Structural investigations on 4-chloro-6-phenyl-7,8,9,14-tetrahydroquinolino [2′,3′:7,6]cyclohept[b]indoles

Article abstract of DOI:10.1007/s10870-009-9668-z

Several 4-chloro-6-phenyl-7,8,9,14-tetrahydroquinolino[2′,3′:7, 6]cyclohept[b]indole derivatives were obtained in one pot synthesis reactions via acid catalyzed condensation and cyclization of 1-oxo-1,2,3,4,5,10- hexahydrocyclohept[b]indoles with 2-amino-5-chlorobenzophenone in glacial acetic acid. Parent 4-chloro-6-phenyl-7,8,9,14-tetrahydroquinolino[2′,3′: 7,6]cyclohept[b]indole and the 10, 11, 12 and 13-methyl derivatives all crystallize in the triclinic space group P overline{1}. The 11-methyl derivative crystallizes with Z?= 2, the 10 and 12-methyl isomers cocrystallize as a solid solution of the two molecules, and the 13-methyl derivative and the parent compound each with Z?= 1. The unit cell parameters for the four structures are a = 10.1826(8), b = 12.3918(7), c = 16.3825(8)A, α = 91.626(1), β = 95.718(1), γ = 94.966(1)° and V = 2,047.7(2) A³ for the 11 methyl derivative; a = 10.168(2), b = 10.304(2), c = 10.610(2)A, α = 89.169(3), β = 87.774(3), γ = 63.726(2)° and V = 996.0(3) A³ for the solid solution of the 10 and 12-methyl derivative, a = 9.0412(5), b = 10.4926(6), c = 10.9093(6)A, α = 94.482(1), β = 102.181(1), γ = 95.812(1)° and V = 1,001.13(10) A³ for the 13-methyl compound, and a = 9.6463(6), b = 10.2395(6), c = 10.6062(6)A, α = 91.7263(8), β = 94.7200(8), γ = 114.0812(7)° and 950.85(10) A³ for the unsubstituted parent compound. The molecular shape of the molecules is not affected by the substitution pattern and all molecules exhibit the same conformation with very similar geometries. Intermolecular interactions are limited to weak C-H???Cl hydrogen bonds, a small number of π???π stacking interactions and several C-H???π interactions, which, in combination with shape recognition, dominate the packing of the quinolinocyclohept[b]indoles.

Full text of DOI:10.1007/s10870-009-9668-z

J Chem Crystallogr (2010) 40:402–411
DOI 10.1007/s10870-009-9668-z
ORIGINAL PAPER
Structural Investigations on 4-Chloro-6-Phenyl-7,8,9,
14-Tetrahydroquinolino [20,30:7,6]cyclohept[b]indoles
•
Ezhumalai Yamuna Makuteswaran Sridharan
•
•
Karnam Jayarampillai Rajendra Prasad
Matthias Zeller
Received: 4 September 2009 / Accepted: 3 December 2009 / Published online: 30 December 2009
Ó Springer Science+Business Media, LLC 2009
Abstract Several 4-chloro-6-phenyl-7,8,9,14-tetrahydroqu-
inolino[20,30:7,6]cyclohept[b]indole derivatives were obtained
in one pot synthesis reactions via acid catalyzed condensation
and cyclization of 1-oxo-1,2,3,4,5,10-hexahydrocyclohept[b]
indoles with 2-amino-5-chlorobenzophenone in glacial acetic
acid. Parent 4-chloro-6-phenyl-7,8,9,14-tetrahydroquinolino
[20,30:7,6]cyclohept[b]indole and the 10, 11, 12 and 13-methyl
derivatives all crystallize in the triclinic space group P1. The
11-methyl derivative crystallizes with Z0 = 2, the 10 and
12-methyl isomers cocrystallize as a solid solution of the two
molecules, and the 13-methyl derivative and the parent
compound each with Z0 = 1. The unit cell parameters for
the four structures are a = 10.1826(8), b = 12.3918(7), c =
exhibit the same conformation with very similar geome-
tries. Intermolecular interactions are limited to weak
C–HꢀꢀꢀCl hydrogen bonds, a small number of pꢀꢀꢀp stacking
interactions and several C–Hꢀꢀꢀp interactions, which, in
combination with shape recognition, dominate the packing
of the quinolinocyclohept[b]indoles.
