Tautomeric 2-arylquinolin-4(1H)-one derivatives- spectroscopic, X-ray and quantum chemical structural studies

Article abstract of DOI:10.1016/j.molstruc.2003.10.003

A convenient method for the synthesis of 2-aryl-1-methylquinolin-4(1H) -ones is described. Spectroscopic and X-ray crystallographic techniques as well as quantum chemical calculations have been used to probe the structure of potentially tautomeric 2-arylq

Full text of DOI:10.1016/j.molstruc.2003.10.003

Journal of Molecular Structure 688 (2004) 129–136
www.elsevier.com/locate/molstruc
Tautomeric 2-arylquinolin-4(1H)-one derivatives- spectroscopic,
X-ray and quantum chemical structural studies
a,
Malose J. Mphahlele , Ahmed M. El-Nahas
b,
*
*
aDepartment of Chemistry, University of South Africa, P.O. Box 392, UNISA, Pretoria 0003, South Africa
bDepartment of Chemistry, Faculty of Science, El-Menoufia University, Shebin El-Kom, Egypt
Received 27 August 2003; revised 3 October 2003; accepted 3 October 2003
Abstract
A convenient method for the synthesis of 2-aryl-1-methylquinolin-4(1H)-ones is described. Spectroscopic and X-ray
crystallographic techniques as well as quantum chemical calculations have been used to probe the structure of potentially tautomeric
2-arylquinolin-4(1H)-ones in solution phase, gas phase and solid state. The exclusive NH-4-oxo nature of the title compounds in solution
phase (NMR) and solid state (IR and X-ray) is also corroborated by comparison of their spectroscopic data with those of the corresponding
2-aryl-1-methylquinolin-4(1H)-one and 2-aryl-4-methoxyquinoline derivatives. Results from mass spectrometric analysis confirm the
coexistence of the 4-quinolinone and 4-hydroxyquinoline isomers in the gas phase and this is supported by quantum chemical computations.
q 2003 Elsevier B.V. All rights reserved.
Keywords: 2-Arylquinolin-4(1H)-ones; Solution phase, solid state and gas phase studies
1. Introduction
quantum chemical calculations (semi-empirical and ab
initio methods) and to a lesser extend on X-ray crystal-
lography [3,4]. In spite of the extensive synthetic [5] and
pharmacological investigations of the 2-aryl-4-quinolones
as antibacterial [4] and antitumour agents [5], to our
knowledge, the tautomerism of these compounds has not
been documented. We therefore investigated the geometry
of the title compounds in solution, gas and solid state using
spectroscopic, X-ray crystallographic and quantum chemi-
cal techniques to provide a more focused qualitative
structural analysis of these systems. The results of spectro-
scopic and X-ray crystallographic methods have been
interpreted in combination with results of computer
modelling and by comparison with spectroscopic data of
the corresponding fixed derivatives (NMe and OMe).
Our research interest currently focuses on the synthesis
and structural property studies of the medicinally important
2-arylquinolin-4(1H)-one derivatives with potential to exist
in tautomeric equilibrium with the 2-aryl-4-quinolinol
isomers [1,2]. Understanding of tautomeric equilibria of
heterocyclic compounds is critical in the rationalization of
chemical and physical properties, reactivity of heterocycles,
the mechanism of enzymatic catalysis and drug-receptor
interaction [3]. Recently, we have reported the synthesis [1]
and tautomeric studies of 2-aryl-3-bromoquinolin-4(1H)-
ones [2], which are found to exist exclusively in solution
phase (NMR) and solid state (IR and X-ray) as the NH-
4-oxo derivatives. The coexistence of the 4-quinolinone and
4-hydroquinoline isomers in the gas phase was confirmed by
mass spectrometry and this was supported by B3LYP gas
phase calculations [2]. Most of the studies on the tautomeric
equilibria of 2-substituted-4-quinolinols versus 2-substi-
tuted-4-quinolone isomers carried out to-date are based
largely on the UV, IR and NMR spectroscopic data,
2. Results and discussion
Compounds 4 used as substrates in this investigation
were prepared by cyclization of systems 3 which were, in
turn, prepared by condensing 2-aminoacetophenones 1 with
benzoyl chloride derivatives 2 following literature
procedure (Scheme 1) [5b]. The antitumour activity of the
2-aryl-4-quinolin-4(1H)-ones appears to be influenced by
*
Corresponding authors.
