2a–c, 3a–c and 5 were prepared as follows:
azeto-3,1-benzothiazines 1a–c or azeto-1,3-benzothiazine 4 were
treated with NaOEt.11a,b The ring-transformed products 2 and 3 were
enamines 3a–c are conglomerates with polar space groups P21 and
P212121. Crystallographic data are given in Table 1.
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Table 2 Mean bond lengths and angles for desmotropes 2 and 3
desmotropes, but differ characteristically between the imines (2a–c)
and the enamines (3a–c), which can also be distinguished unambig-
uously by means of spectroscopy. Consequently, only the corre-
sponding mean bond lengths and angles (Table 2) are compared. As
we reported previously,11b the predominant desmotrope in each case
is the imino form, with the flopping proton linked to the sp3 carbon
C(3). This is in accordance with the prediction of Morrison and
Boyd:13 ‘in keto-enol tautomerism, the tautomeric equilibrium
generally favours the structure in which hydrogen is bonded to
carbon rather than to a more electronegative atom; that is, equilib-
rium favours the weaker acid.’ It is worth noting that CH/NH des-
motropes have so far only been observed in pyridoxal8a without
a report of their crystal structures. The unusual feature of the new
desmotropic pairs is that the protonation of C(3) generates chirality,
i.e. the flopping hydrogen may assume either an equatorial (2a) or an
axial (2b–c) position (Scheme 3, Fig. 1).
ꢁ
2a–c/A
ꢁ
3a–c/A
Mean bond lengths
N(1)–C(2)
C(2)–C(3)
C(3)–S(4)
S(4)–C(5)
1.283(2)
1.528(2)
1.819(2)
1.826(2)
1.381(2)
1.364(3)
1.770(2)
1.825(3)
Mean bond angles
2a–c/ꢀ
3a–c/ꢀ
C(9a)–N(1)–C(2)
N(1)–C(2)–C(3)
C(2)–C(3)–S(4)
C(3)–S(4)–C(5)
120.2(2)
122.2(2)
111.2(1)
98.1(1)
135.4(2)
128.8(2)
125.0(2)
99.7(2)
Interestingly, the observed stereoisomerism of the imino forms (2a
vs. 2b–c) does not influence the geometry of the seven-membered ring.
In each of the structures 2, the bulky S(4) atom links two C atoms
3
14
ꢁ
through S(II)–C sp single bonds each 1.82 A in length, while the
adjacent C(3)–C(2) bonds are close to sp3–sp2 single bonds. The C sp2
atom is then linked to N(1) by a double bond with a length of ca.
ꢁ
1.28 A. Similar bond lengths were observed to be predominant in the
amidine moieties of 2-iminothiazolidines and analogous thiazines.14
These characteristic mean bond lengths (Table 2) are accompanied by
characteristic mean bond angles at N(1), C(2) and C(3) of 120.0ꢀ,
122.0ꢀ and 111.2ꢀ, in accordance with the lone pair effect15 on N(1)
and the sp2 and sp3 hybridization of C(2) and C(3), respectively.
Formation of the NH desmotropes (3) (Fig. 2) followed by proton
flopping from C(3) to N(1), is demonstrated by the changes in the
relevant bond lengths and angles (Table 2).
Fig. 1 Molecular conformations of desmotropes 2a (a) and 2b (b).
Discussion
For the three desmotropic pairs (2a/3a, 2b/3b and 2c/3c), the bond
lengths and bond angles present in the puckered seven-membered
heterorings are fairly consistent within each group of the
Scheme 3 Atomic numbering for Fig. 1, 2, 3 and 4.
1714 | CrystEngComm, 2010, 12, 1712–1717
Fig. 2 Molecular conformations of desmotropes 3a (a) and 3b (b).
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As expected, the N(1)–C(2) bond length is elongated by an average
ꢀ
ꢁ
of 0.1 A with opening of the C(9a)–N(1)–C(2) angle from ca. 120 to
135ꢀ, while the C(2)–C(3) bond is substantially shortened, from 1.53
3
to 1.33 A. The change in the hybridization of C(3) from sp to sp is
2
ꢁ
also well indicated by the shortening of the S(II)–C(3) bond length
ꢁ
from 1.82 to 1.77 A, while the C(2)–C(3)–S(4) angle opens from
111.2ꢀ to 125.0ꢀ The substantial differences in the relevant three bond
lengths and angles (the S(4)–C(5) bond lengths and the angles at S(4)
are common standards) suggest that the crystals of the six desmo-
tropes selected for X-ray data collection remained stable in solid state
(either 2 or 3) from their crystallization, during their transportation
from Gyula (in the east of Hungary) to Budapest and in the course of
the subsequent days or weeks while they were waiting for diffraction
data.
