13C NMR studies on the structure of 5H- and 6H-indolo-[2,3-b] quinolines and the related compounds

Article abstract of DOI:10.1016/S0022-2860(03)00523-4

A set of ¹³C NMR data which included one-bond spin-spin coupling constants has been obtained for a large series of heteroaromatic compounds. It contains, among others, 6-substituted quinolines, their N-oxides, 2- and 5-methoxyindoles. The results obtained for these basic molecules were compared with those measured for a series of variously substituted 5H- and 6H-indolo[2,3-b]quinolines, which shed new light on the electronic structure of the two latter groups of the compounds.

Full text of DOI:10.1016/S0022-2860(03)00523-4

Journal of Molecular Structure 661-662 (2003) 209–218
www.elsevier.com/locate/molstruc
13C NMR studies on the structure of 5H- and 6H-indolo-[2,3-b ]
quinolines and the related compounds
a,
K. Kamienska-Trela , L. Kania , M. Bechcicka , Ł. Kaczmarek
a
a
b
*
´
aInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44, 01-224 Warsaw, Poland
bPharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland
Received 5 May 2003; accepted 19 May 2003
Dedicated to Professor Bernhard Schrader
Abstract
A set of 13C NMR data which included one-bond spin–spin coupling constants has been obtained for a large series of
heteroaromatic compounds. It contains, among others, 6-substituted quinolines, their N-oxides, 2- and 5-methoxyindoles. The
results obtained for these basic molecules were compared with those measured for a series of variously substituted 5H- and 6H-
indolo[2,3-b ]quinolines, which shed new light on the electronic structure of the two latter groups of the compounds.
q 2003 Elsevier B.V. All rights reserved.
Keywords: One-bond carbon–carbon couplings; Carbon-13 chemical shifts; Substituents effects; Indolo[2,3-b ]quinolines
1. Introduction
The compounds are of particular interest since, as
has been shown by one of us, [4,5] they reveal
significant activity against prokaryotic and eukary-
otic organisms and appear to be a new class of
cytotoxic DNA intercalators and topoisomerase II
inhibitors. The structure activity relationship studies
have shown that their cytotoxic activity is mainly
determined by both the position and character of
substituents introduced to the indolo[2,3-b]quinoline
framework.
Recently we have published the results of exten-
sive 1H and 13C NMR studies on 6H-indolo[2,3-
b]quinolines and their derivatives which included an
analysis of vicinal and long-range proton–proton
coupling constants as well as 13C chemical shifts, dð
13
CÞ; and one-bond carbon–carbon coupling constants,
1
1JCC; [1]. We have also published H NMR data and
13C chemical shifts for a set of 5H-indolo[2,3-
1
b]quinolines [2]. We have found that the H NMR
Therefore, further studies which would provide
additional information on the electronic structure of
both 5H-indolo[2,3-b]quinolines and 6H-indolo[2,3-
b]quinolines seemed to be of significant interest. We
came to the conclusion that it would be particularly
spectra of both these groups of compounds reveal very
strong concentration dependence which has been
interpreted in terms of dimerization effects [1,3].
*
Corresponding author. Tel.: þ48-22-632-32-21; fax: þ48-22-
1
interesting to compare the JCC coupling values
obtained for these two groups of compounds with
632-66-81.
´
E-mail address: kkt@icho.edu.pl (K. Kamienska-Trela).
0022-2860/$ - see front matter q 2003 Elsevier B.V. All rights reserved.
doi:10.1016/S0022-2860(03)00523-4

´
K. Kamienska-Trela et al. / Journal of Molecular Structure 661-662 (2003) 209–218
210
1
those in analogously substituted quinolines and
indoles, two basic moieties forming indoloquino-
lines. Quite surprisingly, we have found that the
1JCC data published in the literature for these crucial
in organic chemistry molecules are rather scarce.
A full set of JCC couplings has been determined by
van der Berg et al. [6] for indole and its derivative
tryptophan from an analysis of their 13C enriched
1
samples. Several different sets of JCC couplings
have been published for quinoline by various groups
Scheme 1. The studied compounds.