Tel.: þ27-12-429-8805; fax: þ27-12-429-8549 (M.J. Mphahlele).
E-mail address: mphahmj@unisa.ac.za (M.J. Mphahlele).
0022-2860/$ - see front matter q 2003 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2003.10.003

130
M.J. Mphahlele, A.M. El-Nahas / Journal of Molecular Structure 688 (2004) 129–136
Scheme 1.
the change in substituents on the heterocyclic ring [6,7].
In order to obtain qualitative information on the tautomeric
structure prevailing in solution, gas and solid state, we
required model molecules in which the potential for
prototropic shift is eliminated. Consequently we prepared
the corresponding N-methyl derivatives 7 to compare their
spectroscopic data with those of precursors 4 and the
isomeric 2-aryl-4-methoxyquinolines. Previous synthetic
routes leading to the 2-substituted 1-methylquinolin-4(1H)-
one derivatives either involve multiple steps with reduced
overall yields [8] or produce mixtures of O-methylated and
N-methylated derivatives that are difficult to separate by
conventional column chromatographic techniques [5,9].
Graveoline has been isolated in 87% yield as a sole product
from the reaction of norgraveoline and methyl iodide-
potassium carbonate mixture in refluxing acetone [10],
however, the generality of this observation has not been
demonstrated. The reaction of methyl iodide with 2-phenyl-
4-quinolone, on the other hand, is reported to yield the
N-methyl phenylquinolinium iodide [11]. To our
knowledge, the shortest route (one-step synthesis) reported
to-date for the synthesis of 2-aryl-1-methyl-4-quinolones in
appreciable yields involves the condensation of lithium
enolates of acetophenone derivatives with substituted
N-methylisatoic anhydrides [8]. Although the reaction is
high yielding, each reaction when using different substrates
has its unique temperature requirements for completion [8].
In order to circumvent the problem of non-regioselec-
tivity of direct methylation of 4, we attempted to convert
substrates 3 to their N-methyl derivatives 6 with the aim of
cyclizing the latter to 7. Systems 3 were treated with
1.2–1.5 equiv. of sodium hydride in dry THF followed by
quenching with 1.2–1.5 equiv. of methyl iodide to afford
after 18 h traces of the starting material, the expected
derivative 6 (minor) and 7 (major), respectively (Scheme 1).
The 1H NMR spectra of compounds 6 are characterized by
the presence of two sets of methyl signals at d ca. 1.80 ppm
(COCH3) and d ca. 3.38 ppm (NCH3) and a group of signals
in the aromatic region. In view of the ready availability of
the substrates and the mild reaction conditions, the
generalized approach reported in this paper represents a
convenient alternative to existing methods for the synthesis
of N-methyl 2-aryl-4-quinolones. A three-step synthetic
approach leading to the formation of analogous N-benzyl-2-
arylquinolin-4(1H)-ones had been reported before [12].
The isomeric 2-aryl-4-methoxyquinolines are well known
natural products some of which have been found to possess
antimalarial activity and for this reason, numerous methods
have been developed for their synthesis [13]. Hitherto this
investigation, we also reported the synthesis and character-
ization of the 2-aryl-4-methoxyquinolines obtained via
iodine-methanol promoted oxidation of the 2-aryl-1,2,3,4-
tetrahydro-4-quinolinones [14].