The endocyclic torsion angles display great similarity among the
imino forms, whereas somewhat different conformations are
observed among the enamines (Table 3). In 2a–c the seven-membered
heterorings are puckered and, irrespective of the position of the
desmotropic proton (equatorial in 2a and b-axial in 2b–c), their
conformations are similar (Table 3). They are 1,3-biplanar, and
therefore differ substantially from the canonical forms given by
Hendrickson16 for cycloheptane. The asymmetry parameter17 DC2 ¼
4.5ꢀ (2a), 5.0ꢀ (2b) and 5.3ꢀ (2c) reveals in each of them a twofold axis
passing through S(4) and bisecting the N(1)–C(9a) bond on
the opposite side of the ring. The rotation of the phenyl ring around
the exocyclic C(2)–C(13) bond in 2a makes an angle of ca. 45ꢀ
with the best planes of the para-substituted aryl rings in 2b–c. In
contrast, superposition of the molecules of 2b and 2c reveals their
conformational similarity, which is maintained in the solid state. The
imino desmotropes 2b and 2c exhibit a high degree of isostructurality
(Iv ¼ 94%)18 with a the unit cell similarity index P ¼ 0.009 (Fig. 3). In
the imino structures, apart from a few weak non-bonding interac-
tions, no hydrogen-bond is formed.
Fig. 3 Superposition of the unit cells of desmotropes 2b and 2c, showing
their isostructural nature.
The proton migration from C(3) to N(1) alters the puckering of the
heteroring in the enamines: they lose their C2 symmetry. The endo-
and exocyclic torsion angles (Table 3) for 3a and 3c are similar; only
the conformations of the ethoxycarbonyl moieties differ. Presumably
these minor differences that give rise to their crystallization in the
different, but related polar space groups P21 and P212121. Although
the conformation of the p-methyl derivative 3b differs from that of 3c,
their unit cell parameters are similar (P ¼ 0.019)18a and the space
group symmetry P212121 is the same for both. However, despite these
similarities, they are not isostructural (Iv ¼ 42%)18c as are 2b and 2c.
Such structures are termed as homomorphous18b (Fig. 4).
Fig. 4 The homomorphous18b unit cells of desmotrope 3b (a) and 3c (b)
with substantially different close packing.
Table 3 Endocyclic torsion angles of the seven-membered heterorings and three relevant exocyclic torsion angles for 2a–c and 3a–c, respectively
Torsion angles/ꢀ
2a
2b
2c
3a
3b
3c
N(1)–C(2)–C(3)–S(4)
C(2)–C(3)–S(4)–C(5)
C(3)–S(4)–C(5)–C(5a)
S(4)–C(5)–C(5a)–C(9a)
C(5)–C(5a)–C(9a)–N(1)
C(5a)–C(9a)–N(1)–C(2)
C(9a)–N(1)–C(2)–C(3)
N(1)–C(2)–C(13)–C(18)
C(3)–C(2)–C(13)–C(14)
C(10)–C(3)–C(2)–C(13)
81.2(1)
82.9(2)
ꢁ45.9(2)
ꢁ41.0(2)
76.1(2)
ꢁ0.5(3)
ꢁ55.2(3)
ꢁ3.9(3)
24.8(3)
26.7(3)
26.9(3)
82.8(1)
ꢁ47.0(1)
ꢁ39.7(1)
76.6(1)
ꢁ2.0(2)
ꢁ54.9(2)
ꢁ2.8(2)
28.4(2)
29.8(2)
26.7(2)
ꢁ1.0(4)
44.8(3)
12.4(3)
28.2(2)
ꢁ80.7(1)
66.4(2)
7.3(3)
ꢁ1.9(3)
47.3(2)
ꢁ82.5(2)
57.8(3)
4.6(3)
ꢁ23.4(4)
ꢁ6.9(4)
ꢁ71.6(3)
ꢁ70.6(3)
6.0(3)
ꢁ42.4(1)
ꢁ43.3(1)
75.5(1)
ꢁ84.3(2)
60.5(3)
2.5(4)
1.7(2)
ꢁ58.0(2)
ꢁ4.4(2)
ꢁ13.9(2)
ꢁ14.9(2)
133.9(1)
ꢁ25.2(5)
ꢁ4.4(5)
ꢁ69.4(3)
ꢁ75.6(3)
ꢁ3.6(3)
ꢁ45.6(3)
6.5(3)
55.9(2)
56.1(2)
22.7(2)
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crystal structures (Table 1) exclude the usual uncertainties (e.g.
