Journal of Molecular Structure 688 (2004) 87–94
www.elsevier.com/locate/molstruc
Structures and vibrational spectra of indolecarboxylic acids.
Part II. 5-Methoxyindole-2-carboxylic acidq
Barbara Morzyk-Ociepaa, Danuta Michalskab,*, Adam Pietraszkoc
a
Institute of Chemistry and Environmental Protection, Pedagogical University, Al. Armii Krajowej 13/15, 42-200 Cze˛stochowa, Poland
b
Institute of Inorganic Chemistry, Wrocław University of Technology, ul. Smoluchowskiego 23, 50-370 Wroclaw, Poland
c
Institute of Low Temperature and Structural Research, Polish Academy of Science, ul. Okólna 2, 50-950 Wroclaw, Poland
Received 28 July 2003; accepted 24 September 2003
Abstract
The crystal and molecular structure of 5-methoxyindole-2-carboxylic acid (5-MeOICA) are determined by single crystal X-ray diffraction
analysis, infrared spectra and density functional (B3LYP) calculations. The title compound crystallizes in the monoclinic system, space
b ¼ 91:1ð1Þ8; V ¼ 3541:0ð1Þ A
3 and z ¼ 16: There are two independent
group C2=c; with a ¼ 13:079ð3Þ; b ¼ 7:696ð2Þ; c ¼ 35:185ð7Þ A;
molecules of 5-MeOICA in the asymmetric unit cell. The molecular ribbons, constituted by two independent molecular chains, are held
together by intermolecular O – H· · ·O and N – H· · ·O hydrogen bond interactions. The carboxylic O atom is the acceptor of two hydrogen
bonds. In molecular ribbon, the relative orientation of the A and B carboxylic groups is nearly perpendicular, which leads to formation of the
zig-zag pattern of H-bonds. The molecular layers, separated by about 3.344 Å, are arranged in stacks. Interestingly, the layers in the adjacent
stacks are oriented in a herringbone-like pattern.
The B3LYP-calculated bond lengths and angles are in good agreement with experimental data. Examination of the infrared spectrum of 5MeOICA supports the conclusions from the X-ray diffraction studies. The characteristic bands at 3336, 1695 and 1206 cm21 have been
assigned to the stretching vibrations of the N – H, CyO and C – O groups, respectively.
q 2003 Elsevier B.V. All rights reserved.
Keywords: 5-Methoxyindole-2-carboxylic acid; Crystal; Molecular structure; Hydrogen bond; Density functional theory
1. Introduction
5-Methoxyindole-2-carboxylic acid (5-MeOICA) is a
potent inhibitor of respiration and potassium-ion transport
in the Archaebacterium Haloferax-Volcanii) [1]. Moreover,
5-MeOICA is a specific inhibitor of binding proteindependent transport systems [2]. It has been reported that
5-methoxyindole-6-hydroxy-2-carboxylic acid is produced
during progression of malignant melanoma [3,4]. Thus, this
compound has been applied as the biochemical marker for
survival prognosis of patients with malignant melanoma,
and for early detection of the metastases of this cancer
[3 – 8]. Furthermore, it can be used as the diagnostic marker
q
Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.molstruc.2003.09.029
* Corresponding author. Tel.: þ 48-713203759; fax: þ 48-713284330.
E-mail address: [email protected] (D. Michalska).
0022-2860/$ - see front matter q 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2003.09.029
indicating growth of malignant transformation in large
pigmented naevi during childhood [9].
In Part I [10] we have determined the crystal and
molecular structure of the parent molecule, indole-2carboxylic acid (ICA). In this paper, its 5-methoxy
derivative, 5-MeOICA, is examined using single crystal
X-ray diffraction analysis, infrared spectra and density
functional (B3LYP) method.
2. Experimental
2.1. Preparation of crystals of 5-MeOICA
An amount of 1 mmol (0.0584 g) of NaCl dissolved in
10 cm3 of water was added to 1 mmol (0.1912 g) of
5-MeOICA (Lancaster) in 50 cm3 ethanol. The mixture
was heated at 240 K until the organic compound dissolved.