´
K. Kamienska-Trela et al. / Journal of Molecular Structure 661-662 (2003) 209–218
211
of authors [7–9]. The most complete and correct set
of 1JCC data for this compound has been obtained by
Gronowitz et al. [9].
d
In order to get a deeper insight into the electronic
structure of the compounds being the main object of
1
our interest we have decided to measure the JCC
couplings for a series of selected derivatives of
quinoline and its N-oxide as well as for several
substituted indoles, and to compare them with those
obtained for the parent 5H- and 6H-indolo[2,3-
b]quinolines and their derivatives. The results of the
analysis which also includes the relevant substituent
13C chemical shift (SCS) effects are discussed in the
presented work (Scheme 1).
d
d
d
d
d
2. Results and discussion
1
The JCC coupling constants and chemical shifts
measured for quinoline, quinoline N-oxide and their
derivatives are presented in Table 1 and those
obtained for N-methylindole and its derivatives are
displayed in Table 2. Tables 3 and 4 contain the 1JCC
couplings for 6H- and 5H-indolo[2,3-b]quinolines,
respectively. In Table 5 the 13C chemical shifts for
5H-indolo[2,3-b ]quinolines measured consistently at
the constant concentration and assigned on the basis
of the INADEQUATE and SPT INEPT spectra are
collected. We would like to point out here that the
combination of these two methods allowed us to
assign unambiguously all the very closely positioned
(within tenth of ppm) signals even those correspond-
ing to the quaternary 4a, 5a, 10a and 10b carbon
atoms, which were especially difficult to interpret by
the traditional methods applied in our previous work
[2]. Therefore, the assignment of quite a number of
the signals has been corrected in the present work in
comparison with that published earlier.
d
The most striking feature of the whole 1JCC pattern
in the quinoline system consists in the fact that
d
1
the JCC coupling values alternate along the frame-
1
1
1
work of this molecule, the JC6C7; JC9C10 and JC2C3
couplings, of 52.7, 53.3 and 51.0 Hz, respectively,
being considerably smaller than those across the
d
d
1
neighboring bonds. In particular, JC3C4 is larger by
7.2 Hz than 1JC2C3 and 1JC6C7 smaller than 1JC5C6 and
1JC7C8 by 7.6 and 7.1 Hz, respectively (see results for
1 in Table 1 and Scheme 2).

´
K. Kamienska-Trela et al. / Journal of Molecular Structure 661-662 (2003) 209–218
212
Table 2
One-bond spin–spin coupling constants, 1JCC (in Hz), in indole (9), N-methylindole, (10), 2-ethoxy-N-methylindole (11) and 5-methoxyindole
(12)
No 1JC2C3 ðdðC2ÞÞ 1JC3C9 ðdðC3ÞÞ 1JC4C9 ðdðC4ÞÞ 1JC4C5 ðdðC5ÞÞ 1JC5C6 ðdðC6ÞÞ 1JC6C7 ðdðC7ÞÞ 1JC7C8 ðdðC8ÞÞ 1JC8C9 ðdðC9ÞÞ
9a
68.9 (124.2)
54.7 (102.2)
54.2 (100.4)
57.0 (75.9)
54.8 (101.7)
63.0 (120.6)
61.2 (121.1)
62.2 (127.4)
63.3 (102.1)
57.8 (119.7)
58.1 (120.5)
58.7 (118.6)
71.8 (153.7)
56.0 (121.9)
60.1 (111.0)
60.1 (108.9)
64.5 (135.6)
65.7 (136.4)
68.0 (108.0)
66.0 (130.8)
53.0 (127.7)
b
– (128.3)
10 68.6 (128.4)
11 83.1 (153.5)
12 68.3 (125.1)
56.3 (118.9)
b
–
(119.5)
59.4 (119.2)
b
52.2 (132.8)
55.4 (128.0)
69.2 (111.8)
–
(111.7)
dð13CÞ chemical shifts (in ppm) are given in parentheses. Measured in CDCl3.
Taken from Ref. [6].
a
b
Could not be observed.
N-oxidation of quinolines causes a considerable
1
N-oxide and a large set of their derivatives where
1
1
increase of the JCC couplings across two bonds
1
an increase of JC2C3 and JC5C6 couplings only, by
10 Hz, takes place upon the N-oxidation of pyridine
[10]. The remaining couplings in all four b
compounds considered here are only slightly, within
1–2 Hz, affected by N-oxidation.