3. Solution phase studies using NMR spectroscopy
The 1H NMR spectra of the compounds 4 are
characterized by the olefinic proton (3-H) signal, aromatic
signals and the imine proton signal at d ca. 6.32–6.50 ppm,

M.J. Mphahlele, A.M. El-Nahas / Journal of Molecular Structure 688 (2004) 129–136
131
Table 1
13C NMR chemical shifts (ppm) of systems 4 and 7 (in DMSO-d6, 75 MHz)
4/7
R
R0, R00
X
CH2O2
NCH3
C-2
C-3
C-4
C-4a
C-5
C-6
C-7
C-8
C-8a
4a
4b
4c
4d
7a
7b
7c
7d
7e
7f
H
H
H
–
–
150.0
149.0
150.1
150.4
154.8
153.6
156.9
154.7
152.2
152.2
152.3
107.3
107.3
106.5
107.1
112.6
112.8
108.9
112.7
112.1
112.1
112.1
176.9
176.8
175.8
177.5
177.6
177.5
171.0
177.6
176.2
176.9
176.1
124.9
125.0
125.1
126.9
126.8
126.8
124.3
126.7
122.7
122.6
122.6
123.2
123.3
122.8
123.8
123.7
123.7
124.5
123.5
103.7
103.5
103.6
124.7
124.7
124.5
125.3
126.7
126.7
126.7
128.1
145.3
145.3
145.4
131.8
131.8
131.1
132.3
132.3
132.4
134.6
132.2
153.3
152.2
152.0
118.7
118.7
120.6
119.4
115.9
115.9
118.8
115.9
95.5
140.5
140.4
142.5
141.2
141.9
141.9
141.2
142.0
139.1
139.0
139.1
H
H
F
–
–
H
H
Cl
–
–
H
H
OCH3
H
–
–
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
–
37.2
37.2
39.4
37.3
37.8
37.7
37.8
H
F
–
H
Cl
–
H
OCH3
H
–
OCH2O
OCH2O
OCH2O
102.0
102.1
102.1
F
95.5
7g
Cl
95.5
For atom labeling see Fig. 1. For the sake of clarity, the chemical shift values of the aryl substituent have not been included.
d ca. 6.50–8.20 ppm and d ca. 11.71 ppm, respectively.
Their 13C NMR spectra are characterized by a group of
resonances in the aromatic region and the carbonyl carbon
signal at d ca. 175.0–176.5 ppm. The 1H NMR spectra of 7,
on the other hand, are characterized by the presence of the
N-methyl signal at d ca. 3.51 ppm, the vinylic proton (3-H)
signal at d ca. 6.51 ppm and the aromatic proton signals.
Their 13C NMR spectra are characterized by the N-methyl
signal in the region d 37.2–39.0 ppm, signals corresponding
to aromatic carbons and the carbonyl carbon at d ca.
171.0–178.0 ppm (Table 1). The O-methyl and C-4 signals
of the 2-aryl-4-methoxyquinolines, on the other hand,
resonate at dC ca. 58.0 ppm (dH ca. 4.50 ppm) and dC ca.
168.0 ppm, respectively [14]. The NMR spectral data of
systems 4 differ from those of the 2-aryl-4-methoxyquino-
line derivatives [14] and are comparable to those of
compounds 7. The striking similarity between the NMR
spectral data of 4 and 7 rules out the possibility of 5 and
confirms the carbonyl nature of the title compounds.
Thus compounds 4 exist exclusively as the NH-4-oxo
tautomers in a polar solvent such as DMSO in analogy with
the structures of the 2-aryl-3-bromoquinolin-4(1H)-ones [2]
and 4-quinolinone [3,4].
[4]. Single crystals of the 2-(40-fluorophenyl) derivative
suitable for X-ray crystallographic analysis were obtained by
slow evaporation of the ethanol solution and the compound is
found to exist exclusively as the NH-4-oxo derivative 4b.
In the crystal lattice (Fig. 1a) compounds 4 adopt a
conformation in which the B-ring lies at 157.38 relative to
the co-planar A- and C-rings (see Table 3 for torsion angles).