88
B. Morzyk-Ociepa et al. / Journal of Molecular Structure 688 (2004) 87–94
Table 1
Crystal data and structure refinement for 5-methoxyindole-2-carboxylic
acid (5-MeOICA)
Empirical formula
Formula weight
Temperature (K)
Crystal system
Space group
Unit cell dimensions (Å and deg)
Volume (Å3)
Z (molecule/cell)
Density calculated (mg m23)
Absorption coefficient (mm21)
Fð000Þ
u range for data collection (8)
Reflections collected/unique
Data/restraints/parameters
Goodness-of-fit on F 2
Final R indices ½I . 2sigmaðIÞ
R indices (all data)
C10 H9 N O3
152.94
293(2)
Monoclinic
C2=c
a ¼ 13:079ð3Þ
b ¼ 7:696ð2Þ
c ¼ 35:185ð7Þ
b ¼ 91:06ð3Þ
3541.0(14)
16
1.434
0.107
1600
3.12–29.5
16784/4676 ½RðintÞ ¼ 0:0398
4676/0/326
1.193
R1 ¼ 0:0447; wR2 ¼ 0:0678
R1 ¼ 0:0833; wR2 ¼ 0:0750
After 6 days dark-yellow crystals of the title compound
were formed.
2.2. X-ray analysis
The crystal data and the refinement procedure are given
in Table 1. All measurements were performed using an
automatic X-ray four-circle EXCALIBUR single crystal
diffractometer with CCD area detectors and graphite
monochromated Mo Ka radiation ðl ¼ 0:071073 nmÞ:
The details of the data collection are analogous to those
described in Ref. [10]. The structure was solved by direct
methods (program SHELXS -97 [11] and refined by the
full-matrix least-squares method based on F 2 using
SHELXL -97 [12]. All non-hydrogen atoms were refined
anisotropically by unit-weighted full-matrix least square
methods. Hydrogen atoms were included from the
difference Fourier Dr maps and refined with isotropic
thermal parameters.
2.3. Infrared measurements
The FT-infrared spectrum of crystalline 5-MeOICA in the
region 4000 –400 cm21 was measured on a Nicolet-Nexus
spectrometer using the KBr pellets.
2.4. Theoretical methods
Full geometry optimization has been performed for 16
possible conformers of the title molecule. Calculations were
performed by HF and density functional three-parameter
hybrid (B3LYP) methods [13,14] with 6-311þ þ G(df,p)
basis set [15]. (The figures with the conformers and
the calculated relative energies are available in
Supplementary materials).
All computations were carried out with the GAUSSIAN 98
programs [16].
Fig. 1. The overall view and labeling of the atoms in two independent molecules (designated as A and B) of 5-methoxyindole-2-carboxylic acid (5-MeOICA).
B. Morzyk-Ociepa et al. / Journal of Molecular Structure 688 (2004) 87–94
3. Results and discussion
3.1. Description of the structure
The single crystal X-ray diffraction analysis has revealed
that the title compound crystallizes in the monoclinic system,
space group C2=c; with two independent molecules in the
asymmetric unit cell. The overall view and labeling of the
atoms in two independent molecules (designated as A and B)
are displayed in Fig. 1. Table 2 lists the selected bond lengths
and angles, along with the theoretical values calculated by the
B3LYP method. Although the calculations have been
performed for an isolated molecule in the gas phase,
the
agreement
between
the
theoretical
and
experimental results is quite good. It should be noted that
the theoretical isomer of the lowest energy is analogous to the
experimentally determined structure of 5-MeOICA.
According to the X-ray results, the corresponding bond
lengths in A and B molecules show small differences (up to
89
^ 0.004 Å) for C0 – C1, C1 – C2, C3 – C8, C6 – C7 and
C5 – O3 bonds. More pronounced differences are observed
for the bonds involved in intermolecular hydrogen bonds.
For example, the O2 –H0 bond is slightly longer in B than in
A (1.002 vs. 0.988 Å, respectively). The opposite effect is
observed for the N1 –H1 bond, which is slightly longer in A
(0.952(14) Å) than in B (0.924(14) Å).
The corresponding bond angles in A and B molecules are
very similar, except for the C5 – O3 – C9 angle, which is
smaller, by about 18, in B.