only, namely, JC2C3 increases by ca. 8 Hz and
1JC9C10 by ca. 6 Hz (compare pairs 1a, 1b; 2a, 2b;
3a, 3b and 5a, 5b); a moderate increase of 2.5 Hz is
1
observed also for JC8C9: All these three bonds are
in the direct vicinity of the nitrogen bearing a lone
electron pair. This observation is in agreement with
our recent observations made for pyridine, its
The influence of substituents on the coupling
values is strong but short-ranged and limited to the
1
closest bonds. Thus, an increase of both JC5C6 and
Table 3
13
One-bond couplings, JCC in Hz, and C chemical shifts, dð13CÞ in ppm (in parentheses), in the parent 6,11-dimethyl-6H-indolo[2,3-
1
b]quinoline (13) and its 2-methyl (14), 2-amino (15), and 2,9-dimethoxy (16) derivatives
Carbon atoms coupled and (Cn)
1JCC and dð13CÞ
13
14
15
16
C1–C2 (C1)
60.6 (124.0)
52.8 (122.5)
62.4 (123.0)
53.4 (131.8)
59.9 (130.7)
64.5 (127.6)
55.5 (144.8)
56.3 (151.7)
55.3 (142.5)
66.9 (108.3)
58.8 (127.0)
57.5 (119.5)
57.6 (123.4)
63.8 (121.3)
59.0 (116.1)
67.1 (138.6)
55.8 (123.8)
58.6
68.2 (105.4)
58.4 (141.5)
61.7 (120.9)
64.9 (129.0)
73.1 (102.4)
64.6 (154.8)
62.5 (120.5)
64.6 (129.1)
56.2 (142.2)
56.5 (151.2)
56.5 (137.2)
67.8 (108.4)
61.3 (114.1)
69.0 (153.6)
70.0 (108.5)
67.0 (121.3)
59.0 (116.1)
67.6 (137.2)
56.2 (123.9)
60.5
C2–C3 (C2)
C3–C4 (C3)
–
a (128.5)
C4–C4a (C4)
C4a–C11a (C4a)
C5a–C10b (C5a)
C6a–C10a (C6a)
C6a–C7 (C7)
C7–C8 (C8)
64.4 (128.0)
55.4 (146.5)
55.8 (152.1)
56.3 (142.6)
67.2 (108.4)
58.9 (127.2)
–
–
–
a (141.4)
a (150.6)
a (142.6)
66.7 (108.2)
58.6 (127.0)
56.8 (119.3)
57.7 (123.4)
63.6 (121.2)
C8–C9 (C9)
–
a (119.7)
C9–C10 (C10)
C10–C10a (C10a)
C10a–C10b (C10b)
C10b–C11 (C11)
C11–C11a (C11a)
C1–C11a
57.9 (123.4)
63.7 (121.3)
59.1 (116.2)
67.2 (138.7)
55.7 (124.0)
–
a (116.3)
67.4 (136.5)
55.8 (125.1)
61.8
a
–
C11–CH3 (CH3)
C2–CH3 (CH3)
(6-NCH3)
43.0 (15.0)
43.1 (14.9)
44.8 (21.8)
(27.4)
43.2 (14.9)
–
43.3 (14.9)
–
–
(27.4)
(27.4)
(27.4)
The data for the compounds 13, 14 and 16 have been taken from Ref. [1], those for compound 15 have been measured in this work.
Could not be determined.
a

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K. Kamienska-Trela et al. / Journal of Molecular Structure 661-662 (2003) 209–218
213
Table 4
One-bond spin–spin coupling constants, 1JCC (in Hz), in 5-methyl-5H-indolo[2,3-b]quinoline (17) and its derivatives
Carbon atoms coupled
1JCC
17
18
19
20
21
22
23
24
25
26a
b
b
C1–C2
58.0
54.0
60.0
65.2
61.8
51.9
50.8
67.0
57.7
57.4
58.2
63.2
61.8
58.5
54.0
59.8
65.6
–
58.4
54.4
59.8
65.0
60.2
b
71.4
65.9
62.1
65.9
62.2
53.3
50.1
66.7
57.7
57.1
57.6
62.9
–
71.3
66.1
62.0
65.7
63.3
70.4
66.0
62.0
65.8
58.6
54.1
59.9
65.2
b
C2–C3
54.0
60.5
64.8
63.1
–
–
C3–C4
60.3
65.6
63.4
53.6
50.6
67.3
58.1
58.0
59.1
63.6
60.6
64.9
C4–C4a
b
b
b
b
b
C4a–C11a
C5a–C10b
C6a–C10a
C6a–C7
–
–
–
–
–
b
b
b
b
b
b
–
–
–
–
–
53.4
51.2
67.6
60.3
67.8
69.9
65.5
–
b
b
b
b
b
b
–
–
–
–
–
–
b
67.1
57.5
56.3
57.9
63.1
66.9
57.7
57.0
57.6
63.3
67.2
58.1
58.0
58.6
64.0
66.5
59.9
70.0
70.0
65.9
–
67.7
b
–
C7–C8
58.1
59.5
59.4
C8–C9
62.9
b
–
C9–C10
C10–C10a
C10a–C10b
C10b–C11
C11–C11a
C1–C11a
C11–CH3
C2–CH3
C9–CH3
b
–
65.4
c
c
c
c
c
c
c
c
c
–
–
–
–
–
–
–
–
–
c
c
b
b
–
67.3c
54.5
60.3
42.7
–
–
64.9
54.3
60.3
42.5
–
67.0
54.8
60.8
42.6
45.2
45.3
67.2
54.3
63.5
42.5
–
–
67.2
54.4
61.2
42.1
–
67.1
54.6
63.4
42.6
–
–
b
b
54.9
59.3
–
53.9
60.6
42.7
45.4
–
–
–
b
–
60.8
42.4
–
b
–
b
–
–
–
–
45.1
–
–
45.0
–
–
0.1 mol dm23 solutions in CDCl3; due to the low solubility of 9-methoxy (27) and 2-fluoro (28) derivatives, INADEQUATE experiment
could not be performed.