At the B3LYP/3-21G level, the computed values for N1-C2-
C10-C20 and C3-C2-C10-C20 torsion angles are 140.38 and
41.08, respectively. The difference between computed and
observed torsion angles may be attributed to crystal packing
which tends to give wider angles. In general, the geometry
optimized enol forms 5a–d are planar whereas the
corresponding keto forms 4a–d deviate from planarity due
to the repulsion between hydrogen atoms attached to N-1 and
Table 2
IR frequencies for compounds 4 and 7
4, 7 (X)
n
max (cm21) (KBr pellet)
4a (H)
4b (F)
3423, 1636, 1581, 1545, 1516, 1470,
1404, 1256, 840, 772, 689, 524
3400, 2970, 1633, 1604, 1591, 1548,
1507, 1164, 852, 796, 570, 515
3420, 3087, 2930, 1642, 1598, 1500,
1424, 1331, 1098, 828, 532
3412, 1613, 1591, 1569, 1542, 1291,
1276, 1250, 1017, 849, 757
1636, 1594, 1583, 1547, 1474, 1356,
1256, 840, 529, 524
4c (Cl)
4d (OMe)
7a (H)
7b (F)
4. Solid state studies using IR spectroscopy
and X-ray crystallography
The solid state structures of the title compounds were
investigated using FT-IR spectroscopy (Table 2) and X-ray
crystallography. Their carbonyl nature was confirmed in the
solid state by their IR frequencies [nmax (cm21) ca.
1632–1643 (CyO)] that are comparable to those of the
corresponding derivatives 7 (Table 2).
1623, 1601, 1550, 1509, 1223, 1136,
851, 806, 774
7c (Cl)
7d (OMe)
7e (H)
1620, 1582, 1534, 1467, 1169, 1032,
965, 847, 727
1618, 1600, 1512, 1496, 1402, 1295,
1181, 1031, 840, 758
1626, 1585, 1495, 1472, 1286, 1273,
1250, 1097, 1037, 890, 702
1626, 1581, 1510, 1498, 1482, 1272,
1033, 934, 841
Despite the enormous chemical [5] and pharmacological
interest [4,5] in systems 4, to our knowledge, no information
has been published on their X-ray crystal data [2,4a].
The scarcity of X-ray crystallographic data for systems 4
can be attributed to their amorphous nature in the solid state
7f (F)
7g (Cl)
1626, 1581, 1511, 1498, 1448, 1286,
1273, 1162, 1034

132
M.J. Mphahlele, A.M. El-Nahas / Journal of Molecular Structure 688 (2004) 129–136
Fig. 1. (a) ORTEP diagram of 4b, showing crystallographic labeling. Thermal ellipsoids are drawn at the 50% probability level. (b) X-Ray crystal structure for
4b, showing the hydrogen bonding pattern.
C-60 (Fig. 1a). The observed geometry of systems 4 differs
remarkably from that of the 2-aryl-3-bromoquinolin-4(1H)-
ones described before [2] in which the aryl substituent
deviates considerably (125.98) from co-planarity probably to
relieve steric interaction between 1-H and Br and the ortho
hydrogens (20-H and 60-H).
Systems 4 exhibit strong intermolecular hydrogen
bonding with the O· · ·H and N–H interatomic distances of
˚
1.914 and 0.898 A, respectively (Fig. 1b).
