1H, 13C and 15N NMR and GIAO CPHF calculations on two quinoacridinium salts

Article abstract of DOI:10.1002/1097-458X(200006)38:6<482::AID-MRC677>3.0.CO;2-P

The complete ¹H, ¹³C and ¹⁵N NMR assignments of two closely related quinoacridinium salts, 8,13-diethyl-6-methyl-8H-quino[4,3,2-kl]acridinium iodide and, 8,13-diethyl-3,6,11-trimethyl-8H-quino[4,3,2-kl]acridinium iodide, are described. The multinuclear 1D NMR and 2D shift-correlated NMR techniques HMQC, HSQC and HMBC were applied, accompanied by ab initia GIAO CPHF calculations of shielding constants. Copyright

Full text of DOI:10.1002/1097-458X(200006)38:6<482::AID-MRC677>3.0.CO;2-P

MAGNETIC RESONANCE IN CHEMISTRY
Magn. Reson. Chem. 2000; 38: 482–485
Reference Data
1H, 13C and 15N NMR and GIAO CPHF calculations on
two quinoacridinium salts
RESULTS AND DISCUSSION
For the reliable assignment of the 1H, 13C and 15N spectra, 2D NMR
methods and theoretical calculations had to be applied. The NMR data
for 1 and 2 are collected in Tables 1 and 2, respectively.
Jolanta Jaroszewska-Manaj,1 Dorota Maciejewska2
2
The discrimination between the chemical shifts of two N-ethyl groups
at the N-8 and N-13 atoms in 2 was decisive and was deduced by the
∗
and Iwona Wawer
analysis of the calculated nitrogen shielding constants and the 1H–15
N
1
1
and H–13C HMQC spectra. According to the resonance forms (two of
the 18 possible are illustrated in Scheme 1), the positive charge can
be located at N-8 and/or N-13, which means that it is delocalized over
the molecule. Nitrogen N-13 shows a slightly pyramidal configuration of
bonds in the crystal;8 however, it results from overcrowding (presence of
ethyl groups). The calculated shielding constants of 1 (Table 1) showed
that N-8 is significantly more shielded than N-13, and therefore the
signal of 15N at ꢀ243.9 ppm in the spectrum of 1 (ꢀ244.6 ppm for 2)
was assigned to N-8 and the signal at ꢀ235.8 ppm (ꢀ236.8 ppm for
2) to N-13. The 1H–15N correlation showed that the peak of N-8 was
bonded to 1H signals of H-7, H-9 and H-15, whereas the N-13 peak was
bonded to H-1 and H-17.
Department of Chemistry, Warsaw University, Pasteura 1,
02-093 Warsaw, Poland
Department of Physical Chemistry, Faculty of Pharmacy,
2
Medical University of Warsaw, Banacha 1, 02-097 Warsaw
Received 12 October 1999; revised 7 February 2000; accepted 8
February 2000
ABSTRACT: The complete 1H, 13C and 15N NMR assignments of
two closely related quinoacridinium salts, 8,13-diethyl-6-methyl-8H-
quino[4,3,2-kl]acridinium iodide and, 8,13-diethyl-3,6,11-trimethyl-8H-
quino[4,3,2-kl]acridinium iodide, are described. The multinuclear 1D
NMR and 2D shift-correlated NMR techniques HMQC, HSQC and
HMBC were applied, accompanied by ab initio GIAO CPHF calcu-
Unambiguous assignments of the 1H and 13C chemical shifts for both
ethyl groups made possible the identification of other proton and carbon
signals, by analysing the HSQC, HMQC and HMBC spectra.10 The
remainder of the skeleton of 1 was deduced from the HMBC experiment
optimized for J D 5 Hz. Two-, three- and four-bond 1H–13C cross peaks
were observed (Fig. 1). The assignments for 2 were made mainly on
the basis of the HMQC and HSQC spectra.
The calculated carbon shielding constants for 1 were used to confirm
the assignments of 13C NMR spectra. A linear correlation between
theoretical and experimental results was obtained (Fig. 2) for aromatic
carbons. Usually, successful correlations are obtained between shielding
constants (calculated using x-ray crystal geometry) and chemical shifts