Keywords Crystal structure ꢀ Disorder ꢀ Solid solution ꢀ
Z0 = 2 ꢀ Quinolinocyclohept[b]indoles
Introduction
˚
16.3825(8)A, a = 91.626(1), b = 95.718(1), c = 94.966(1)°
The indole nucleus is present in a large number of naturally
occurring as well as biologically active molecules, which
makes indole derivatives molecules of considerable con-
temporary interest and importance [1]. Alkaloids that con-
tain indole units such as prenylated indoles, carbazoles,
indoloquinoline or cyclohept[b]indole alkaloids often show
high levels of biological activities such as anti-fungal, anti-
bacterial, anti-tumor or anti-HIV properties and some also
exhibit interaction with DNA molecules [2–5]. One growing
class of biologically relevant indole derivatives are cy-
clohept[b]indoles, such as e.g. the naturally occurring pyr-
ido fused cyclohept[b]indole alkaloids Ervitsine and
Ervatamine [6]. Motivated by their biological relevance
[7, 8] a range of synthetic methods have been developed to
construct this type of molecules [9–12], and our laboratories
have recently reported the synthesis and crystallographic
studies for several cyclohept[b]indoles derivatives [13]. In
continuation of these studies we now utilized the reagent
2-amino-5-chlorobenzophenone in order to develop a via-
ble synthetic route to quinolino fused cyclohept[b]indoles
of potential pharmacological interest such as 4-chloro-6-
phenyl-7,8,9,14-tetrahydroquinolino [20,30:7,6]cyclohept[b]
3
and V = 2,047.7(2) A for the 11 methyl derivative; a =
˚
˚
10.168(2), b = 10.304(2), c = 10.610(2)A, a = 89.169(3),
b = 87.774(3), c = 63.726(2)° and V = 996.0(3) A for
the solid solution of the 10 and 12-methyl derivative, a =
3
˚
˚
9.0412(5), b = 10.4926(6), c = 10.9093(6)A, a = 94.482(1),
b = 102.181(1), c = 95.812(1)° and V = 1,001.13(10) A
for the 13-methyl compound, and a = 9.6463(6), b =
3
˚
˚
10.2395(6), c = 10.6062(6)A, a = 91.7263(8), b = 94.7200(8),
c = 114.0812(7)° and 950.85(10) A for the unsubstituted
parent compound. The molecular shape of the molecules
3
˚
is not affected by the substitution pattern and all molecules
E. Yamuna ꢀ M. Sridharan ꢀ K. J. Rajendra Prasad
Department of Chemistry, Bharathiar University,
Coimbatore 641 046, India
M. Zeller (&)
Department of Chemistry, Youngstown State University,
One University Plaza, Youngstown, OH 44555-3663, USA
e-mail: mzeller@ysu.edu; mzeller@cc.ysu.edu
123

J Chem Crystallogr (2010) 40:402–411
403
indoles. For optimal drug design knowledge of the exact
geometry and shape of the molecules is essential. The
Cambridge Structural Database (as of November 2008) does
however not report any structural data on quinolinocycloh-
ept[b]indoles. Hegde et al. did report the structure of a
pyridino cyclohept[b]indole derivative [14], but in this
single example of a structurally described pyridino cyclo-
heptindole this functionality unit is part of a larger moiety
which is wrapped around a water molecule hydrogen bon-
ded to two indoles and two pyridyl moieties. This forces the
molecule as a whole to be nearly planar, and it might thus
not represent a geometry and conformation typical for
pyridino cyclohept[b]indoles as a whole. In this presentation
we would thus like to present and discuss the synthesis and
structures of four representatives of the quinolinocycloh-
ept[b]indoles family of synthetic indole alkaloids.
7-Methyl-1-oxo-1,2,3,4,5,10-hexahydrocyclohept[b]indole
(2a): white solid (1.36 g, 64%) m.p. 177–178 °C; IR (KBr
1
pellet) mmax: 3,328, 1,618, 1,575 cm-1. H NMR (CDCl3):
d8.86 (b s, 1H, N–H), 7.42–7.16 (m, 3H, C6–, C8–, C9–H),
3.14–3.11 (m, 2H, C5–2H), 2.85–2.82 (m, 2H, C2–2H), 2.45
(s, 3H, C7–CH3), 2.11–2.05 (m, 2H, C4–2H), 2.02–1.95 (m,
2H, C3–2H).
Mixture of 8-methyl-1-oxo-1,2,3,4,5,10-hexahydrocyc-
lohept[b]indole (2b) and 6-methyl-1-oxo-1,2,3,4,5,10-hexa-
hydrocyclohept[b]indole (2e): white solid (1.43 g, 67%) m.p.
118–120 °C; IR (KBr pellet) mmax: 3,329, 1,610, 1,569 cm-1
.
1H NMR (CDCl3): (2b, 8-methyl isomer) d. 8.93 (b s, 1H, N–
H), 7.52–6.79 (m, 3H, C6–, C7–, C9–H), 3.12–3.09 (m, 2H,
C5–2H), 2.84–2.80 (m, 2H, C2–2H), 2.45 (s, 3H, C8–CH3),
2.08–2.02 (m, 2H, C4–2H), 1.99–1.96 (m, 2H, C3–2H) and
(2e, 6-methylisomer)d9.10(bs, 1H, N–H), 7.52–6.79(m, 3H,
C7–, C8–, C9–H), 3.41–3.38 (m, 2H, C5–2H), 2.84–2.80
(m, 2H, C2–2H), 2.71 (s, 3H, C6–CH3), 2.08–2.02 (m, 2H,
C4–2H), 1.99–1.96 (m, 2H, C3–2H).
Experimental
9-Methyl-1-oxo-1,2,3,4,5,10-hexahydrocyclohept[b]indole
(2c): white solid (1.38 g, 65%) m.p. 139–140 °C; IR (KBr
1
pellet) mmax: 3,298, 1,605, 1,537 cm-1. H NMR (CDCl3):
Materials
d8.84 (b s, 1H, N–H), 7.67–7.03 (m, 3H, C6–, C7–, C8–H),
3.17–3.13 (m, 2H, C5–2H), 2.86–2.83 (m, 2H, C2–2H), 2.49 (s,
3H, C9–CH3), 2.13–2.06 (m, 2H, C4–2H), 2.02–1.97 (m, 2H,
C3–2H).
