Solid state structure by X-ray and 13C CP/MAS NMR of new 5,5′-diethoxy-3,3′-methanediyl-bis-indole

Article abstract of DOI:10.1016/j.molstruc.2006.08.003

5,5′-Diethoxy-3,3′-methanediyl-bis-indole 1 was synthesized by novel protocol and its solid state structure was analyzed using X-ray diffraction and ¹³C CP/MAS NMR methods. Double resonances were observed in the spectrum of 1, and different str

Full text of DOI:10.1016/j.molstruc.2006.08.003

Journal of Molecular Structure 831 (2007) 174–179
www.elsevier.com/locate/molstruc
13
Solid state structure by X-ray and C CP/MAS NMR
of new 5,50-diethoxy-3,30-methanediyl-bis-indole
a
b
a,
*
Magdalena Rasztawicka , Irena Wolska , Dorota Maciejewska
a
Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02 097 Warsaw, Poland
Department of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, 6 Grunwaldzka Street, 60 780 Poznan´, Poland
b
Received 6 April 2006; received in revised form 31 July 2006; accepted 2 August 2006
Available online 14 September 2006
Abstract
5,50-Diethoxy-3,30-methanediyl-bis-indole 1 was synthesized by novel protocol and its solid state structure was analyzed using X-ray
diffraction and 13C CP/MAS NMR methods. Double resonances were observed in the spectrum of 1, and different structure of both
indole systems in one molecule (shown by X-ray studies) is responsible for this spectral pattern. In the crystal only one intermolecular
hydrogen bond (N1–H1ꢀ ꢀ ꢀO110) was revealed, which is uncommon among bis-indole derivatives.
Ó 2006 Elsevier B.V. All rights reserved.
Keywords: 5,50-Diethoxy-3,30-methanediyl-bis-indole; X-ray data; 13C CP/MAS NMR analysis
1. Introduction
in the 13C CP/MAS NMR spectrum (Fig. 1) for the
majority of C atoms. This could have been caused by
the presence of two energetically similar conformers of
1 in solid state, or by a different packing mode of both
indole rings in one conformer as we defined it previously
for 5,50-dimethoxy-3,30-methanediyl-bis-indole 2 [1].
In the present paper, we report our novel protocol of the
synthesis of alkoxy indoles and bis-indoles, spectral data
for new intermediate (E)-5-ethoxy-2-nitro-b-morpholino-
styrene 1a as well as the single crystal X-ray diffraction
analysis, and fully resolved 13C CP/MAS spectra of new
5,50-diethoxy-3,30-methanediyl-bis-indole 1 in the tempera-
ture range 298–358 K.
In the course of our studies on bis-indoles [1,2] we are
interested in optimization of the synthetic procedure
leading to substituted indoles and subsequently to new
3,30-diindolylmethanes, which could inhibit human breast
cancer cell growth [3,4]. For 5,50-disubstituted-3,30-meth-
anediyl-bis-indoles, we observed a diversified resonance
pattern in solid state 13C CP/MAS NMR spectra and
various intermolecular interactions detected by X-ray
analysis, which could be responsible for their biological
function [5]. Moreover, X-ray studies revealed a butter-
fly-like shape for several of those bis-indoles, which is
analogous to the one proposed for inhibitors of HIV-1
reverse transcriptase [6]. The different structure in solid
state was dependent on the nature of substituents at
C5, C50 atoms of indole rings. Then we decided to con-
tinue studies on this class of compounds, and for new
2. Experimental
2.1. Syntheses
5,50-diethoxy-3,30-methanediyl-bis-indole
we observed double signals with intensity ratios of 1:1
1
(Scheme 1)
All chemicals were purchased from major chemical sup-
pliers as high or highest purity grade and used without fur-
ther purification. Melting points were determined with a
Digital Melting Point Apparatus 9001 and are uncorrected.
All reported elemental analyses were averaged from two
*
Corresponding author. Tel./fax: +480225720643.
E-mail address: domac@farm.amwaw.edu.pl (D. Maciejewska).
0022-2860/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2006.08.003