for solid compounds.11 The good correlation, with R D 0.99, shows that
the heterocyclic skeleton is rigid in solution. The discrimination between
C-12a and C-12b is easy because these signals are at two extremes of the
plot; however, assuming that the tendency for shielding is reproduced
properly, the less differentiated carbons can also be assigned.
lations of shielding constants. Copyright
Ltd.
2000 John Wiley & Sons,
KEYWORDS: NMR; 1H NMR; 13C NMR; 15N NMR; 2D NMR
(HMBC, HSQC, HMQC); GIAO CPHF calculations; quinoacridine
salts; synthesis
INTRODUCTION
The synthesis of the ‘pyridoacridines’ and related compounds have
been published1,2 and their biological activity (cytotoxic, mutagenic or
antibacterial properties) depends both on the number of phenyl rings and
on the type of substituents.3,4 NMR spectra of pyridoacridines, isolated
from a new group of marine alkaloids, have recently been reported.1,2,5–7
In the course of our studies on the synthesis of hemicyanine and
cyanine dyes, it was observed that a new heterocyclic salt 8,13-diethyl-
6-methyl-8H-quino[4,3,2-kl]acridinium iodide (1) is formed;8,9 conden-
sation of the quinaldinium salt bearing methyl groups at the phenyl
ring affords the corresponding substituted quinoacridinium salt 8,13-
diethyl-3,6,11-trimethyl-8H-quino[4,3,2-kl]acridinium iodide (2) (see
Scheme 1).
EXPERIMENTAL
Synthesis
All compounds were synthesized (Scheme 2) and purified in the labo-
ratory of Physical Organic Chemistry, Warsaw University. The purity
of the quinolines was checked by TLC.6 2,6-Dimethylquinoline was
synthesised according to the Doebner and von Miller method. Ethy-
lation was done by heating 2,6-dimethylquinoline with ethyl iodide,
as described in a previous paper.6 A new derivative of quinoacri-
dine, 8,13-diethyl-3,6,11-trimethyl-8H-quino[4,3,2-kl]acridinium iodide
(2) was obtained by analogy with our procedure8 by heating 1-ethyl-6-
methyl-quinaldinium iodide with piperidrine (2 : 1 mol/mol) in ethanol.
The red product was recrystalized from methylene chloride (yield
78.5%) (m.p. 199–200 °C). Elemental analysis: C62.56, H5.39, N6.21;
C26H27N2I requires C63.16, H5.50, N5.67%.
NMR spectra
1H and 13C NMR spectra were recorded on a Bruker DRX500 spectro-
meter operating at 500.13 MHz for 1H and 125.75 MHz for 13C. Satu-
rated solutions of quinoacridinium salts (ca 30 mg) in DMSO-d6 were
prepared; the temperature was stabilized at 300K. All 1D and 2D exper-
iments (HMQC, HSQC and HMBC)10 were run using the programs
from the Bruker software library. The values of J.13C, 1H/ were mea-
sured in the gated decoupled spectra, obtained with a relaxation delay
Scheme 1. The quinoacridinium cations with atom num-
bering.
* Correspondence to: I. Wawer, Department of Physical Chemistry, Faculty of
Pharmacy, Medical University of Warsaw, Banacha 1, 02 097 Warsaw, Poland;
e-mail: wawer@pluton.farm.amwaw.edu.pl
Contract/grant sponsor: Warsaw University; Contract/grant number: BW-1383/
18/97.
1 D 1.5 ms and a gated-off decoupler delay 2 D 1 ms. For 1H–13
C
2D experiments the 1H spectral width was 4640 Hz and the 13C width
was 22 936 Hz. Typically 2048 data points were acquired. The spec-
trum was collected as 1024 ð 512 blocks of data and was processed by
sinusoidal multiplication in each dimension followed by symmetriza-
tion of the final data matrix after zero filling in the F1 dimension.
Contract/grant sponsor: Medical University of Warsaw; Contract/grant number:
FW-28/W-1/99.
Copyright 2000 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2000; 38: 482–485