Melting points (m.p.) were determined on a Mettler FP
51apparatus (Mettler Instruments, Switzerland) and are
uncorrected. IR spectra were recorded on a Schimadzu
FTIR-8201PC spectrophotometer (Schimadzu, Japan) from
1-Oxo-1,2,3,4,5,10-hexahydrocyclohept[b]indole (2d):
white solid (1.29 g, 61%) m.p. 151–152 °C; IR (KBr pellet)
1
KBr pellets. H NMR spectra were recorded on a Bruker
max: 3,292, 1,635, 1,569 cm-1. 1H NMR (CDCl3): d8.96 (b
AMX 400 (400 MHz) spectrometer using tetramethylsilane
(TMS) as an internal reference. The chemical shifts are
expressed in parts per million (ppm). The purity of the
products was tested by TLC with plates coated with silica
gel-G with petroleum ether and ethyl acetate as developing
solvents. All chemicals were purchased from Sigma–
Aldrich, Bangalore, India.
m
s, 1H, N–H), 7.67–7.11 (m, 4H, C6–, C7–, C8–, C9–H), 3.17–
3.14 (m, 2H, C5–2H), 2.87–2.83 (m, 2H, C2–2H), 2.12–2.06
(m, 2H, C4–2H), 2.04–1.99 (m, 2H, C3–2H).
Synthesis of the quinolinocyclohept[b]indoles 4a, 4b/e,
4c and 4d: a mixture of the appropriate 1-oxo-1,2,3,4,5,10-
hexahydrocyclohept[b]indole (2a, 2b/e, 2c or 2d, 0.01 mol)
and 2-amino-5-chlorobenzophenone (3, 0.01 mol) in glacial
acetic acid with few drops concentrated sulfuric acid added
was refluxed for 5 h. The reaction was monitored by TLC.
After completion of the reaction, the mixture was poured
onto crushed ice, extracted with chloroform and the organic
layer dried over anhydrous sodium sulfate. The crude prod-
uct obtained on filtration and removal of the solvent was
purified by column chromatography over silica gel using
petroleum ether : ethyl acetate (98:2, Rf = 0.06) and affor-
ded the 4-chloro-6-phenyl-7,8,9,14-tetrahydroquinolino[20,
30:7,6]cyclohept[b]indoles (4a to 4d).
The 1-oxo-1,2,3,4,5,10-hexahydrocyclohept[b]indole syn-
thons 2a, 2b/e, 2c and 2d were prepared by fischer indole
cyclisation as described below based on a published proce-
dure [13]. The appropriate hydrazone [15] (1a, 1b, 1c or 1d,
0.01 mol) in a mixture of acetic acid (20 mL) and concen-
trated HCl (5 mL) was refluxed on an oil bath for 2 h. The
contents were then cooled and poured into ice water with
stirring. The separated brown solids were filtered and puri-
fied by passing through a column of silica gel and eluting
with petroleum ether:ethyl acetate (98:2) yielding 1-oxo-
2,3,4,5,10-hexahydrocyclohept[b]indoles (2). Cyclization
of cycloheptan-1,2-dione-1-(m-methyl)phenyl hydrazone
(1b) gave both possible positional isomers, 6-methyl-1-oxo-
2,3,4,5,10-hexahydrocyclohept[b]indole (2e) and 8-methyl-
1-oxo-2,3,4,5,10-hexahydrocyclohept[b]indole (2b), which
were recovered as a 1:1 mixture after column chromatogra-
phy and were used as such in the next reaction step.
4-Chloro-11-methyl-6-phenyl-7,8,9,14-tetrahydroquinoli-
no[20,30:7,6]cyclohept[b]indole (4a): yellow solid (1.8 g,
44.11%) m.p. 240–242 °C; IR(KBr pellet) mmax: 3,450, 2,919,
1,563 cm-1. 1H NMR (CDCl3): d9.71 (bs, 1H, N14–H), 8.00
(d, 1H, C2–H, J = 8.92 Hz), 7.52–7.12 (m, 10H, C3–, C5–,
0
0
0
0
0
C10–, C12–, C13–, C2 –, C3 –, C4 –, C5 –, C6 –H), 3.13 (t, 2H,
123

404
J Chem Crystallogr (2010) 40:402–411
C9–2H, J = 6.36 Hz). 2.83 (t, 2H, C7–2H, J = 5.16 Hz),
2.46 (s, 3H, C11–CH3), 2.08–2.03 (m, 2H, C8–2H).
0.394(2) in the crystal investigated. The two moieties were
restrained to have approximately the same geometry
(excluding the 10- and 12-methyl groups) and the ADPs of
equivalent atoms were constrained to be identical. The C–
Cmethyl distances involving the 10 and 12-methyl groups in
both molecules were also restrained to be approximately the
same. The atoms C11, C12, C14, C15 and C20 are heavily
overlapping with their counterparts in the other moiety and
were restrained to be isotropic within a standard deviation of
Mixture of 4-chloro-12-methyl-6-phenyl-7,8,9,14-tetrahydroqu-
inolino[20,30:7,6]cyclohept[b]indole (4b) and 4-chloro-10-
methyl-6-phenyl-7,8,9,14-tetrahydroquinolino[20,30:7,6]
cyclohept[b]indole (4e): yellow solid (1.92 g, 47.02%)
m.p. 206–208 °C. IR (KBr) mmax:3,450, 3,023, 2,923,
1,563 cm-1. 1H NMR (CDCl3) (12-methyl isomer): d9.67
(bs, 1H, N14–H), 8.01 (d, 1H, C2–H, J = 8.92 Hz0), 7.57–
2
0
0
˚
0.01 A . In all four structures the hydrogen atoms were
7.11 (m,0 10H, C3–, C5–, C10–, C11–, C13–, C2 –, C3 –, C4 –,
0
C5 –, C6 –H), 3.15 (t, 2H, C9–2H, J = 6.32 Hz), 2.84–2.79
placed in calculated positions and were refined with isotropic
displacement parameters 1.2 (N–H, C–H and CH2) or 1.5
(CH3) times that of the adjacent carbon or nitrogen atom.