a
In CD3OD.
b
Due to the low intensity of satellite lines could not be determined.
c
Tightly coupled system AB.
1JC6C7 by ca. 12 Hz occurs upon introduction of
the methoxy (compounds 3a and 3b) and nitro
(compound 4) substituents into position 6. An
increase of JC5C6 by ca.16.5 Hz and JC6C7 by
14.5 Hz is caused by the 6-fluoro substituent (com-
pounds 5a and 5b). The remaining couplings in all
five compounds remain practically unchanged. An
increase of 1JC2C3 only, by ca. 13 Hz, is exerted by the
2-chloro substituent in compounds 7a and 8a.
A comparison of the 1JCC data for indole 9 and N-
methylindole 10 shows that the influence of N-
methylation on the coupling values in the indole
molecule is non-significant. An alternation of the
coupling values analogous to that in quinoline occurs
in both these molecules. However, differences,
across the C2C3 bond. It is by 2.3 Hz larger than the
corresponding coupling in unsubstituted pyrrole,
1JC2C3 of 66.3 Hz [11], and slightly larger than that
in unsubstituted ethylene, 1JCyC of 67.8 Hz [12]. The
smallest couplings in the indole molecule are those
1
1
1
across the C8C9 and C3C9 bonds, JC8C9 of 53.0 Hz
1
and JC3C9 of 54.2 Hz, respectively. The latter
1
coupling which corresponds to the JC3C4 coupling
in the pyrrole molecule is by 2.3 Hz larger than the
coupling measured recently for 2-methylpyrrole [11].
It should be mentioned at this point that 1JC3C4 has not
been determined yet in pyrrole itself due to the
symmetry of this molecule. However, one can expect
that the 2-methyl substituent does not influence
significantly the magnitude of the couplings across
the C3C4 bond.
1
1
Dð JC4C5 2 1JC5C6Þ of 1.8 Hz and Dð JC5C6 2 1JC6C7
Þ
1
of 3.8 Hz only in 10, are significantly smaller than the
corresponding D1JCC values in the C5-C6-C7-C8
fragment of quinoline 1a (see above). The largest 1JCC
coupling of 68.6 Hz in N-methylindole 10 is that
An increase of JC2C3 by 14.2 Hz occurs in 2-
ethoxy-N-methylindole, 11, and by similar value
1
1
increase the JC4C5 and JC5C6 couplings in 5-
methoxyindole, 12 (Table 2).