5. Gas phase studies using mass spectrometry
Table 3
The C-ring of the molecular ions of systems 4 and 7
fragment by elimination of CO (M-28) to afford radical-
cations in relatively high abundance (Table 4). The 2-aryl-4-
methoxyquinolines, on the other hand, are known to
undergo fragmentation pattern typical for ether derivatives
[14]. The presence of 5 in the gas phase is confirmed by the
cation fragments corresponding to the extrusion of hydroxyl
Selected torsion angles [8] for compound 4b
C10-C2-C3-C4
N1-C2-C10-C60
C3-C2-C10-C60
N1-C2-C10-C20
C3-C2-C10-C20
2 178.22(13)
23.52(19)
2155.71(14)
2157.29(13)
23.5(19)

M.J. Mphahlele, A.M. El-Nahas / Journal of Molecular Structure 688 (2004) 129–136
133
Table 4
Selected mass fragments of systems 4 and 6 with relative intensities in parentheses
Compounds
Molecular formula
Mþ (%)
m=z (%)
m=z (%)
4a
4b
4c
4d
7a
7b
7c
7d
7e
7f
C15H11NO
221 (94.8)
239 (85.7)
255 (100)
251 (100)
235 (88.9)
253 (83.0)
269 (75.2)
265 (100)
279 (74.4)
297 (63.1)
313 (55.6)
204 (M-OH, 16.1)
193 (M-CO, 100)
211 (M-CO, 100)
227 (M-CO, 70.9)
223 (M-CO, 93.7)
207 (M-CO, 100)
225 (M-CO, 100)
241 (M-CO, 100)
237 (M-CO, 72.9)
251 (M-CO, 68.6)
269 (M-CO, 100)
285 (M-CO, 100)
C15H10NOF
15H10NO35Cl
222 (M-OH, 30.1)
C
238 (M-OH, 19.1)
C16H13NO2
16H13NO
236 (M-OH, 20.1)
C
–
–
–
–
–
–
-
C16H12NOF
C16H12NO35Cl
C17H15NO2
C17H13NO3
C17H13NO3F
C17H13NO335Cl
7g
radical [M-17] in 16–31% relative abundance. Although
tautomerism is a difficult subject to study in the gas phase
using spectroscopic methods, quantum chemical calcu-
lations became a valuable tool for determination of
structures and energies of molecules in the gas and solution
phases to complement experimental data.
Table 5) as determined by PM3 indicate the predominance
of the NH-4-oxo form. This energy difference may be
significantly affected by inclusion of zero-point energy
(ZPE) correction and, therefore, ZPE calculation seems to
be necessary for accurate estimation of tautomerization
energies. Calculations were carried at higher levels of
theory, namely B3LYP hybrid density functional method
[16] and Moller Plesset perturbation theory [17] at second
order. Full geometry optimizations have been carried out
without symmetry constraints using the three-parameter
hybrid density functional theory (DFT) functional of Becke
(B3LYP) [16] with the 3-21G basis set. Frequency
calculations were done at the HF/3-21G level and indicate
that all of the investigated forms are minima (no imaginary
6. Quantum chemical calculations
Geometry optimization of 4a–d and 5a–d were first
accomplished using PM3 with the MOPAC program as
implicated in Alchemy 2000 software package [15].
The small energy differences between 4 and 5 (Scheme 1,
Table 5
Calculated energies (kcal/mol and a.u.) and dipole moments (m) for the quinolone 4 and quinolinol 5 forms at different levels of theory
Compounds
PM3
B3LYP/6-31 þ G(d), MP2/6-31 þ G(d)
4/5
R0, R00
H
X
H
DHf (4)
D Hf (5)
DHf (5–4)
m (4)
m (5)
Eabs (4)
Eabs (5)
Erel (4–5)a
m (4)
m (5)
a
27.9
215.3
21.4
28.6
0.7
4.85
1.75
2708.24337b
2708.25657a
2706.08105c
0.23757d
2708.23621b
2708.24450a
2706.07882c
0.23638d
4.5b
7.6a
1.4c
0.7e
6.698b
2.168b
b
c
H
H
H
F
215.0
21.9
0.3
0.5
0.8
4.06
4.34
5.76
2.52
2.06
1.63
2807.48221b
2807.49497a
2805.09057c
0.22917d
2807.47817b
2807.48572a
2805.08930c
0.22804d
3.8b
5.8a
0.8c
0.7e
5.665b
5.634b
6.803b
2.961b
3.105b
3.756b
Cl
21167.83820b
21167.85030a
21165.10456c
0.22736d
21167.83237b
21167.83943a
21165.10381c
0.22622d
3.7b
6.8a
0.5c
0.7e
d
OMe
210.4
29.6
2822.76990b
2822.78260a
2820.28458c
0.27239d
2822.76238b
2822.77186a
2820.28199c
0.27120d
4.7b
6.7a
1.6c
0.7e
a
b
c
d
e
Uncorrected absolute (a.u.) and relative (kcal/mol) energies from PCM-B3LYP/6-31 þ G(d)//B3LYP/3-21G.