Crystal data and crystallographic experimental details
for compounds 4a, b/e, c and d are listed in Table 1, non-
covalent interactions are listed in Table 2.
(m, 2H, C7–2H), 2.49 (s, 3H, C12–CH3), 2.08–2.02 (m, 2H,
C8–2H). (10-methyl isomer): d9.85 (bs, 1H, N14–H), 8.00
(d, 1H, C2–H, J = 8.92 Hz), 7.57–7.11 (m, 10H, C3–, C5–,
0
0
0
0
0
C11–, C12–, C13–, C2 –, C3 –, C4 –, C5 –, C6 –H), 3.47 (t, 2H,
C9–2H, J = 6.28 Hz), 2.84–2.79 (m, 2H, C7–2H), 2.74 (s,
3H, C10–CH3), 2.08–2.02 (m, 2H, C8–2H).
4-Chloro-13-methyl-6-phenyl-7,8,9,14-tetrahydroquino-
lino[20,30:7,6]cyclohept[b]indole 4c): yellow solid (1.84 g,
45.09%) m.p. 197–198 °C. IR (KBr) mmax:3,431, 2,924,
Results and Discussion
1
1,586 cm-1. H NMR (CDCl3): d9.68 (bs, 1H, N14–H),
8.06 (d, 1H, C2–H, J = 80.92 Hz), 7.61–7.25 (m, 10H, C3–,
The quinolinocyclohept[b]indole derivatives that are the
topic of this study were prepared from easily accessible
1-oxo-1,2,3,4,5,10-hexahydrocyclohept[b]indole synthons
(2) by acid catalyzed condensation with 2-amino-5-chlor-
obenzophenone. Compounds (2) in turn were obtained by
Fischer indole cyclization of the approproriate cycloheptan-
1,2-dione-1-phenyl hydrazole as shown in Scheme 1, and
were purified by column chromatography. One of the reac-
tions yielded a mixture of two hexahydrocyclohept[b]in-
doles isomers, the 10 and 12 isomers 2b and 2e of 2 as
evidenced by the presence of two distinct sets of N–H and
0
0
0
0
C5–, C10–, C11–, C12–, C2 –, C3 –, C4 –, C5 –, C6 –H), 3.20–
2.83 (m, 4H, C7– and C9–2H), 2.63 (s, 3H, C13–CH3),
2.11–2.05 (m, 2H, C8–2H).
4-Chloro-6-phenyl-7,8,9,14-tetrahydroquinolino[20,30:7,6]cy-
clohept[b]indole (4d): yellow solid (1.82 g, 44.6%) m.p. 202–
204 °C. IR (KBr) mmax:3,450, 2,925, 1,605 cm-1. 1H NMR
(CDCl3): d9.82 (bs, 1H, N14–H), 8.02 (d, 1H, C2–H,
J = 9.04 Hz), 7.62–7.09 (m, 11H, C3–, C5–, C10–, C11–,
0
0
0
0
0
C12–, C13–, C2 –, C3 –, C4 –, C5 –, C6 –H), 3.18 (t, 2H,
C9–2H, J = 6.36 Hz), 2.86–2.83 (m, 2H, C7–2H), 2.17–2.06
(m, 2H, C8–2H).
1
aliphatic protons in the H NMR spectrum of the mixture.
The isomers could not readily be separated by column
chromatography and the mixture was thus used without
further resolution in the synthesis of the quinolinocycloh-
ept[b]indoles (4).
Crystallographic Studies
Diffraction data were collected on a Bruker AXS SMART
APEX CCD diffractometer at 100(2) K using monochro-
matic Mo Ka radiation with the omega scan technique. Data
for 4a, 4b/e, 4c and 4d were collected, their unit cells
determined, and the data integrated and corrected for
absorption and other systematic errors using the Apex2 suite
of programs [16]. The structures were solved by direct
methods and refined by full matrix least squares against F2
with all reflections using SHELXTL [17]. Refinement of an
extinction coefficient was found to be insignificant. All non-
hydrogen atoms were refined anisotropically. Crystals of 4b/
e consisted of a mixture of the 10-methyl and 12-methyl
derivatives 4b and 4e of 4-chloro-6-phenyl-7,8,9,14-tetra-
hydroquinolino[20,30:7,6]cyclohept[b]indole. The two com-
pounds are disordered as a solid solution over the same
crystallographic position. The two molecules are distinct and
well resolved with a refined occupancy ratio of 0.606(2) to
The 4-chloro-6-phenyl-7,8,9,14-tetrahydroquinolino[20,30:
7,6]cyclohept[b]indole derivatives (4) were obtained in one
pot reactions via acid catalyzed condensation and cyclization
of the respective 1-oxo-1,2,3,4,5,10-hexahydrocyclohept[b]
indole (2) and 2-amino-5-chlorobenzophenone (3) in glacial
acetic acid (Scheme 1). Derivatives 4a, 4c and 4d were
obtained as pure compounds after column chromatography
and single crystals were obtained by crystallization from
ethanol. The mixture of 4b and 4e obtained from 2b/e was
however again not resolvable by chromatography and crys-
tallization from ethanol yielded a solid solution of the two
compounds as will be described below.