´
K. Kamienska-Trela et al. / Journal of Molecular Structure 661-662 (2003) 209–218
214
Table 5
13C chemical shifts, dð13CÞ in ppm, in 5H-indolo[2a,3-b]quinoline (17) and its derivatives
Cn
17
18
19
20
21
22
23
24
25
26
27a
28b
C1
129.9
121.8
130.3
114.1
136.9
156.2
155.5
117.7
129.3
119.8
120.6
124.0
128.1
128.0
120.7
32.9
–
125.6
121.5
130.0
114.3
136.6
155.5
155.2
117.6
128.3
119.6
123.1
124.9
125.6
139.7
121.3
32.8
15.2
–
125.2
131.0
131.5
114.3
134.8
155.3
155.1
117.5
128.2
119.4
123.1
124.9
125.4
139.5
121.3
32.9
125.6
121.2
129.9
114.2
136.7
155.3
153.1
117.2
129.4
128.8
123.5
125.0
125.6
139.4
121.3
32.8
125.2
130.9
131.4
114.1
134.7
154.9
152.7
116.9
129.3
128.6
123.4
124.8
125.3
139.4
121.2
32.9
107.0
154.4
119.2
115.5
131.4
154.9
155.1
117.4
128.4
119.3
123.1
124.5
125.8
139.0
122.1
33.0
125.3
130.7
131.6
114.0
134.9
154.9
149.5
117.5
115.0
153.6
108.6
125.3
125.7
139.7
121.0
32.7
106.4
154.2
119.0
115.4
131.4
154.8
153.2
116.9
129.4
128.4
123.5
124.6
125.8
138.6
122.0
32.9
107.1
154.2
119.3
115.4
131.6
154.5
149.5
117.4
115.2
153.6
108.7
124.9
126.0
139.2
121.8
32.9
125.5
120.7
129.7
113.8
136.6
154.2
148.4
117.6
117.1
139.4
110.2
125.4
125.5
139.3
120.8
32.4
14.8
–
125.6
121.3
130.1
114.1
136.7
154.8
149.2
117.6
115.1
153.8
108.6
125.2
125.6
140.0
121.0
32.7
110.4
157.5
118.1
115.8
133.2
155.2
155.4
117.6
128.8
119.7
123.3
124.4
126.6
138.5
122.2
33.1
15.3
–
C2
C3
C4
C4a
C5a
C6a
C7
C8
C9
C10
C10a
C10b
C11
C11a
5-NCH3
11-CH3
2-CH3
9-CH3
2-OCH3
9-OCH3
15.2
15.2
15.2
15.4
15.2
15.3
15.3
15.1
–
21.1
–
21.1
–
21.1
–
–
–
–
–
–
21.6
21.6
–
–
21.6
–
–
–
–
–
–
–
–
–
55.8
–
55.7
55.8
–
–
–
–
–
–
–
–
–
56.2
–
56.2
–
56.2
–
0.1 mol dm23 solutions in CDCl3.
a
Saturated solution in CDCl3 (0.07 mol dm23).
b
1JC2–F ¼ 241:5 Hz; 2JC1–F ¼ 22:6 Hz; JC3–F ¼ 24:7 Hz; 3JC4–F ¼ 8:3 Hz; 3JC11a–F ¼ 7:9 Hz; 4JC11–F ¼ 3:6 Hz; JC4a–F ¼ 0 Hz:
2
4
The consequences of the fusion of indole and
unsubstituted ethylene (67.8 Hz, [12]) indicating that
the C10b–C11 bond order is very high. Quite a large
increase is also observed for 1JC10aC10b; of ca. 5 Hz in
6H- and of ca. 7 Hz in 5H-indoloquinolines in relation
quinoline moieties into indolo[2,3-b ]quinoline sys-
tem can be summarized as follows (Scheme 2). First
of all, the couplings of ring A in 6H-indolo[2,3-
b]quinoline, 13, are almost identical with those in the
benzene ring of quinoline, 1, whereas the couplings in
the same ring in 5H-indolo[2,3-b ]quinoline, 18, are
very similar to those in the benzene ring of N-
1
to the JC3C4 coupling in N-methylindole 10. The
coupling values across the remaining bonds clearly
depend on the state of the nitrogen atom involved in a
given ring. Thus, the presence of the sp3 nitrogen atom
in ring B in 5H-indoloquinolines causes a consider-
able increase of the coupling across bond C4aC11a in
comparison with their 6H- counterparts and, vice
versa, a similar increase is observed for the couplings
across bonds C5aC10b and C6aC10a in 6H-indolo-
quinolines where, in turn, the nitrogen atom 6
becomes the sp3 type.
1
methylindole, 10, the JC4aC11a coupling being the
only exception (Scheme 2). The couplings in the
C7C8C9C10 fragments (ring D) undergo equalization
in comparison with the starting indole molecule and
their values are close to that in benzene (56 Hz [12]).
As will be shown further, this pattern is surprisingly
precisely reflected in the SCS effects.
1
The most striking change caused by the fusion is
1
observed for the JCC coupling across the C10bC11
Substituent effects on JCC couplings are very
similar to the effects observed in 6-substituted
quinolines and 5-substituted indole (see above).
An inspection of the 13C chemical shift data
presented in Tables 5 and 6 clearly shows that the
influence of substituents (SCS, Substituent Chemical
bond whose value increases by almost 10 Hz in both
5H- and 6H-indoloquinolines in comparison with the
1JC3C4 coupling in quinoline. Its value of ca. 67 Hz in
all the compounds studied is very close to that in

´
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215
Scheme 2. Carbon–carbon couplings, 1
JCC; (in Hz) for the parent representatives of the compounds studied.