Uncorrected absolute (a.u.) and relative (kcal/mol) energies and dipole moments (Debye) from B3LYP/6-31 þ G(d)//B3LYP/3-21G.
Uncorrected absolute (a.u.) and relative (kcal/mol) energies from MP2/6-31 þ G(d)//B3LYP/3-21G.
Zero-point energies (ZPE, a.u.) from HF/3-21G.
ZPE, correction (kcal/mol).

134
M.J. Mphahlele, A.M. El-Nahas / Journal of Molecular Structure 688 (2004) 129–136
eigenvalues of the Hessian matrix). The zero-point
vibrational energy corrections were retrieved from the
frequency calculations and used to correct the tautomeriza-
tion energies. Single point energy calculations in the gas
phase have been carried out at the B3LYP and MP2 levels of
theory using the 6-31 þ G(d) basis set at the B3LYP/3-21G
geometries. Solvation in DMSO has been modelled at the
B3LYP/6-31 þ G(d)//B3LYP/3-21G level using the
Polarized Continuum Model (PCM) of Tomasi and co-
workers [18]. DFT and Hartree–Fock (HF) calculations
were carried out with GAUSSIAN 98 program [19] and MP2
calculations were performed using the PC GAMESS version
[20a] of the GAMESS (US) QC package [20b]. The results
of quantum chemical calculations are listed in Table 5.
ZPE correction adds 0.7 kcal/mol to the stability of
5a–d. DFT calculations at the B3LYP level indicate that the
stability of 4a–d increases to 3–4 kcal/mol even after the
inclusion of ZPE correction. On the other hand, corrected
MP2 energies give small energy difference between 4 and 5
in favor of the NH-4-oxo isomers in the gas phase except for
5c, which is 0.2 kcal/mol more stable. The small energy
differences between 4 and 5 observed using PM3 and MP2
calculations explain the coexistence of both tautomers in the
gas phase as determined by mass spectrometry. The overall
dipole moments of systems 4 calculated using PM3 and
B3LYP methods are higher than those of the
corresponding isomers 5 thus predicting the greater stability
of the NH-4-oxo form in polar media. PCM-B3LYP/6-
31 þ G(d) calculations in DMSO reveal that systems 4 are
more stable than 5 by 5–7 kcal/mol after ZPE correction
(Table 5). The tautomerization energies in DMSO correlate
linearly with the difference in dipole moments between keto
and enol isomers.
8. Experimental
Melting points were recorded on a Thermocouple digital
melting point apparatus and are uncorrected. IR spectra
were recorded as KBr pellets at the University of Pretoria’s
Raman and Infrared Facility using Bruker IFS 113V FT-IR
spectrometer (number of scans ¼ 32, resolution ¼ 2 cm21).
NMR spectra were obtained as DMSO-d6 solutions using
Varian Mercury 300 MHz NMR spectrometer and the
chemical shifts are quoted relative to the solvent peaks.
The low-resolution mass spectra were recorded at Rhodes
University using Finnigan Mat GCQ instrument. XRD data
collection and solution were carried out at the Jan Boeyens
Structural Chemistry Laboratory (University of the Witwa-
tersrand). The synthesis and characterization of 4a and 7a
have been described before [5]. Analytical data for new
compounds 4b–d, 6a–g and 7b–g which were prepared
following literature method [5] are as follows:
2-( p-Fluorophenyl) derivative 4b. Solid (55%); m.p.
322–325 8C (AcOH) and dH (300 MHz, DMSO-d6) 6.32
(1H, s, 3-H), 7.33 (1H, t, J 7.5 Hz, 6-H), 7.42 (2H, t, J
8.2 Hz, 20-H and 60-H), 7.66 (1H, t, J 7.7 Hz, 7-H), 7.75 (1H,
d, J 8.3 Hz, 8-H), 7.91 (2H, t, J 7.5 Hz, 30-H and 50-H), 8.09
(1H, d, J 8.1 Hz, 6-H) and 11.71 (1H, s, NH).