The five compounds 4a to 4e are based on the same
chemical scaffold and are distinguished from each other
only by the presence, absence or position of a methyl group
at the indole phenyl ring. Compound 4d represents the
123

J Chem Crystallogr (2010) 40:402–411
405
Table 1 Crystal data and structure refinement of 4a, 4b and 4c
4a
4b/e
4c
4d
Empirical formula
C27H21ClN2
408.91
0.61(C27H21ClN2)
0.39(C27H21ClN2)
408.91
C27H21ClN2
C26H19ClN2
Formula weight
Solvent
408.91
394.88
Cryst. habit, color
Temperature (K)
Crystal system
Space group
Plate, yellow
100(2)
Block, colourless
100(2)
Block, yellow
100(2)
Block, yellow
100(2)
Triclinic
Triclinic
Triclinic
Triclinic
P1
P1
P1
P1
Unit cell dimensions
a = 10.1826(8),
b = 12.3918(7),
a = 10.168(2),
b = 10.304(2),
a = 9.0412(5),
b = 10.4926(6),
a = 9.6463(6),
b = 10.2395(6),
˚
˚
c = 10.610(2)A,
˚
˚
c = 16.3825(8)A,
a = 91.626(1),
b = 95.718(1),
c = 94.966(1)°
2,047.7(2)
c = 10.9093(6)A,
a = 94.482(1)
b = 102.181(1)
c = 95.812(1)°
1,001.13(10)
2
c = 10.6062(6)A,
a = 91.7263(8)
b = 94.7200(8)
c = 114.0812(7)°
950.85(10)
2
a = 89.169(3),
b = 87.774(3),
c = 63.726(2)°
996.0(3)
3
˚
Volume (A )
Z
4
2
Density (calcd.) (Mg/m3)
Absorption coefficient (mm-1
F(000)
1.326
1.363
1.356
1.379
)
0.203
0.209
0.208
0.216
856
428
Crystal size (mm)
h range for data collection (°)
Index ranges
0.55 9 0.55 9 0.25
1.65–28.28
-13 B h B 13,
-16 B k B 16,
-21 B l B 21
21,271
0.47 9 0.39 9 0.31
1.92–28.28
-13 B h B 13,
-13 B k B 13,
-14 B l B 14
10,287
0.55 9 0.51 9 0.41
1.92–31.57
0.55 9 0.50 9 0.36
1.93–31.52
-13 B h B 13,
-14 B k B 14,
-14 B l B 14
11,284
-13 B h B 13,
-15 B k B 15,
-15 B l B 15
11,987
Reflections collected
Independent reflections
R(int)
10,107
4,892
6,070
5,742
0.0158
0.0202
0.0145
0.0167
Absorption correction
Max./min. transmission
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I [ 2r (I)]
Multi-scan
0.951/0.853
543/0/10107
1.044
Multi-scan
0.937/0.758
331/85/4892
1.043
Multi-scan
Multi-scan
0.918/0.842
272/0/6070
1.017
0.925/0.855
1.040
R1 = 0.0374,
wR2 = 0.1001
R1 = 0.0431,
wR2 = 0.1042
0.383 and -0.388
R1 = 0.594,
wR2 = 0.1361
R1 = 0.800,
wR2 = 0.1482
0.601 and -0.413
R1 = 0.0456,
wR2 = 0.1248
R1 = 0.0513,
wR2 = 0.1304
0.529 and -0.478
R1 = 0.0377,
wR2 = 0.1017
R1 = 0.0419,
wR2 = 0.1058
0.531 and -0.247
R indices (all data)
-3
)
˚
Largest diff. peak and hole (e 9 A
unsubstituted parent structure, compounds 4a, 4b, 4c and
4e are the 11, 12, 13 and 10-methyl derivatives. All four
structures, pure compounds 4a, 4c and 4d and the mixed
crystals of 4b/e, crystallize as racemates in the triclinic
space group P1. Crystallographic details are given in
Table 1, Ortep style plots in Figs. 1, 4, 6, and 8.