M. Rasztawicka et al. / Journal of Molecular Structure 831 (2007) 174–179
175
(2.5 ml) was added and the dark red solution was then
allowed to cool to room temperature. After nearly 24 h
at 4 °C orange crystals were formed. After filtration and
recrystallization from ethanol the obtained yield was
1.62 g (36.5% yield) of orange crystals with m.p. 121.8–
122.0 °C. Found: C, 60.29; H, 6.67; N, 10.03%. Calcd for
C14H18N204 278.14: C, 60.42; H, 6.52; N, 10.07%. 1H
NMR (400 MHz, CDCl3): 1.44 (t, J = 7.0 Hz, 3H, 12-
CH3), 3.17 (t, J = 4.6 Hz, 4H, 9-CH2, 90-CH2), 3.75 (t,
J = 4.6 Hz, 4H, 10-CH2, 100-CH2), 4.09 (q, J = 7.0 Hz,
2H, 11-CH2), 6.26 (d, J = 13.6 Hz, 1H, 7-H), 6.60 (dd,
J1 = 2.4 Hz, J2 = 9.2 Hz, 1H, 4-H), 6.73 (d, J = 13.6 Hz,
1H, 8-H), 6.84 (d, J = 2.4 Hz, 1H, 6-H), 7.97 (d,
13
J = 9.2 Hz, 1H, 3-H) ppm. C NMR (100 MHz, CDCl3):
14.84 (C-12), 48.90 (C-9, C-90), 64.15 (C-11), 66.43 (C-10,
C-100), 95.65 (C-7), 109.80 (C-6), 110.55 (C-4), 128.32 (C-
3), 138.05 (C-1), 139.40 (C-2), 143.98 (C-8), 162.45 (C-5)
Scheme 1. Reagents and conditions for preparation of 5,50-diethoxy-3,30-
methanediyl-bis-indole 1 with atom numbering of product 1 and interme-
diates 1a and 1b.
~
ppm. IR (nujol): m 3100–3000, 3000–2800, 1630, 1620,
1610, 1460, 1570 (NO2), 1450, 1330 (NO2), 1320, 1230,
1170, 1030, 870, 850, 760 cmꢁ1
.
independent determinations. Prefabricated silica gel sheets
(Merck Kieselgel 60 F254) were used for TLC.
2.1.2. 5-Ethoxyindole 1b [7]
(E)-5-Ethoxy-2-nitro-b-morpholinostyrene 1a (5.56 g,
0.02 mol) was dissolved in 170 ml of benzene and then
2 g of 10% Pd/C was added. The mixture was kept for
8 h at 50 °C and at a pressure of 8 atm in an autoclave.
Finally, the catalyst was removed from light green solution
by filtration. After solvent evaporation, the residue was
separated chromatographically on silica gel with toluene.
The oily residue of 1b was crystallized from hexane. The
obtained yield was 1.16 g (36.0 %) of white crystal with
m.p. 39.2–39.8 °C (35 °C [7]). 1H NMR (400 MHz,
CDCl3): 1.43 (t, J = 7.0 Hz, 3H, 12-CH3), 4.07 (q,
2.1.1. (E)-5-Ethoxy-2-nitro-b-morpholinostyrene 1a
A mixture of morpholine (7.49 g, 0.105 mol) and triethyl
orthoformate (7.41 g, 0.050 mol) with 0.2 ml CH3COOH
was stirred at 122 °C for 4 h. The ethanol forming during
the reaction and excess of orthoformate were evaporated.
The residue, white precipitate of trimorpholylmethane
was mixed at 115 °C with 3-methyl-4-nitroethoxybenzene
(2.97 g, 0.016 mol) (obtained from 3-methyl-4-nitrophenol
and ethyl iodide [7]). Next the mixture was heated at
150 °C for 7 h and then cooled to 70 °C. The ethanol
13
Fig. 1. The C CP/MAS NMR spectrum of 5,50-diethoxy-3,30-methanediyl-bis-indole 1 in solid state at 298 K. Assignment of resonances is shown in
table.