3-phenyl-1H-indazole10d) concerning their desmotropy. It is note-
worthy, however, that the single-crystals of each desmotrope were
sufficiently stable to provide convincing models of the crystal struc-
tures. A faint conformational disorder is demonstrated only by the
ethoxycarbonyl moiety in 2b. The cross-connections between the six
structures led to the following observations: While the conforma-
tional similarity between the imino forms resulted in the isostructural
nature of 2b/2c, the alternative stereoisomerism of 2a vs. 2b–c is so far
a unique phenomenon in the field of desmotropy. Although the
enamines display a relaxed conformational similarity, the puckering
of their 4,1-benzothiazepine moieties differs characteristically from
that of the imino forms. This indicates that desmotropy, similarly to
polymorphism, may lead to substantial differences in the conforma-
tions of a molecule. In other words, prototropic19 desmotropy, on the
border of similarity and dissimilarity phenomenologically resembles
conformational20 polymorphism which, is the most common form of
polymorphism.21 At any rate, while the relationship between des-
motropy and polymorphism is debated,4 the former can be regarded
as a special form of morphotropism.22
Scheme 4 Atomic numbering for Fig. 5
Acknowledgements
Fig. 5 Molecular conformation of 5, showing the rearrangement of the
heteroring due to the migration of the methylene group from the vicinity
of the sulfur atom to the vicinity of the nitrogen atom, which terminates
tautomerism.
The authors express their thanks to the Hungarian Scientific
Research Foundation (OTKA) for financial support (grant
ꢀ ꢀ
T049712). They are indebted to Prof. Matyas Czugler for his kind
ꢀ ꢀ ꢀ
interest and to Mrs E. Juhasz Dinyane for technical assistance.
Consequently, P indicates isostructurality only together with a high
volumetric index.18b
Notes and references
x Examples of desmotropy taken from the Table 1 of Holczer et al.4 I:
hydantoins (1H/3H-desmotropes);6a,e II: thiohydantoins (1H/3H-
desm.);6b III: imidazolidinones, (1H/3H-desm.);6c IV: imidazolidinthiones
(1H/3H-desm.);6d V: irbesartan (1H/2H/3H/4H-desm.);7 VI: pyridoxal
(CH/NH-desm.);8a VII: 1H-4-nitropyrazoles (1H/2H, 3(5)-methyl
desm.);8b VIII:phenylazopyridines (OH/NH-desm.);9 IX: antraquinoles
(CHOH/CHOH-desm.);10a X: thiohydantoin anion (1H/3H-desm.);10b
XI: rhodanine (NH/SH-desm.);10c XII: 1H-phenylpyrazoles (1H/2H-3(5)-
phenyl desm.)10d
The internal consistency of the relevant bond lengths and angles
within the tautomeric forms (2 vs. 3) indicates that neither the elec-
tron-donating methyl nor the electron-withdrawing chloro substit-
uent hinders their desmotropy. This can be regarded as a robust
phenomenon that is barely affected by the structural differences
discussed above. Neither does hydrogen-bonding play an important
role. In 3a the NH moiety is not involved in hydrogen bonding,
while in 3c and 3b there is a stronger (N(1)–H(1).O(2)[2 ꢁ x,
{ In 1972 the crystal structures of both desmotropes were solved by one
of the present authors (AK) and A. J. M. Duisenberg. The remaining
crystals were then kept sealed for at least 10 years, after which the X-ray
data were re-measured on both crystals. No spontaneous interconversion
was observed in either case. Since new informations was not obtained,
ꢀ
ꢁ
ꢁ½ + y, ½ ꢁ z]: 2.934, 2.09 A, 175 ) and a weaker (N(1)–
ꢀ
ꢁ
H(1).O(2)[ꢁ½ + x, ½ ꢁ y, ꢁz]: 3.063, 2.24 A 164 ) hydrogen-bond.