exception of the torsion angle of the phenyl group the
molecules are virtually superimposable (see Fig. 2 for a
least square overlay). Both symmetrically independent
molecules are arranged in pairs of enantiomers around
inversion centers located in the plane through the origin
perpendicular to the c-axis for one crystallographically
independent molecule and in the parallel plane through the
center of the cell for the other, thus leading to a structure
with alternating double layers of A and B molecules as
shown in Fig. 3. In contrast to the majority of structures
with Z0 [ 1 and no strong directional forces [18] there is no
The structures of 4c and 4d crystallize with each one
molecule in the asymmetric part of the unit cell. Compound
4a does exhibit two crystallographically independent
molecules A and B in its structure. The two molecules have
the same conformation and geometry and, with the
123

406
J Chem Crystallogr (2010) 40:402–411
Table 2 Non-covalent interactions in the structures of 4a, 4b/e, 4c
and 4d
Table 2 continued
Hydrogen bonding and C–Hꢀꢀꢀp interactions
Hydrogen bonding and C–Hꢀꢀꢀp interactions
D–HꢀꢀꢀA
D–H
HꢀꢀꢀA
DꢀꢀꢀA
D–HꢀꢀꢀA
D–HꢀꢀꢀA
D–H
HꢀꢀꢀA
DꢀꢀꢀA
D–HꢀꢀꢀA
pꢀꢀꢀp interactions
Molecule 4a
Centroids
Cg4Cg3iii
CgꢀꢀꢀCg
3.8527(8)
CgI_Perp
3.1475(4)
CgJ_Perp
3.5902(5)
N1B–H1BꢀꢀꢀN2B
N1A–H1AꢀꢀꢀN2A
0.88
0.88
2.45
2.41
2.75
2.81
2.75
2.69
2.88
2.73
2.79
2.60
2.686(1)
2.658(1)
3.665(1)
3.780(1)
3.718(1)
3.566(1)
3.790(1)
3.480(1)
3.274(1)
3.525(1)
96
97
Molecule 4a: Symmetry codes: (i) x, y ? 1, z; (ii) x ? 1, y, z; (iii)
x - 1, y ? 1, z; (iv) –x ? 2, -y, -z ? 1; (v) x - 1, y, z; (vi) x ? 1,
y - 1, z, (vii) –x ? 1, -y ? 2, -z ? 2. Centroid codes: Cg1: N1A,
C1A, C6A, C7A, C13A; Cg2: N2A, C12A, C11A, C15A, C16A,
C21A; Cg3: C1A, C2A, C3A, C4A, C5A, C6A; Cg4: C16A, C17A,
C18A, C19A, C20A, C21A; Cg5: N1B, C1B, C6B, C7B, C13B; Cg6:
N2B, C12B, C11B, C15B, C16B, C21B; Cg7: C1B, C2B, C3B, C4B,
C5B, C6B; Cg8: C16B, C17B, C18B, C19B, C20B, C21B
C8B–H8B2ꢀꢀꢀCl1Bi 0.99
C10B–H10CꢀꢀꢀCl1Aii 0.99
C9A–H9A1ꢀꢀꢀCg6iii 0.99
154
167
166
147
153
136
113
164
C8B–H8B1ꢀꢀꢀCg8iv
C9B–H9B1ꢀꢀꢀCg6iv
0.99
0.99
C19A–H19AꢀꢀꢀCg7v 0.99
C19B–H19BꢀꢀꢀCg4vi 0.99
C27B–H27BꢀꢀꢀCg5iv 0.99
pꢀꢀꢀp interactions
Molecule 4b/e: Symmetrycodes: (i) x,y,-1 ? z;(ii) 1 - x, -y, 1 - z,
(iii) -x, -y, 1 - z. Centroid codes: Cg1: N2, C1, C6, C7, C13, Cg2:
N2B, C1B, C6B, C7B, C13B; Cg3 N1, C12, C11, C14, C15, C20; Cg4:
C1, C2, C3, C4, C5, C6; Cg5: C15, C16, C17, C18, C19, C20; Cg7:
N1B, C12B, C11B, C14B, C15B, C20B
Centroids
CgꢀꢀꢀCg CgI_Perp
3.8124(8) 3.5050(5) 3.5051(5)
3.8127(8) 3.5107(5) 3.5035(5)
3.9265(7) 3.2261(5) -3.7964(5)
CgJ_Perp
Cg1ꢀꢀꢀCg1vii
Molecule 4c: Symmetry codes: (i): 1 - x, 1 - y, 2 - z; (ii) -x, 1 - y,
2 - z. Centroid codes: Cg1: N1, C7, C6, C10, C9; Cg2: N2, C8, C14,
C15, C16, C21; Cg3: C16, C17, C18, C19, C20, C21
Cg1ꢀꢀꢀCg3vii
Cg2ꢀꢀꢀCg8iii
Molecule 4d: Symmetry codes: (i) x, y, -1 ? z; (ii) -x, 1 - y, 1 - z;
(iii) 1 - x,1 - y,1 - z. Centroid codes: Cg 1: N1, C1, C6, C7, C8;
Cg2: N2, C9, C10, C11, C12, C17; Cg3: C1, C2, C3, C4, C5, C6; Cg4:
C12, C13, C14, C15, C16, C17
Molecule 4b/e
N2B–H2BꢀꢀꢀN1B
N2–H2AꢀꢀꢀN1
C10–H10BꢀꢀꢀCl1i
C9–H9BꢀꢀꢀCg3ii
C9–H9BꢀꢀꢀCg8ii
C22–H22ꢀꢀꢀCg1ii
C22–H22ꢀꢀꢀCg2ii
C9B–H9B2ꢀꢀꢀCg3ii
C9B–H9B2ꢀꢀꢀCg7ii
pꢀꢀꢀp interactions
Centroids
0.88
0.88
0.99
0.99
0.99
0.95
0.95
0.99
0.99
2.34
2.36
2.81
2.82
2.83
2.66
2.71
2.86
2.89
2.606(17) 97.3
2.634(11) 98.3
3.751(9) 159
3.551(19) 131
3.59(3)
3.534(3)
3.594(4)
3.67(2)
3.72(3)
134
153
155
140
142
CgꢀꢀꢀCg CgI_Perp CgJ_Perp
3.835(16) -3.612(2) 3.172(12)
Cg4ꢀꢀꢀCg5iii
Cg4ꢀꢀꢀCg6iii
Molecule 4c
3.82(3)
3.617(2)
-3.159(19)
N1–H1ꢀꢀꢀN2
0.88
0.99
0.99
0.95
2.43
2.84
2.83
2.61
2.6694(14) 96.1
3.6953(14) 145
3.7472(14) 154
3.4670(18) 151
C11–H11BꢀꢀꢀCg3i
C12–H12BꢀꢀꢀCg2i
C23–H23ꢀꢀꢀCg1i
pꢀꢀꢀp interactions
Centroids
CgꢀꢀꢀCg CgI_Perp CgJ_Perp
3.8595(7) -3.6183(4) -3.6183(4)
Cg2ꢀꢀꢀCg2ii
Cg2ꢀꢀꢀCg3ii
Molecule 4d
3.8058(7) -3.6247(4) 3.6443(5)
Scheme 1 Synthesis of compounds 2 and 4
N1–H1ꢀꢀꢀN2
0.88
0.99
0.99
0.99
0.95
2.38
2.79
2.98
2.80
2.62
2.6405(12) 97.6
3.7209(11) 157
3.8281(13) 145
3.6973(13) 151
3.5200(12) 159
approximate or pseudo-symmetry in the structure of 3a,
and the two molecules are not related by pseudo
translation.