Shift) on the shielding of the carbon atoms is limited
to that ring only at which the substituent is attached.
The shieldings of the remaining carbon atoms in
the molecule remain unchanged through the whole
series of the compounds studied, which provides a
good basis for their interpretation. Thus, the a-SCS
and d-SCS effects are almost independent of the
compound for which they are measured, aðOCH3Þ of
ca. 234 ppm and dðOCH3Þ of ca. þ5 ppm being
observed for all the compounds studied. The magni-
tude of the b-SCS effects, on the contrary, is strongly
dependent on the position of the substituent. An
inspection of Table 6 where the b-SCS increments Aij
are collected (i denotes the carbon at which the
substituent is attached and j that on which the
influence is exerted) reveals that the b-SCS effects
of the methoxy group exerted on carbons C8 and C10
of ring D do not differ substantially from each other
and are very similar in 5H-and 6H-indoloquinolines,
ca. 213 ppm for carbon 8 and ca. 215 ppm for
carbon 10 in both groups of compounds. Moreover,
they are very similar to that in methoxybenzene
(214.4 ppm). The same is valid for the amino
substituent (Table 6). This is at variance with the
situation encountered in ring A where the b-SCS
effect on carbon 1 is about three times larger than that
exerted on carbon 3, 221.7 and 27.9 ppm, respect-
ively in 2-methoxy-6H-indoloquinolines. Similar
values are found for 6-methoxyquinoline and its
N-oxide (in parentheses), A65ðOCH3Þ ¼ 222:3
(223.1) ppm and A67ðOCH3Þ ¼ 26:7 (27.2) ppm.
The A21ðOCH3Þ ¼ 218:8 ppm and A23ðOCH3Þ ¼
210:8 ppm found in 2-methoxy-5H-indolo[2,3-
b ]quinolines are, on the other hand, very close
to the corresponding b-SCS effects observed
in 5-methoxyindole, A54 ¼ 217:9 Hz and A56
¼
210:1 ppm; respectively. An analogous pattern
of the b-SCS effects occurs for the 2-amino and
2-fluoroderivatives (Table 6).
The discussed above JCC coupling and 13C
1
chemical shift results reflect most obviously the well
known fact that the mobile p bond orders in quinoline
and indole are not uniformly distributed through these
molecules and that some of the bonds may be

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216
Table 6
b-SCS effects, Aij; of the substituent at carbon i on carbon j (in ppm) in substituted 5,11-dimethyl-5H- and 6,11-dimethyl-6H-indolo[2,3-
b]quinolines and related compounds
Compound
A2;1 (OCH3)
A2;3 (OCH3)
A9;8 (OCH3)
A9;10 (OCH3)
6H-Indolo[2,3-b] quinolines
Quinoline
221.7a
222.3b,c
223.1b
27.9a
26.7c,d
27.2d
213.0a
214.9a
–
–
–
–
Quinoline-N-oxide
Benzene
2 14.4e
5H-Indolo[2,3-b] quinolines
N-Methylindole
218.8f
210.8f
210.1h,j
A2,3 (NH2)
27.6
213.2g
–
214.5g
–
217.9h,i
A2,1 (NH2)
218.6
A9,8 (NH2)
A9,10 (NH2)
6H-Indolo[2,3-b] quinolines
Quinoline
223.0b,k
27.6b,k
–
–
5H-Indolo[2,3-b] Quinoline
Benzene
211.2
212.9
213.4e
A2,1 (F)
216.6
217.2b
214.4b
215.2
A2,3 (F)
210.2
29.9d
27.5d
211.9
6H-Indolo[2,3-b] quinoline
Quinoline
Quinoline-N-oxide
5H-Indolo[2,3-b] quinoline
Benzene
2 13.0e
a
Taken from Ref. [1].
b
Corresponds to bond C5C6.
c
In agreement with data in Ref. [13].
d
Corresponds to bond C6C7.
e
Taken from Ref. [12].
f
Average for compounds 22, 24 and 25.
Average for compounds 23, 25 and 27.
Corresponds to bond C4C5.
g
h
i
In agreement with data in Ref. [14].
j
Corresponds to bond C5C6.
k
Taken from Ref. [15].
considered to be partially fixed. Indeed, the ab initio
GIAO CHF calculated bond orders for quinoline and
indole presented in Table 7, which are in agreement
with those already published in the literature [13,18],
clearly show that in quinoline the bond orders
alternate, the largest ones being found for bonds
C3C4, C5C6 and C7C8. The same occurs in indole
where, in turn, bonds C2C3, C4C5 and C6C7 are the
strongest.