483
Reference Data
Table 1. 15N, 13C and 1H chemical shifts and 2D heteronuclear correlations for 1 [DMSO-d6, υ(ppm);
reference TMS) and shielding constants, ꢀ(ppm)
n-Bond connectivitiesŁ
(C ! H)
Type
C, H, N
13C/15N,
ꢀ(ppm)
13C/15N,
υ(ppm)
13C, (J)
(Hz)
1H,
No.
3J
2J
4J
υ(ppm) (J,Hz)
1
2
3
CH
CH
CH
CH
C
C
CH
C
84.05
65.68
73.69
72.88
80.51
60.57
89.34
42.71
93.51
49.34
145.70
49.25
85.49
57.40
80.75
67.60
91.35
28.87
90.10
129.51
61.40
156.39
185.69
153.96
185.63
179.20
120.47
130.65
126.77
124.43
123.20
130.96
115.64
148.16
112.75
138.77
ꢀ243.9
141.80
116.69
135.76
122.63
129.08
114.95
152.69
115.18
ꢀ235.8
136.28
43.04
dd 164.2; 6.9
dd 165.0; 8.5
dd 165.0; 7.7
dd 162.7; 7.7
s
H-3
H-4
H-1
H-2
8.14, d (8.3)
7.86, dd (8.3; 1.2)
7.68, t (7.5)
4
8.62, d (7.5)
4a
4b
5
6
7
7a
8
8a
9
10
11
12
12a
12b
12c
13
13a
14
15
16
17
18
H-1, H-3, H-5
s
H-5
dd 168.0; 6.5
q 5.4
dt 163.4; 5.4
s
H-7
8.32 s
7.94 s
H-18
CH
C
N
H-5, H-18
H-14
C
t 6.2
dd 165.7; 7.0
dd 165.0; 8.5
dd 166.5; 7.7
dd 165.0; 7.7
s
s
H-10, H-12, H-14
H-11
H-12
H-9
H-10
H-9, H-11
H-12, H-16
H-5, H-7
CH
CH
CH
CH
C
C
C
N
C
CH2
CH3
CH2
CH3
CH3
8.18, d (9.0)
8.07, dd (7.8; 1.2)
7.61, t (7.8)
H-9
8.38, d (8.4)
t 5.2
H-12
t 3.1
td 142.0; 4.1
q 128.0
td 145.0; 3.1
qd 128.7; 3.1
qd 128.0; 4.6
H-2, H-4, H-16
H-15
H-14
H-17
H-16
4.78, q (7.0)
1.54, t (7.0)
5.07, q (6.8)
1.14, t (6.8)
2.76, s
11.86
51.97
15.37
22.60
H-5, H-7
Table 2. 15N, 13C and 1H chemical shifts and 2D heteronuclear correlations for 2 [DMSO-d6,
υ(ppm); reference TMS]
n-Bond connectivities
(C ! H or N ! H)
Type
C, H, N
13C/15N,
υ(ppm)
1H,
No.
3J
2J
4J
υ(ppm) (J,Hz)
1
2
3
CH
CH
CH
CH
C
C
CH
C
120.47
132.09
132.55
124.40
123.34
131.12
115.59
148.04
112.68
138.88
ꢀ244.6
140.31
117.13
137.60
136.85
128.02
115.19
152.05
115.44
ꢀ236.8
134.60
43.21
8.00, d (8.5)
7.67, dd (8.5; 1.5)
H-4
H-5
H-1
H-1
H-1
H-1
H-2
H-1, H-5
H-4
4
8.42, s
4a
4b
5
6
7
7a
8
8a
9
10
11
12
12a
12b
12c
13
13a
14
15
16
17
18
19
20
H-18
8.26, s
7.86, s
H-7, H-18
CH
C
N
H-5, H-18
H-14
H-7, H-9, H-15
H-10, H-12, H-14
H-5
C
CH
CH
CH
CH
C
C
C
8.07, d (9.0)
7.89, dd (9.0; 1.5)
H-12
H-9
H-10
H-9
H-12, H-16
H-5, H-7
H-1, H-17
H-2, H-4, H-16
H-12
H-12
H-9
8.13, s
H-5, H-7, H-9
H-12
N
C
H-1
CH2
CH3
CH2
CH3
CH3
CH3
CH3
H-15
H-14
H-17
H-16
4.73, q (7.0)
1.53, t (7.0)
5.05, q (6.8)
1.12 t (6.8)
2.76, s
2.54, s
2.54, s
12.12
51.97
15.37
22.86
20.86
20.56
H-5, H-7
H-2, H-4
H-10, H-12
Copyright 2000 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2000; 38: 482–485

484
Reference Data
Figure 1. 1H–13C HMBC spectrum of quinoacridinium salt 1.
Figure 2. Plot of calculated shielding constants ꢀ(ppm) versus
13C chemical shifts υ(ppm) in DMSO for aromatic carbons of 1.
ꢀ D 270.4–1.565υ; r D ꢀ0.991.
Two-dimensional 1H–15N NMR measurements were carried out on a
Varian UNITY plus 500 spectrometer using the phase-sensitive gradient-
selected inverse technique. The experiments were optimized for 2J/3J
coupling constants of ca 6 Hz (D6 D 0.08 s) and performed with four
scans of 128 echo and four scans of 128 anti-echo accumulations; 2D
experimental data were zero-filled to 512 points along the nitrogen direc-
tion. The chemical shifts were referenced against internal TMS (1H, 13C)
and external neat CH3NO2 (15N).
Scheme 2. Synthesis of quinoacridinium salt.
Magn. Reson. Chem. 2000; 38: 482–485
Copyright 2000 John Wiley & Sons, Ltd.