C20–H20AꢀꢀꢀCl1i
C18–H18AꢀꢀꢀCg4ii
C19–H19AꢀꢀꢀCg2ii
C26–H26ꢀꢀꢀCg1ii
The structure 4b/e is an example of a solid solution of
two chemically distinct molecules. This is especially
123

J Chem Crystallogr (2010) 40:402–411
407
Fig. 3 Packing and intermolecular interactions in 4a. View down the
a-axis. Colour coding indicates the two kinds of crystallographically
independent molecules. Black dots are crystallographic inversion
centers, turquoise dotted lines are C–Hꢀꢀꢀp and C–HꢀꢀꢀCl interactions
Fig. 1 Ortep representation of the two crystallographically indepen-
dent molecules of 4a (50% probability level)
the two molecules are disordered among each other and
occupy the same site (Fig. 4). The occupancy ratio for the
crystal investigated refined to 0.606(2) to 0.394(2), which
agrees well with the value found by NMR spectroscopy,
which shows two distinct well separated peaks in the
region typical for N–H hydrogen atoms and also separate
CH3 NMR signals with an integral ratio of 52:48.
There are no signs of additional ordering of the two
molecules in the structure of 4b/e. Its diffraction pattern
did not show any satellite reflections or other signs of a
possible supercell or commensurate or incommensurate
modeling, thus indicating that 4b/e is indeed an example of
a true solid solution. In order to be able to be accommo-
dated within the same available space despite of the dif-
ferent methyl substitution pattern the scaffolds of the two
molecules do slightly yield towards the steric pressure and
the hexahydrocyclohept[b]indole units do bend by 0.7 to
Fig. 2 Least square overlay of the two independent molecules in 4a
noteworthy as solid solutions of organic compounds are—
in contrast to solid solutions of purely inorganic com-
pounds—relatively rare. Thalladi and coworkers, for
example, give in a recent article on solid solutions and
cocrystals [19] only nine ‘‘notable exceptions’’ of publi-
cations that present true organic solid solutions [20–26]. A
solid solution of two indoloacridines chemically related to
the quinolinocyclohept[b]indoles described here was
recently reported by our laboratories [27]. Similar to the
two indoloacridines the molecules of 4b and 4e do, when
crystallized together from ethanol, not resolve in separate
crystals but co-crystallize as mixed crystals with both 4b
and 4e present in the structure. Despite of being positional
isomers with distinctly different molecular shapes the
compounds do not form traditional co-crystals with both
molecules located on different sites within the unit cell, but
˚
0.8 A so as to accommodate the methyl groups within the
space available without any strongly repulsive interactions
between neighboring molecules (Fig. 5).
In all four structures the shape of the molecules is very
similar and is characterized by the presence of three
roughly planar moieties within each molecule: the indole
and the 4-chloro-quinoline moieties and the phenyl ring
substituted onto the quinoline. None of these sections
˚
shows a deviation from planarity larger than 0.0348 A
(Fig. 6). The phenyl rings are all roughly perpendicular to
the plane of the quinoline units with dihedral angles
between 78.20(3)° for one molecule of 4a and 89.24(5)° in
4c. The indole and quinoline sections are fused with each
other via the central non planar cyclohepta-1,3-diene unit,
which forces the molecules as a whole to assume a rigid but
123

408
J Chem Crystallogr (2010) 40:402–411
Fig. 4 Ortep representation of
the molecules in 4b/e (50%
probability level). Dark
coloured atoms in the
disordered regions belong to
compound 4e, lighter grey
atoms and dashed bonds to
compound 4b
Fig. 5 Packing in 4b/e. View
down the b-axis. Colour coding
indicates the two compounds 3b
and 3e (red and green). Orange
sections are common to both
molecules. (Color figure online)
Fig. 6 Ortep representation
of the asymmetric unit of 4c
(50% probability level)
123

J Chem Crystallogr (2010) 40:402–411
409
Fig. 7 Packing and
intermolecular interactions in
4c. View down the b-axis.
Turquoise dotted lines indicate
C–Hꢀꢀꢀp and C–HꢀꢀꢀCl
interactions, green dotted lines
indicate pꢀꢀꢀp stacking
interactions (red dots represent
the ring centroids involved).