In contrast, with the migration of the endocyclic CH2 moiety along
the C(5a)–C(9a) bond of the condensed phenyl ring the 1,4-benzo-
thiazepine derivative 5 does not exhibit tautomerism (Scheme 4,
Fig. 5). Apart from the enamine structure that crystallizes with
a monoclinic unit cell, space group P21/c (Table 1) no imino form has
been obtained so far. The position of the tetrahedral CH2 moiety
seems to hinder the conjugation between the phenyl ring and the co-
planar part of the heteroring. However, since replacement of the
phenyl group by either a cyclohexyl or a naphthyl ring depresses the
formation of the imino tautomers, the explanation requires further
investigations which are in progress.
ꢀ
ꢀ
these results (A. Kalman and Gy. Argay) have remained unpublished.
k In vol. 76 of the Advances in Heterocyclic Chemistry, Katritzky referred
to vol. 77, in which the tautomerism of rings larger than five-membered
will be presented.
1 (a) P. Jacobson, Ber. Dtsch. Chem. Ges., 1887, 20, 1732;
(b) P. Jacobson, Ber. Dtsch. Chem. Ges., 1888, 21, 2628.
2 (a) C. Laar, Ber. Dtsch. Chem. Ges., 1885, 18, 648; (b) C. Laar, Ber.
Dtsch. Chem. Ges., 1886, 19, 730.
3 A. Hantzsch and W. A. Herrmann, Ber. Dtsch. Chem. Ges., 1887, 20,
2803.
ꢀ
4 W. Holczer, R. M. Claramunt, C. Lopez, I. Alkorta and J. Elguero,
Solid State Nucl. Magn. Reson., 2008, 34, 68.
5 (a) L. M. Jackman and I. Jen, J. Am. Chem. Soc., 1975, 97, 2811;
(b) A. R. Katritzky (editor) Advances in Heterocyclic Chemistry,
2000, 76, Academic Press, San Diego (the number of cited papers is
z 2500).
Summary
The desmotropy (predicted by spectroscopic studies) of three pairs of
4,1-benzothiazepine derivatives was established unambiguously by
X-ray crystallography. Since the tautomeric equilibria in solution
were previously established in spectroscopic investigations11 the six
ꢀ
6 (a) K. Lempert, J. Nyitrai, P. Sohar and K. Zauer, Tetrahedron Lett.,
1964, 5, 2679; (b) K. Lempert, J. Nyitrai and P. Sohar, Tetrahedron
ꢀ
Lett., 1965, 6, 1795; (c) J. Nyitrai and K. Lempert, Tetrahedron,
1969, 25, 4265; (d) J. Nyitrai and K. Lempert, Acta Chim. Budapest,
1716 | CrystEngComm, 2010, 12, 1712–1717
This journal is ª The Royal Society of Chemistry 2010

View Article Online
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1972, 73, 43; (e) K. Lempert, J. Nyitrai, K. Zauer, A. Kalman,
Gy. Argay, A. J. M. Duisenberg and P. Sohar, Tetrahedron, 1973,
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A. Kalman, D. Lazar, B. Ribar and G. Toth, Acta Crystallogr.,
Sect. B: Struct. Crystallogr. Cryst. Chem., 1977, 33, 99;
ꢀ
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29, 3565.
€
(e) Gy. Argay, A. Kalman, A. Kapor and B. Ribar, Acta
Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem., 1980, 36, 363.
15 R. J. Gillespie, J. Chem. Educ., 1963, 40, 295.
7 Zs. Bocskei, K. Simon, R. Rao, A. Caron, C. A. Roger and M. Bauer,
Acta Crystallogr., Sect. C: Cryst. Struct. Commun., 1998, 54, 808.
8 (a) L. F. Sala, A. E. Martell, R. J. Montekaitis and E. H. Abbott,
Inorg. Chim. Acta, 1987, 135, 123; (b) C. Foces-Foces, A. Llamas-
16 J. R. Hendrickson, J. Am. Chem. Soc., 1967, 89, 7036.
17 W. L. Duax, C. M. Weeks and D. C. Rohrer, Top. Stereochem., 1976,
9, 271.
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Saiz, R. M. Claramunt, C. Lopez and J. Elguero, J. Chem. Soc.,
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18 (a) A. Kalman, L. Parkanyi and Gy. Argay, Acta Crystallogr., Sect.
B: Struct. Sci., 1993, 49, 1039; (b) Acta Chim. Hung. (Models in
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Chem. Commun., 1994, 1143; (c) M. Kubicki, Acta Crystallogr.,
Sect. B: Struct. Sci., 2004, 60, 191.