The conjugated six-membered and five-membered rings
of the title molecule are nearly coplanar, for example,
the N1 –C1 – C2 –C3 torsional angle is almost zero (0.0(1)
and 2 0.5(1)8, in A and B, respectively). The carboxylic
group is only slightly distorted from the plane of the rings: the
dihedral angle between the best least-squares planes formed
by the indole ring atoms (C1, C2, C3, C4, C5, C6, C7, C8 and
N1), plane I, and the carboxylic group atoms (C0, O1 and O2
atoms), plane II, is 1.94(0.16)8 in A, and 1.61(0.16)8 in B.
Table 2
The selected bond lengths (Å) and bond angles (8), with e.s.d.s. in parentheses, determined for 5-MeOICA by X-ray diffraction and the corresponding
theoretical parameters, calculated by the B3LYP/6-311þþ G(df,p) method
Experiment
O(1A)–C(0A)
O(2A)–C(0A)
O(2A)–H(0A)
C(0A)–C(1A)
C(1A)–C(2A)
C(1A)–N(1A)
C(2A)–C(3A)
C(3A)–C(8A)
C(3A)–C(4A)
C(4A)–C(5A)
C(5A)–C(6A)
C(6A)–C(7A)
C(7A)–C(8A)
C(8A)–N(1A)
N(1A)–H(1A)
C(5A)–O(3A)
O(3A)–C(9A)
O(1A)–C(0A)–O(2A)
O(1A)–C(0A)–C(1A)
O(2A)–C(0A)–C(1A)
C(0A)–C(1A)–N(1A)
N(1A)–C(1A)–C(2A)
C(1A)–C(2A)–C(3A)
C(2A)–C(3A)–C(8A)
C(2A)–C(3A)–C(4A)
C(3A)–C(4A)–C(5A)
C(4A)–C(5A)–C(6A)
C(5A)–C(6A)–C(7A)
C(6A)–C(7A)–C(8A)
C(7A)–C(8A)–C(3A)
C(7A)–C(8A)–N(1A)
C(8A)–N(1A)–C(1A)
O(3A)–C(5A)–C(4A)
O(3A)–C(5A)–C(6A)
C(5A)–O(3A)–C(9A)
1.226(1)
1.326(1)
0.988(17)
1.451(2)
1.374(1)
1.381(1)
1.419(2)
1.407(2)
1.416(2)
1.367(2)
1.411(2)
1.369(2)
1.394(2)
1.379(1)
0.952(14)
1.374(1)
1.424(2)
122.6(1)
125.2(1)
112.2(1)
122.0(1)
109.3(1)
107.5(1)
106.6(1)
133.6(1)
118.0(1)
121.4(1)
121.6(1)
117.6(1)
121.6(1)
130.0(1)
108.1(1)
125.0(1)
113.6(1)
117.8(1)
B3LYP
O(1B)– C(0B)
O(2B)– C(0B)
O(2B)– H(0B)
C(0B)–C(1B)
C(1B)–C(2B)
C(1B)–N(1B)
C(2B)–C(3B)
C(3B)–C(8B)
C(3B)–C(4B)
C(4B)–C(5B)
C(5B)–C(6B)
C(6B)–C(7B)
C(7B)–C(8B)
C(8B)–N(1B)
N(1B)– H(1B)
C(5B)–O(3B)
O(3B)– C(9B)
O(1B)– C(0B)–O(2B)
O(1B)– C(0B)–C(1B)
O(2B)– C(0B)–C(1B)
C(0B)–C(1B)–N(1B)
N(1B)– C(1B)–C(2B)
C(1B)–C(2B)–C(3B)
C(2B)–C(3B)–C(8B)
C(2B)–C(3B)–C(4B)
C(3B)–C(4B)–C(5B)
C(4B)–C(5B)–C(6B)
C(5B)–C(6B)–C(7B)
C(6B)–C(7B)–C(8B)
C(7B)–C(8B)–C(3B)
C(7B)–C(8B)–N(1B)
C(8B)–N(1B)–C(1B)
O(3B)– C(5B)–C(4B)
O(3B)– C(5B)–C(6B)
C(5B)–O(3B)–C(9B)
1.226(1)
1.326(1)
1.002(17)
1.454(2)
1.371(1)
1.381(1)
1.420(2)
1.410(2)
1.416(2)
1.370(2)
1.411(2)
1.372(2)
1.399(2)
1.379(1)
0.924(14)
1.378(1)
1.425(2)
122.4(1)
125.5(1)
112.1(1)
122.3(1)
109.7(1)
107.4(1)
106.6(1)
133.6 (1)
117.9(1)
121.5(1)
121.7(1)
117.5(1)
121.6(1)
130.1(1)
108.0(1)
124.5(1)
114.0(1)
116.8(1)
1.214
1.353
0.968
1.456
1.379
1.379
1.423
1.419
1.410
1.382
1.417
1.376
1.400
1.370
1.008
1.366
1.416
122.7
124.1
113.2
118.8
109.3
107.0
106.9
133.3
118.3
121.0
121.6
117.8
121.4
130.8
109.0
124.7
114.3
118.3
90
B. Morzyk-Ociepa et al. / Journal of Molecular Structure 688 (2004) 87–94
Table 3
Hydrogen bonds distances (Å) and angles (8) in 5-MeOICA
D –H· · ·A
D –H
H…A
D…A
,D–H· · ·A
O(2A)–H(0A)· · ·O(1B)i