2-( p-Chlorophenyl) derivative 4c. Solid (65%); m.p.
270–273 8C (AcOH) and dH (300 MHz, DMSO-d6) 6.41
(1H, s, 3-H), 7.28 (1H, t, J 7.5 Hz, 6-H), 7.57-7.62 (3H, m,
20-H, 60-H and 7-H), 7.74 (1H, d, J 7.8 Hz, 8-H), 7.90 (2H, d,
J 7.8 Hz, 30-H and 50-H), 8.09 (1H, d, J 7.5 Hz, 6-H) and
11.76 (1H, brs, NH).
2-( p-Methoxyphenyl) derivative 4d. Solid (80%); m.p.
290–293 8C (AcOH) and dH (300 MHz, DMSO-d6) 3.84
(3H, s, OCH3), 6.31 (1H, s, 3-H), 7.12 (2H, d, J 8.5 Hz, 20-H
and 60-H), 7.31 (1H, t, J 7.5 Hz, 6-H), 7.64 (1H, t, J 7.5 Hz,
7-H), 7.76 (1H, d, J 8.4 Hz, 8-H), 7.80 (2H, d, J 8.4 Hz,
30-H and 50-H), 8.07 (1H, d, J 7.5 Hz, 6-H) and 11.46 (1H,
brs, NH).
7. Conclusion
A comparison of spectroscopic data of 2-aryl-4-
methoxyquinolines [14] and N-methyl isomers 7 with
those of 4 provides qualitative information on the tautomer
that exists in solution and solid state. DFT results modelled
in DMSO and X-ray data all point to the exclusive carbonyl
nature of the title compounds in solution and solid state in
agreement with spectroscopic data, respectively. In the gas
phase where solvent-assisted stabilization and intermolecu-
lar hydrogen bond are absent, both tautomers coexist as
confirmed by mass spectrometry and supported by PM3,
B3LYP, and MP2 gas phase calculations. Conjugative
effects of the 2-aryl substituent as well as electronic effects
of the substituents at its para position appear not to
influence the tautomeric equilibrium. Our results which
incorporate X-ray data of the 2-aryl-4-quinolones
complement previously reported spectroscopic and
computational data of 4-quinolone versus 4-quinolinol
equilibrium [2–4].
8.1. Synthesis of 2-aryl-1-methylquinolin-4(1H)-one
derivatives. General procedure
A stirred suspension of 3 (1 equiv.) in dry THF (5 ml per
mmol of 3) was treated with NaH (1.2 equiv.) at room
temperature. After 1 h at room temperature, the mixture was
treated with methyl iodide (1.2 equiv.) and stirring
continued for 18 h. The mixture was quenched with ice-
cold water and then extracted with chloroform.
The combined chloroform solutions were dried over
Na2SO4, filtered and then evaporated under reduced
pressure. The residue was purified by column chromatog-
raphy (elution with hexane–EtOAc, 3:2 v/v) to afford
N-Methyl 2-phenyl derivatives (R0, R00 ¼ H): 6a brown
syrup (12%) and dH (300 MHz, CDCl3) 1.82 (3H, s,
COCH3), 3.43 (3H, s, NCH3), 7.20–7.66 (8H, m, C6H5, 3-
H, 4-H and 5-H) and 8.52 (1H, dd, J 1.5 and 8.1 Hz, 6-H);

M.J. Mphahlele, A.M. El-Nahas / Journal of Molecular Structure 688 (2004) 129–136
135
and 7a Solid (75%); m.p. 143–145 8C (EtOH) (Lit., [5]
145–147 8C).
N-Methyl 2-( p-chlorophenyl) derivatives (R0, R00 ¼
OCH2O): 6 g Solid (10%); m.p. 212–213 8C (EtOH) and
dH (300 MHz, CDCl3) 1.81 (3H, s, COCH3), 3.39 (3H, s,
NCH3) 6.08 (2H, s, CH2O2), 6.87 (1H, s, 3-H), 7.26 (4H, s,
C6H4Cl) and 7.86 (1H, s, 6-H); and 7 g Solid (55%); m.p.