Table 7
Ab initio GIAO-CHF bond orders of quinoline and indole
Quinoline
Bond
Indole
Bond
Bond order
Bond order
N1–C2
N1–C9
C2–C3
C3–C4
C4–C10
C5–C10
C5–C6
C6–C7
C7–C8
C8–C9
C9–C10
1.90
1.58
1.73
2.05
1.74
1.73
2.04
1.76
2.06
1.71
1.79
N1–C2
N1–C8
C2–C3
C3–C9
C9–C4
C4–C5
C5–C6
C6–C7
C7–C8
C8–C9
–
1.49
1.47
2.07
1.65
1.80
1.96
1.82
1.96
1.81
1.77
–
The similarity of the substituent effects observed
for quinoline and the ring A in 6H-indolo[2,3-
b]quinolines allows the conclusion that the electron
distribution in the latter is very close to that in
quinoline whereas the same ring in 5H-indolo[2,3-
b]quinolines resembles that in indole. The rings D in
both groups of compounds are almost purely aro-
matic, the order of bond C9C10 being only slightly
larger than that of bond C8C9.
The triple-z basis set with two polarization functions ðtz þ 2pÞ
[17] was used for the bond orders calculations by the Roby–
Davidson procedure [16].

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217
All quinoline N-oxides (1b–3b, 5b) were syn-
thesized according to the general procedures treating
an appropriate quinoline with an excess of meta-
chloroperoxy-benzoic acid in chloroform. The
products were isolated and purified by column
chromatography (Merck Kieselgel 60). The samples
of indole (9) and N-methyl indole (10) were of
commercial origin (Aldrich company) and were used
as received. The alkoxy derivatives of indole (11 and
12) were prepared according to the procedures
described in the literature [20,21, respectively].
Scheme 3. The two possible shapes of the C–F coupling path across
four bonds.
Finally, it is worth mentioning that the origin of the
interaction between the substituent and bond of the
main framework electrons of the compounds such as
quinoline and naphthalene has attracted much atten-
tion, also recently [19 and references cited therein].
Though this phenomenon was not the main goal of our
studies we would like to emphasize that in the light of
the data collected in our work and those published in
the literature [12] the hindered rotation should not be
invoked as a possible reason of the observed
differences between the magnitude of increments
A56ðOCH3Þ and A67ðOCH3Þ in quinoline and of
A45ðOCH3Þ and A56ðOCH3Þ in indole, since similarly
significant differences are observed for the fluoro and
amino substituents where such interpretation for
obvious reason does not apply.
The indolo[2,3-b ]quinolines of the series 6H- (13–
16) and 5H- (17–28) were synthesized according to
the procedures described earlier by one of us [22].
All NMR measurements were carried out in
standard 5 mm tubes at 300 K using a Bruker AM
500 spectrometer system at a proton and a carbon
resonance frequency 500.13 and 125.76 MHz,
respectively. The experiments were performed in
CDCl3, unless otherwise stated. The solvent signal,
calibrated against Me4Si, was used as a reference for
proton and carbon-13 spectra. The 13C–13C spin–spin
coupling constants were measured at the natural
abundance of the isotope using the INADEQUATE
At the end a short comment should be made on
nJCF couplings, which are a useful diagnostic tool in
assignment of the carbons. Their values decrease
monotonically upon increase of the number of
separating bonds. This is also valid in the case of
the compounds studied in our work with one
method (32-phase Freeman cycle with automatic data
1
storage); the experiments were adjusted for JCC
¼
60 Hz: The applied digital resolution was in the range
of 0.16 to 0.25 Hz per point to obtain a reliable
coupling constant value.
4
exception. Whereas the JCF coupling of ca. 5 Hz
was found for C4 in compounds 5a and 5b and for
C11 in compound 28, the coupling between fluorine
and C9 in 5a and 5b, and between fluorine and C4a in
28 is equal to zero. These results reflect the well
known fact that the coupling across path a are larger
than those across path b (Scheme 3).
The ab initio GIAO-CHF molecular orbital calcu-
lations were performed using Tur-bomole program of
Biosym/MSIe [16] installed on the work station IBM
RS6000. The double-z basis set with a polarization
function ðdz þ pÞ [17] was used for the geometry
optimization. The triple-z basis set with two polariz-
ation functions ðtz þ 2pÞ [17] was used for the SCF
electron energy, charge distribution and bond orders
calculations by the Roby–Davidson procedure [16].