O(2B)–H(0B)· · ·O(1A)ii
N(1A)–H(1A)· · ·O(1B)ii
N(1B)–H(1B)· · ·O(1A)i
0.988(17)
1.002(17)
0.952(14)
0.924(14)
1.710(18)
1.771(17)
2.131(14)
2.142(14)
2.651(1)
2.707(1)
3.068(2)
3.050(2)
157.6(15)
154.0(15)
167.8(11)
167.2(12)
Symmetry transformations used to generate equivalent atoms: (i) 2x þ
1; 2y; 2z þ 1; (ii) 2x þ 1=2; 2y þ 1=2; 2z þ 1:
The 5-methoxy group is tilted away from the molecular
plane: the dihedral angle between the plane I and plane III,
formed by the methoxy group atoms (C5, O3, C9) is
5.24(0.19)8 in A, and 2.79(0.19)8 in B.
Comparison of the bond lengths in the title molecule with
those of indole-2-carboxylic acid (ICA) [10] gives
information on the effect of the 5-methoxy group on the
geometry of the indole ring. In both the A and B molecules
of 5-MeOICA, the C4 – C5 and C5 –C6 bonds are longer,
by about 0.01 Å, than the corresponding bonds in ICA.
Thus, in the title molecule, the double bond character of
these bonds decreases. This effect can be attributed to
the p-conjugative effect of the methoxy substituent on the
aromatic ring [17].
Hydrogen bond lengths and bond angles of the
title molecule are listed in Table 3. Fig. 2 illustrates
the molecular ribbon constituted by two independent
molecular chains of A and B molecules held together by a
hydrogen bond network. It is seen that A molecules are
oriented almost perpendicularly to the direction of B
molecules, which leads to formation of the zig-zag pattern
of H-bonds. The carboxylic O1 atom is the acceptor of two
hydrogen bonds, while both the O2 – H and N1 – H groups act
as the donors. The O(2A)-H(0A)· · ·O(1B)i (i: 2x þ
1; 2y; 2z þ 1 distance (2.651 Å) is slightly shorter than the
O(2B) – H(0B)· · ·O1Aii distance of 2.707 Å (ii: 2x þ 1=2;
2y þ 1=2; 2z þ 1). In contrast to the above, the
N(1A) –H(1A)· · ·O(1B)ii distance of 3.068 Å is slightly
longer than N(1B) – H(1B)· · ·O1Ai (3.050 Å). Thus, in
5-MeOICA, the intermolecular N –H· · ·O hydrogen bond is
weaker than O –H· · ·O hydrogen bond.
It should be emphasized that, in contrast to typical
carboxylic acid dimers in the solid state (e.g. acetic acid
dimers), both indole-2-carboxylic acid (ICA) and its 5-methoxy derivative form a non-linear O2–H· · ·O1 hydrogen bonds.
In the title compound, the O2 – H· · ·O1 angle is equal
157.6(15)8 in A, and 154.0(15)8 in B. In ICA the corresponding
bond angle is similar, 159.2(10)8 [10]. This effect is due to
nearly orthogonal arrangement of the carboxylic groups
participating in intermolecular hydrogen bonding.
Fig. 3 shows the arrangement of the molecules in the unit
cell, viewed down b-axis. Fig. 4 illustrates the projection of
the crystal on the 110 plane. It is interesting to note that
Fig. 2. The molecular ribbon constituted by two independent molecular chains of A and B molecules held together by hydrogen bonds (H-bonds are indicated
by dashed lines).