485
Reference Data
6. Jaroszewska J, Wawer I, Oszczapowicz J. Org. Magn. Reson. 1984;
22: 323, and references cited therein
Calculations
7. Kim J, Pordesimo EO, Toth SI, Schmitz FJ, van Altena I. J. Nat.
Prod. 1993; 56: 1813; Fixler N, Demeunyck M, Borchier MC,
Garcia J, Lhomme J. Magn. Reson. Chem. 1997; 35: 697; Cimino G,
Crispino A, De Stefano S, Gavagnin M, Sodano G. Tetrahedron
1987; 43: 4023.
8. Oszczapowicz J, Jaroszewska-Manaj J, Ciszak E, Gdaniec M. Tetra-
hedron 1988; 44: 6645.
The shielding constants were calculated using the GIAO CPHF approach
implemented in the Gaussian 98 package12 with the standard 6–31GŁŁ
basis set on molecular geometry taken from the semi-empirical cal-
culation by the PM3 method using the HyperChem 5.02 package.13
The conformations of ethyl groups and the shieldings for ethyl groups
carbons were not analysed.
9. Oszczapowicz J, Jaroszewska J. Pol. J. Chem. 1978; 53: 2163.
10. Reynolds WF, McLean S, Tay L, Yu M, Enriquez RG, Estwick DM,
Pascoe KO. Magn. Reson. Chem. 1997; 35: 455; Bax A, Sum-
mers MF. J. Am. Chem. Soc. 1986; 108: 2093; Doddrell DM,
Pegg DT, Bendall MR. J. Magn. Reson. 1982; 48: 323; Bax A,
Subramanian S. J. Magn. Reson. 1986; 67: 565–9.
Acknowledgements
This research was supported by project BW-1383/18/97 from Warsaw
University and grant FW-28/W-1/99 from the Medical University of
Warsaw.
11. Szelejewska-Woz´niakowska A, Chilmonczyk Z, Les´ A, Wawer I.
Solid State NMR 1998; 13: 63.
12. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA,
Cheeseman JR, Zakrzewski VG, Montgomery Jr JA, Stratmann RE,
Burant JC, Dapprich S, Millam JM, Daniels AD, Kudin KN,
Strain MC, Farkas O, Tomasi J, Barone V, Cossi M, Cammi R,
Mennucci B, Pomelli C, Adamo C, Clifford S, Ochterski J, Peters-
son GA, Ayala PY, Cui Q, Morokuma K, Malick DK, Rabuck AD,
Raghavachari K, Foresman JB, Cioslowski J, Ortiz JV, Baboul AG,
Stefanov BB, Liu G, Liashenko A, Piskorz P, Komaromi I, Gom-
perts R, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY,
Nanayakkara A, Gonzalez C, Challacombe M, Gill PMW, John-
son B, Chen W, Wong MW, Andres JL, Gonzalez C, Head-
Gordon M, Replogle ES, Pople JA. Gaussian 98, Revision A.7.
Gaussian, Inc.: Pittsburgh, PA, 1998.
REFERENCES
1. Molinski TF. Chem. Rev. 1993; 93: 1825.
2. Fixler N, Demeunynck M, Lhomme J. Synth. Commun. 1997;
27: 2311; Hilger CS, Fugman B, Steglich W. Tetrahedron Lett.
1985; 26: 5975; Bontemps N, Bonnard I, Banaigs B, Combaut G,
Francisco Ch. Tetrahedron Lett. 1994; 35: 7023.
3. Kaczmarek Ł, Balicki R, Nantka-Namirski P, Peczyn´ska-Czoch W,
Mordarski M. Arch. Pharm. (Weinheim) 1988; 321: 463.
4. Peczyn´ska-Czoch W, Pognan F, Kaczmarek Ł, Boratyn´ski J. J. Med.
Chem. 1994; 37: 3503.
13. Hyperchem 5.02 Package. Hypercube: Waterloo, Ontario, Canada,
1997.
5. Batterham TJ. NMR Spectra of Simple Heterocycles. Wiley: New
York, 1973.
Copyright 2000 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2000; 38: 482–485