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Chemistry), 1993, 130, p. 279; (c) L. Fabian and A. Kalman, Acta
9 G. R. Desiraju, J. Chem. Soc., Perkin Trans. 2, 1983, 1025.
10 (a) P. Boldt, S. Zippel and M. Ratkowsky, J. Chem. Soc., Perkin
Crystallogr., Sect. B: Struct. Sci., 1999, 55, 1099.
19 Quasi -tautomeric pairs such as: N-(2,6-dimethylphenyl)-N-mesyl-2-
´
Trans. 1, 1996, 2615; (b) J. S. Casas, E. E. Castellano, A. Macıas,
N. Playa, A. Sanchez, J. Sordo, J. M. Varela and J. Zukerman-
ꢀ
ꢀ
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amino-1,3-thiazine: (a) A. Kalman, Gy. Argay and I. Vassanyi,
Tetrahedron Lett., 1977, 18, 4237; (b) 2-(2,6-dimethylphenyl)imino-
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Schpector, Inorg. Chim. Acta, 1995, 238, 129; (c) E. B. Aronova and
´
A. I. Ginak, Russ. J. Gen. Chem., 2002, 75, 1885; (d) M. A. Garcıa,
C. Lopez, R. M. Claramunt, A. Kenz, M. Pierrot and J. Elguero,
ꢀ
3-mesylthiazine: A. Kalman and Gy. Argay, Cryst. Struct.
Commun., 1978, 7, 653, should be regarded as isomers.
ꢀ
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Helv. Chim. Acta, 2002, 85, 2763.
20 (a) J. Bernstein, Conformational Polymorphs, in Organic Solid State
Chemistry, ed. G. R. Desiraju, Elsevier, Amsterdam, 1987, (ch. 13);
(b) Polymorphism in Molecular Crystals, in IUCr Monographs on
Crystallography 14, Clarendon, Oxford 2002.
ꢀ
11 (a) L. Fodor, J. Szabo, E. Szucs, G. Bernath, P. Sohar and J. Tamas,
Tetrahedron, 1984, 40, 4089; (b) P. Csomos, L. Fodor, J. Sinkkonen,
}
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K. Pihlaja and G. Bernath, Tetrahedron Lett., 2006, 47, 5665;
(c) P. Csomos, L. Fodor, G. Bernath, J. Sinkkonen, J. Salminen,
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21 Other forms of polymorphism are exemplified in: (a) A. Kalman,
€
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L. Fabian, Gy. Argay, G. Bernath and Zs. Gyarmati, J. Am. Chem.
Soc., 2003, 125, 34; (b) P. Bombicz, M. Czugler, R. Tellgren and
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K. Wiinamaki and K. Pihlaja, Tetrahedron, 2008, 64, 1002;
ꢀ
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(d) P. Csomos, L. Fodor, A. Csampai, and P. Sohar, to be published.
12 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., 2008,
64, 112.
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A. Kalman, Angew. Chem., Int. Ed., 2003, 42, 1957; (c) L. Fabian
and A. Kalman, Acta Crystallogr., Sect. B: Struct. Sci., 2004, 60,
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547; (d) L. Fabian, A. Kalman, Gy. Argay, G. Bernath and
13 R. T. Morrison and R. N. Boyd, Organic Chemistry (2nd ed.), 1966,
Allyn and Bacon Inc., Boston, p. 250.
Zs. Cs. Gyarmati, Chem. Commun., 2004, 2114.
ꢀ
14 (a) Gy. Argay, A. Kalman, A. Nahlovski and B. Ribar, Acta
ꢀ
Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem., 1975, 31,
ꢀ
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22 (a) P. Groth, Ber. Dtsch. Chem. Ges., 1870, 3, 449; (b) P. Groth,
An introduction to Chemical Crystallography, translated by
H. Marschall, p. 36. London: Gurney and Jackson;
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1956; (b) Gy. Argay, A. Kalman, A. Kapor and B. Ribar, Cryst.
ꢀ
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(c) A. Kalman and L. Fabian, Acta Crystallogr., Sect. B: Struct.
Sci., 2007, 63, 411.
ꢀ
ꢀ ꢀ
Struct. Commun., 1977, 6, 665; (c) A. Kalman, Gy. Argay, B. Ribar
and L. Toldy, Tetrahedron Lett., 1977, 18, 4241; (d) Gy. Argay,
This journal is ª The Royal Society of Chemistry 2010
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