B. Morzyk-Ociepa et al. / Journal of Molecular Structure 688 (2004) 87–94
Fig. 3. The arrangement of the 5-MeOICA molecules in the unit cell, projected down b-axis.
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B. Morzyk-Ociepa et al. / Journal of Molecular Structure 688 (2004) 87–94
Fig. 4. Projection of the crystal structure of 5-MeOICA on the 110 plane.
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B. Morzyk-Ociepa et al. / Journal of Molecular Structure 688 (2004) 87–94
stacks of layers are alternately directed, similarly as in the
ICA crystal [10]. In the crystal of 5-MeOICA, it is clear that
the molecules in the adjacent stacks are oriented in the
tail-to-tail fashion (the methoxy groups of two adjacent
stacks are in close vicinity to each other). Examination of
the relative positions of atoms in the neighboring layers of
5-MeOICA reveals the characteristic packing motifs: the
carboxylic oxygen atoms in one layer are positioned near
the centroids of the indole rings. For example, the O1B
and O2B atoms in one layer are located above the
five-membered and six-membered rings, respectively, of
the A molecule in the other layer. Thus, the p-orbitals of
lone electron pairs of the oxygen atoms are directed towards
the centroids of the aromatic rings. Such an arrangement of
molecules increases p –p stacking interaction between
neighboring layers. The opposite effect (repulsion between
the lone electron pairs of oxygen atoms in the neighboring
layers) was observed in the crystal of ICA [10]. It should be
emphasized that the distance between the molecular layers in
5-MeOICA (3.344 Å), is shorter than that in ICA (3.819 Å).
Fig. 5 shows the projection of crystal of 5-MeOICA
along c-axis. The most striking feature of this structure is the
herringbone-like arrangement of layers in the adjacent
stocks. The torsion angle between the two adjacent stacks
(determined as the angle between the normals to planes
defined by the indole rings in adjacent stacks) is equal to
66.08. For comparison: the analogous torsion angle between
stacks, in ICA, was equal to 49.58 [10].
93
3.2. Infrared spectrum
The infrared spectrum of crystalline 5-MeOICA is
shown in Fig. 6. The strong band at 3336 cm21 is
assigned to the N – H stretching vibration. The frequency
of this mode is slightly lower than that in indole-2carboxylic acid (3350 cm21, Part I), which indicates that
intermolecular N –H· · ·O hydrogen bonds between A and
B independent molecules are slightly stronger than those
between ICA molecules. This is confirmed by the results
from X-ray analyses, both the N1A – H1A· · ·O1B
(3.068 Å) and N1B – H1B· · ·O1A (3.050 Å) bond
distances are slightly shorter than the N1 – H1· · ·O1
distance in ICA (3.118 Å).
The broad band between 3200 and 2000 cm21 is assigned
to the n(O – H) stretching vibration of the OH group involved
into intermolecular hydrogen bonding. The bands arising
from the aromatic C – H stretching vibrations
(around 3080 cm21) and the methyl group stretching
vibrations (at about 2991– 2910 cm21) are also observed.
The very strong band at 1695 cm21 is undoubtedly due to
the n(CyO) stretching vibration, whereas the strongest band
at 1206 cm21 is attributed to the n(C – O) stretching
vibration in the carboxylic group. It is interesting to note
that the corresponding bands in the spectrum of ICA occur
at similar wavenumbers, 1707 and 1194 cm21, respectively.
Similarity in the frequencies of the corresponding OyC–O
stretching vibrations in both the molecules indicates
Fig. 5. Projection of the crystal structure of 5-MeOICA along c-axis.
94
B. Morzyk-Ociepa et al. / Journal of Molecular Structure 688 (2004) 87–94
Fig. 6. The infrared spectrum of 5-MeOICA.
a similar strength of the O –H· · ·O intermolecular hydrogen
bonds, in the crystals of 5-MeOICA and ICA, which is in
agreement with the X-ray data.
See deposit: CCDC216180 for crystallographic data in
CIF electronic format.
4. Supplementary material
The calculated structures and energies of 16 possible
conformers of 5-MeOICA are available as Supplementary
materials from the authors, upon request.
Acknowledgements
The authors are grateful to the Wrocław Supercomputer
and Networking Center for a generous computer time.
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