176
M. Rasztawicka et al. / Journal of Molecular Structure 831 (2007) 174–179
Table 1
J = 7 Hz, 2H, 11-CH2), 6.47 (d, J = 2.4 Hz, 1H, 4-H), 6.86
(dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H, 6-H), 7.10 (d, J = 2 Hz,
1H, 3-H),7.16 (t, J = 2.8 Hz, 1H, 2-H), 7.26 (d, J = 8.8 Hz,
1H, 7-H), 8.04 (br s, 1H, NH) ppm. 13C NMR (100 MHz,
CDCl3): 15.28 (C-12), 64.37 (C-11), 102.58 (C-4), 103.70
(C-3), 111.84 (C-7), 113.16 (C-6), 124.99 (C-2), 128.51 (C-
8), 131.18 (C-9), 153.64 (C-5) ppm.
Crystal data, data collection and structure refinement for 1
Compound
1
Empirical formula
Formula weight
T (K)
C21H22N2O2
334.41
293(2)
0.71073
Triclinic, P ꢁ 1
˚
Wavelength (A)
Crystal system, space group
Unit cell dimensions
2.1.3. 5,50-Diethoxy-3,30-methanediyl-bis-indole 1
˚
a (A)
8.0728 (9)
10.995 (1)
11.697 (1)
64.95 (1)
71.31 (1)
80.80 (1)
890.6 (2)
2, 1.247
0.081
356
3.31–26.50
ꢁ10 6 h 6 10
ꢁ11 6 k 6 13
ꢁ14 6 l 6 14
˚
b (A)
5-Ethoxyindole 1b (1.80 g, 0.005 mol) was dissolved in
water (25 ml) with formalin (0.185 ml, 0.20 g, 0.0025 mol)
and one drop of concentrated H2SO4 acid was added.
The mixture was kept out of light and stirred at 80–97 °C
for 11 h and then allowed to cool to room temperature.
The water phase was extracted three times with diethyl
ether (10 ml each). The organic phase was dried with
MgSO4. The solvent was evaporated in vacuum. The oily
residue was recrystallized from ethanol three times under
the conditions without light. Th obtained yield was 0.68 g
(81.34%) of white crystals with m.p. 139.7–140.0 °C.
Found: C, 75.41; H, 6.61; N, 8.37%. Calcd for
C21H20N2O2 334.40: C, 75.42; H, 6.63; N, 8.38%. 1H
NMR (400 MHz, CDCl3): 1.40 (t, J = 7.0 Hz, 6H, 12-
CH3, 120-CH3), 4.03 (q, J = 7.0 Hz, 4H, 11-CH2, 110-
CH2), 4.14 (s, 2H, 10-CH2), 6.85 (dd, J1 = 2.4 Hz,
J2 = 8.8 Hz, 2H, 6-H, 60-H), 6.88 (br s, 2H, 2-H, 20-H),
7.06 (d, J = 2.4 Hz, 2H, 4-H, 40-H), 7.22 (d, J = 8.8 Hz,
2H, 7-H, 70-H), 7.77 (br s, 2H, NH) ppm. 13C NMR
(100 MHz, CDCl3): 15.25 (C-12, C-120), 21.49 (C-10),
64.43 (C-11, C-110), 102.47 (C-4, C-40), 111.89 (C-7,
C-70), 112.78 (C-6, C-60), 115.45 (C-3, C-30), 123.21 (C-2,
C-200), 128.17 (C-8, C-80), 131.84 (C-9, C-90), 153.25 (C-5,
˚
c (A)
a (°)
b (°)
c (°)
3
˚
Volume (A )
Z, Dx (Mg/m3)
l (mmꢁ1
F(000)
)
h range for data collection (°)
hkl range
Reflections:
Collected
Unique (Rint
10,825
3672 (0.034)
2468
3672/0/226
1.050
0.0470
0.1293
0.155/ꢁ0.193
)
Observed (I > 2r(I))
Data/restraints/parameters
Goodness-of-fit on F2
R(F) (I > 2r(I))
wR(F2) (all data)
Max/min. Dq (e/A )
3
˚
non-hydrogen atoms were refined with anisotropic thermal
parameters. The coordinates of hydrogen atoms were calcu-
lated from the geometry and refined as a riding model with
their thermal parameters calculated as 1.2 (1.5 for methyl
group) times Ueq of the respective carrier carbon atom.
The CCDC 619208 contain supplementary crystallographic
data for this paper. These data can be obtained free of char-
ge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
~
C-5 ) ppm. IR (nujol): m 3450, 3360 (NH), 3100–3000,
3000–2800, 1630, 1590, 1480, 1450, 1370, 1220, 1190,
1050, 950, 870, 790 cmꢁ1
.
2.2. Crystallography
Crystals of 1 suitable for X-ray analysis were grown by
slow evaporation from acetone solution. All details of the
measurements, crystal data and structure refinement are
given in Table 1. The data were collected on an Oxford Dif-
fraction KM4CCD diffractometer [8] at 293 K, using graph-
ite-monochromated MoKa radiation. A total of 1072
frames were measured in six separate runs. The x-scan
was used with a step of 0.75°, two reference frames were
measured after every 50 frames, they did not show any sys-
tematic changes either in peaks positions or in their intensi-
ties. The unit cell parameters were determined by least-
squares treatment of setting angles of 3143 highest-intensity
reflections selected from the whole experiment. Intensity
data were corrected for the Lorentz and polarization effects
[9]. The structures were solved by direct methods with the
SHELXS97 program [10] and refined by the full-matrix
2.3. NMR spectra
1H NMR and 13C NMR spectra in solution were record-
ed with a Bruker Avance DMX 400, and standard Bruker
software was employed. The solid state 13C CP/MAS
NMR spectra were measured using a Bruker Avance
DMX 400. A powdered sample was spun at 10 kHz. Con-
tact time of 2 ms, repetition time of 20 s, and spectral width
of 24 kHz were used for accumulation of 3000 scans. Non-
protonated carbons were selectively observed by dipolar-
dephasing experiment with delay time 50 ls Temperature
measurement was made with a Bruker B-VT 1000E unit.
Chemical shifts d [ppm] were referenced to TMS. The nota-
tion used in detailed description of NMR resonances is giv-
en in Scheme 1.
least-squares method with the SHELXL97 program [11].
P
The function
w(|Fo|2 ꢁ |Fc|2)2 was minimized with
wꢁ1 = [r2(Fo)2 + (0.0663P)2], where P ¼ ðF 2 þ 2F 2Þ=3. All
o
c