The calculations were carried out on the isolated
molecules in the gas phase with no solvent effects
included. Electron correlation effects were not taken
into account.
A similar effect has already been observed also for
2-fluoro-6H-indolo[2,3-b ]quinoline [1] but an incor-
rect interpretation has been given.
3. Experimental
Quinoline (1a) and its derivatives (2a–4a, 6a–8a)
are available commercially (Aldrich company) and
were used as such after their distillation prior to the
measurements.
Acknowledgements
The research was supported by the Polish State
Committee for Scientific Research, grant KBN 3T09A
007 19.
6-F-quinoline (5a) was prepared by the Skraup
synthesis, using iodine as an oxidizing agent.

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K. Kamienska-Trela et al. / Journal of Molecular Structure 661-662 (2003) 209–218
218
´ ´
[11] A. Da˛browski, K. Kamienska-Trela, J. Wojcik, Spectrochim.
References
Acta Part A 56 (1999) 91.
[12] H.-O. Kalinowski, S. Berger, S. Braun, Carbon-13 NMR
Spectroscopy, Wiley, New York, 1994.
´
[1] K. Kamienska-Trela, L. Kania, J. Sitkowski, Ł. Kaczmarek,
J. Chem. Soc., Perkin 2 (1995) 1617.
´
[2] K. Kamienska-Trela, L. Kania, Ł. Kaczmarek, J. Mol. Struct.
[13] P. Joseph-Nathan, C. Garcia-Martinez, M.S. Morales-Rios,
Magn. Reson.Chem. 28 (1990) 311.
347 (1995) 467.
´ ´
[3] L. Kania, K. Kamienska-Trela, Ł. Kaczmarek, J. Wojcik, Mol.
[14] M. Damak, C. Poupat, A. Ahond, Tetrahedron Lett. (1976)
3531.
Phys. Rep. 33 (2001) 18.
´
[4] W. Peczynska-Czoch, F. Pognan, Ł. Kaczmarek, J. Bora-
[15] A.M. Kook, S.L. Smith, E.V. Brown, Org. Magn. Reson. 22
(1984) 730.
´
tynski, J. Med.Chem. 37 (1994) 3503.
¨ ¨ ¨
[16] R. Ahlrichs, M. Bar, M. Haser, H. Horn, C. Kolmel, Chem.
´
[5] R. Humeniuk, Ł. Kaczmarek, W. Peczynska-Czoch, E.
Marcinkowska, Oncol. Res. 13 (2003) 269.
[6] E.M.M. van den Berg, F.J.H.M. Jansen, A.T.J.W. Goede, A.U.
Baldew, J. Lugtenburg, Rec. Trav. Chim. Pays-Bas 109 (1990)
287.
Phys. Lett. 162 (1989) 165.
¨
[17] A. Schafer, H. Horn, R. Ahlrichs, J. Chem. Phys. 97 (1992)
2571.
[18] V.A. Kovtushenko, Z.V. Voytenko, V.L. Sheptun, A.K.
Tyltin, A.I. Cherniega, Yu.T. Striuczkov, F.S. Babichev,
Khim. Geter. Soedin. (1984) 1497.
[7] (a) L.B. Krivdin, G.A. Kalabin, Zh. Org. Khim. 24 (1988)
2268. (b) L.B. Krivdin, G.A. Kalabin, Prog. NMR Spectrosc.
21 (1989) 293.
[19] R.H. Contreras, O.E. Taurian, F.S. Ortiz, J.E. Peralta, J. Mol.
Struct. 556 (2000) 263.
[8] V. Wray, P.E. Hansen, Annu. Rep. NMR Spectrosc. 11A
(1981) 65.
[20] M. Ma˛kosza, W. Danikiewicz, K. Wojciechowski, Liebigs
Ann. Chem. (1988) 203.
[9] S. Gronowitz, R. Servin, Y. Yang, Magn. Reson. Chem. 27
(1989) 1099.
´
[10] K. Kamienska-Trela, L. Kania, P. Bernatowicz, M. Bechcicka,
[21] W. Plieninger, Chem. Ber. 99 (1966) 3070.
[22] Ł. Kaczmarek, R. Balicki, P. Nantka-Namirski, W. Pec-
´
zynska-Czoch, M. Mordarski, Arch. Pharm. (Weinheim) 321
´
Ł. Kaczmarek, J. Wojcik, Spectrochim. Acta Part A 56 (2000)
2079.
(1988) 463.