(Color figure online)
non-planar geometry. The cycloheptadiene unit is the
only slightly flexible feature within the molecules, so its
geometry is expected to determine the conformation of the
molecules as a whole. In all four molecules the cyclohep-
tadiene is found to be in an approximate C2-twist confor-
mation with dihedral angles between the two double bonds
of 20.0(2)° and 21.4(2)° in 4a, 18(2) and 19(3)° in 4b and
4e, 21.5(2)° in 4c and 16.3(2)° in 4d. The resulting angles
between the planes of the indole and quinoline units reflect
these dihedral angles and range between 20.57(4) and
14.17(4)°. The geometry of the propyl units is also essen-
tially the same for all five compounds. The central meth-
ylene unit is located nearly within the plane of the indole
moiety with a maximum deviation from this plane of
N–HꢀꢀꢀN interactions between the indole N–H groups and
the pyridyl nitrogen atoms. As expected for a hydrogen
bonding motif with a five membered ring (graph set motif
R115) the hydrogen bonds are strained and the N–HꢀꢀꢀH
angles are around 97° (Table 2). The packing of all four
compounds are characterized by the absence of strong
intermolecular interactions. Present are weak dispersive
interactions such as C–HꢀꢀꢀCl hydrogen bonds and inter-
actions that involve the p-electron density of the aromatic
rings (Table 2). Due to the non-planar nature of the mol-
ecules as a whole only a small number of p–p stacking
interactions are present—on average not more than one per
molecule—and these are interactions of each two individ-
ual aromatic rings and not infinite stacks of planar p sys-
tems. The few stacking interactions are augmented by a
larger number of C–Hꢀꢀꢀp interactions and it seems to be
these interactions, in combination with simple shape rec-
ognition, that dominate the packing of 4a to 4d. Figures 7
and 9 show each a view of the packing in the structures 4c
and 4d as examples for all four compounds.
˚
0.456(8) A in one of the molecules of 4b/e, but it deviates
quite substantially from that of the quinoline unit with
displacements from this plane being between 1.118(1) and
˚
1.217(2) A in the four structures. The only other structur-
ally characterized pyridino cyclohept[b]indole derivative
[14] deviates quite substantially from this geometry. In this
molecule described by Hegde et al. the pyridino cyclo-
heptindole unit is part of a larger functional moiety with
nine fused rings that wrap around a central water molecule
which is hydrogen bonded to two indole and two pyridyl
moieties. This forces the molecule as a whole to be nearly
planar with dihedral angles of the cycloheptatriene double
bonds of only 0.23 and 8.17° (for the two independent
pyridino cycloheptindole units) rather than the values
between 16 and 21° found for molecules 4a to 4e.
These first structural investigations of quinolinocycloh-
ept[b]indoles have thus shown that the molecular shape of
the molecules is not affected by the substitution pattern.
Based on the very similar conformations and geometries
found for molecules 4a to 4e it can be safely assumed that
the structures presented here are typical for such molecules
in the absence of strong intermolecular packing forces.
They can thus be used as first approximations for the
solution structures of quinolinocyclohept[b]indoles and
may assist in the investigation of their associated biological
and pharmacological properties (Figs. 8, 9).
The only classical hydrogen bonding interactions
observed in all four structures are intramolecular cyclic
123

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J Chem Crystallogr (2010) 40:402–411
Fig. 8 Ortep representation of
the asymmetric unit of 4d
(50% probability level)
Fig. 9 Packing and
intermolecular interactions in
4d. View down the b-axis.
Turquoise dotted lines indicate
C–Hꢀꢀꢀp and C–HꢀꢀꢀCl
interactions, green dotted lines
indicate pꢀꢀꢀp stacking
interactions (red dots represent
the ring centroids involved).
(Color figure online)
3. Knolker HJ, Reddy KR (2002) Chem Rev 102:4303–4427
4. Kawasaki T, Higuchi K (2005) Nat Prod Rep 22:761–793
5. Bennasar ML, Vidal B, Bosch J (1993) J Am Chem Soc 115:
5340–5341
6. Bennasar ML, Vidal B, Bosch J (1997) J Org Chem 62:3597–
3609
Supplementary Data
CCDC Deposit # 746542–746545. These data may be
obtained free of charge by sending an e-mail to: www.ccdc.
cam.ac.uk/data_request/cif. NMR and IR spectra of com-
pounds 2b/e and 4a to 4d.
7. Bennasar ML, Zulaica E, Juan C, Llauger L, Bosch J (1999)
Tetrahedron Lett 40:3961
8. Bennasar ML, Zulaica E, Sole D, Alonso A (2008) Synlett 667–
670
9. Benoit J, Routier S, Merour JY, Colson P, Hoursier C, Bailly C
(2000) Anticancer Res 20:3307
10. Clivio P, Richard B, Nuzillard JM, Zeches-Hanrot M (1995)
Phytochemistry 40:987–990
11. Bennasar ML, Vidal B, Kumar R, Lasaro A, Bosch J (2000) Eur J
Org Chem 3919
Acknowledgments We acknowledge UGC, New Delhi, India, for
the award of Major Research Project Grant No.F.No.31-122/2005.
M.S thanks UGC, New Delhi for the award of research fellowship.
Our sincere thanks to the Director, ISO Quality Assurance Cell, IICT,
Hyderabad and, The Chairman, NMR Research Center, IISc, Ban-
galore for providing NMR spectra. The X-ray diffractometer was
funded by NSF Grant 0087210, Ohio Board of Regents Grant CAP-
491, and by Youngstown State University.
12. Bennasar ML, Vidal B, Lazaro A, Kumar R, Bosch J (1996)
Tetrahedron Lett 37:3541–3544
13. Sridharan M, Rajendra Prasad KJ, Gunaseelan A, Thiruvalluvar
A, Butcher RJ (2009) Acta Cryst E65:o698
14. Hegde V, Hung C-Y, Madhukar P, Cunningham R, Hopfner T,
Thummel RP (1993) J Am Chem Soc 115:872
15. Kavitha V, Rajendra Prasad KJ (1999) J Heterocycl Comm 5:
481–487
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