M. Rasztawicka et al. / Journal of Molecular Structure 831 (2007) 174–179
177
2.4. Molecular modeling details
actions in solid state differentiate the structure of even sym-
metrically substituted indole rings. The calculated shielding
constants for optimized structure of 1 help us to assign of
1H and 13C resonances in solution spectra.
In order to properly assign the C atom resonances to A
and B indole rings, DFT calculations (B3LYP/6-311** and
CHF with GIAO approach) of 13C shielding constants
were carried out basing on the crystallographic atomic
coordinates. Then the linear correlation between the com-
puted shielding constants r [ppm] and the experimental
chemical shifts d [ppm] was found with correlation coeffi-
cient r2 = 0.992, and the resultant assignment is given in
Fig. 1.
Crystallographic atom coordinates were used for com-
putation of shielding constants r [ppm] of 13C atoms to
assign the double resonances in solid-state NMR spec-
trum. Conformation corresponding to a local minimum
was also analyzed as most adequate in the analysis of
solution spectra. We have employed DFT method with
B3LYP/6-311** hybrid functional for calculations of
geometries, and CHF-GIAO approach for shielding con-
stants calculations [12].
3. Results and discussion
3.1. Chemistry
3.3. X-ray structure of 1
New 5,50-diethoxy-3,30-methanediyl-bis-indole 1 was
prepared according to the procedure given by us in [1]
and shown in Scheme 1. For unknown (E)-5-ethoxy-2-ni-
tro-b-morpholinostyrene 1a more detailed data are given.
High purity 5-ethoxyindole 1b was obtained in reductive
cyclization process from 1a with a higher, sharp melting
point as compared with that obtained by previously pub-
lished procedure [7]. Its structure was proved by spectro-
scopic methods.
The molecular and crystal structure of 1 in solid state
was analyzed by single crystal X-ray diffraction. Crystallo-
graphic data, together with data collection and structure
refinement details are listed in Table 1. Selected bond
lengths, bond angles and torsion angles are listed in
Table 2. The displacement ellipsoid representation of the
molecule, together with the atomic numbering scheme, is
shown in Fig. 2 (the drawings were performed with a
Stereochemical Workstation [13]).
The molecular structure of 1 is very similar to 2 [1].
Two ethoxyindole systems (A and B, see Fig. 2) are con-
nected through a common C atom. Both indole moieties
are quite planar and their planes make an angle of
68.92(4)°. The small tilts between the planes of the
five-membered and six-membered rings are 4.38(8)° and
1.14(7)° in indoles A and B, respectively. The C10 atom
is displaced from the mean plane of indole fragments by
3.2. 13C CP/MAS NMR spectra of 1
The 13C CP/MAS NMR spectrum of 5,50-diethoxy-3,30-
methanediyl-bis-indole 1 in solid state at 298 K is shown in
Fig. 1 together with the assignment of resonances. The sin-
gle resonance observed for C10 atom is most consistent
with an interpretation demanding the presence of only
one molecule in the crystallographic independent unit,
and double resonances of the remaining C atoms could
be accounted for by the structurally distinct both indole
systems of A and B in one molecule.
The spectra in the range of 298–358 K did not show any
changes consistent with significant solid-state motions. As
the temperature is increased the aromatic signals between
113.6 and 115.3 ppm assigned to C6, C60 and C7, C70 pairs
of atoms merge becoming almost a singlet at 114.2 ppm,
and two signals of C12, C120 methyl carbons come closer.
This could be indicative of small motions of ethoxy groups,
and slight changes of the packing motif in the proximity of
C6, C60 and C7, C70 atoms.
A comparison of solid state spectrum of 1 with the solid
state spectrum of 5,50-dimethoxy derivative 2 [1] reveals
twofold multiplicity of resonances associated with C6,
C60 and C7, C70 atoms in 1 which were not observed for
2. This suggests crystallographic asymmetry contrasting
with the structure of 2.
The local minimum geometry computed at DFT level
(with B3LYP/6-311G** functional) showed a symmetrical
molecule with only a single set of calculated shielding con-
stants for both indole rings and both ethoxy substituents.
These data imply that the asymmetric intermolecular inter-
˚
0.089(2) and 0.052 A for indole A and B, respectively.
We have observed different conformations of the ethoxy
groups. The disposition of these groups with respect to
indole fragments can be described by the torsion angles
C4–C5–O11–C11 of 12.1(2)° and C40–C50–O110–C110 of
-1.7(2)°. In consequence the ethyl carbon atom C11 is
˚
found to be 0.364(3) and C12 0.571(3) A out of the
Table 2
˚
Selected bond lengths [A] and angles [deg] and selected torsional angles
[deg]
C3–C10
1.492 (2)
1.508 (2)
1.379 (2)
1.382 (2)
1.419 (2)
1.421 (2)
C30–C10
C5–O11
C50–O110
O11–C11
O110–C110
C3–C10–C30
C4–C5–O11
C40–C50–O110
115.5 (1)
124.3 (1)
124.8 (2)
C2–C3–C10–C30
C4–C5–O11–C11
C3–C10–C30–C20
C40–C50–O110–C110
ꢁ114.3 (2)
12.1 (2)
ꢁ4.8 (3)
ꢁ1.7 (3)

178
M. Rasztawicka et al. / Journal of Molecular Structure 831 (2007) 174–179
ferent packing modes of both indole systems could be
the reason for double resonances in the solid-state
NMR spectra.
As opposed to the above findings, the crystal structure
of 1 is quite different as compared with 2. In the case of
derivative 1, we have not observed any interaction between
NH or CH groups and p-electron systems of indole rings,
which are present in 2 and other bis-indole derivatives
[1,2,5]. Only intermolecular hydrogen bonds N–Hꢀ ꢀ ꢀO
determine the crystal packing of the molecules. They form
infinite chains (Fig. 3) parallel to the [ꢁ101] direction via
intermolecular hydrogen bonds N1–H1ꢀ ꢀ ꢀO110 (x ꢁ 1,y,
z + 1). The geometric parameters are: the N1ꢀ ꢀ ꢀO110
A
B
0
˚
˚
Fig. 2. The molecular structure of 1 with 30% probability displacement
distance is 2.976(1) A, H1ꢀ ꢀ ꢀO11 2.17 A and the angle
N1–H1ꢀ ꢀ ꢀO110 is 156°.
ellipsoids and the atom-numbering scheme.
indole A plane, the other ethyl carbon atom C110 is
4. Conclusions
0
˚
found to be only 0.023(3) and C12 -0.001 A out of the
indole B plane. So, the results show a different structure
of both ethoxyindole fragments of the molecule. We have
also observed such differences of the configuration of
methoxyindole systems for 2, and in both cases those dif-
Small changes in composition of the studied bis-indoles,
an exchange methoxy group to ethoxy one, introduced
more significant differences in the crystal arrangement.
The longer ether chains prevent the formation of
Fig. 3. Infinite chains of the molecules of 1.

M. Rasztawicka et al. / Journal of Molecular Structure 831 (2007) 174–179
179
[8] Oxford Diffraction Poland, CrysAlisCCD, CCD data collection GUI,
version 1.171, 2003.
[9] Oxford Diffraction Poland, CrysAlisRED, CCD data reduction GUI,
version 1.171, 2003.
[10] G.M. Sheldrick, Acta Crystallogr. A46 (1990) 467.
[11] G.M. Sheldrick, SHELXL97, Program for the Refinement of Crystal
Structures, University of Go¨ttingen, Germany, 1997.
N–Hꢀ ꢀ ꢀp impact, which could alter their interactions with
biological target. Only a single chain of intermolecular
hydrogen bonds between N1–H1ꢀ ꢀ ꢀO110 was revealed in
the crystal.
Double resonances in 13C CP/MAS NMR spectrum of 1
do not arise from the presence of two conformers in solid
state, but from a different packing mode of both indole
systems.
[12] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb,
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Clifford, J. Cioslowski, B.B. Stefanov, G. Liu, A. Liashenko, P.
Piskorz, I. Komaromi, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-
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