247–248 8C (EtOH) and dH (300 MHz, CDCl3) 3.51 (3H, s,
CH3), 6.08 (2H, s, CH2O2), 6.15 (1H, s, 3-H), 6.90 (1H, s,
8-H), 7.33 (2H, d, J 8.2 Hz, 30-H and 50-H), 7.46 (2H, d, J
8.1 Hz, 20-H and 60-H) and 7.77 (1H, s, 5-H).
N-Methyl 2-( p-fluorophenyl) derivatives (R0, R00 ¼ H):
6b Solid (10%); m.p. 168–170 8C (EtOH) and dH
(300 MHz, CDCl3) 1.86 (3H, s, COCH3), 3.48 (3H, s,
NCH3), 7.22–7.28 (4H, m, C6H4F), 7.41 (1H, t, J 7.5 Hz,
4-H), 7.50 (1H, d, J 8.7 Hz, 3-H), 7.78 (1H, t, J 7.5 Hz, 5-H),
8.55 (1H, d, J 8.1 Hz, 6-H); and 7b Solid (70%); m.p.
178–180 8C (EtOH) and dH (300 MHz, DMSO-d6) 3.59
(3H, s, CH3), 6.23 (1H, s, 3-H), 7.19 (2H, t, J 8.4 Hz, 20-H
and 60-H), 7.37–7.44 (3H, m, 30-H, 50-H and 6-H), 7.53 (1H,
d, J 8.4 Hz, 8-H), 7.70 (1H, t, J 8.1 Hz, 7-H) and 8.47 (1H, d,
J 8.0 Hz, 5-H).
8.2. X-Ray crystallographic data collection
and processing [21]
N-Methyl 2-( p-chlorophenyl) derivatives (R0, R00 ¼ H):
6c Solid (15%); m.p. 108-111 8C (EtOH) and dH (300 MHz,
CDCl3) 1.85 (3H, s, COCH3), 3.47 (3H, s, NCH3), 7.24 (2H,
d, J 8.4 Hz, 20-H and 60-H), 7.40 (1H, t, J 7.5 Hz, 4-H), 7.49
(1H, d, J 8.7 Hz, 3-H), 7.54 (2H, d J 8.4 Hz, 30-H and 50-H),
7.68 (1H, t, J 7.8 Hz, 5-H) and 8.54 (1H, d, J 8.1 Hz, 6-H);
and 7c Solid (80%); m.p. 174–178 8C (EtOH) and dH
(300 MHz, DMSO-d6) 3.90 (3H, s, CH3), 7.71 (4H, s,
C6H4Cl), 7.78 (1H, t, J 8.0 Hz, 6-H), 8.09 (1H, t, J 8.1 Hz,
7-H), 8.22 (1H, d, J 8.4 Hz, 8-H) and 8.40 (1H, d, J 8.1 Hz,
5-H).
N-Methyl 2-( p-methoxyphenyl) derivatives (R0,
R00 ¼ H): 6d Solid (20%); m.p. 179–182 8C (EtOH) and
dH (300 MHz, CDCl3) 1.85 (3H, s, COCH3), 3.45 (3H, s,
NCH3), 3.87 (3H, s, OCH3), 7.03 (2H, d, J 8.7 Hz, 20-H and
60-H), 7.16 (2H, d, J 8.7 Hz, 30-H and 50-H), 7.34 (1H, t, J
7.6 Hz, 4-H), 7.46 (1H, d, J 8.7 Hz, 3-H), 7.62 (1H, t, J
7.5 Hz, 5-H) and 8.52 (1H, d, J 8.1 Hz, 6-H); and 7d Solid
(56%); m.p. 144–146 8C (EtOH) and dH (300 MHz, CDCl3)
3.61 (3H, s, NCH3), 3.86 (3H, s, OCH3), 4.27 (1H, s, 3-H),
6.99 (2H, d, J 8.7 Hz, 30-H and 50-H), 7.33 (2H, J 7.8 Hz,
20-H and 60-H), 7.39 (1H, dt, J 0.9 and 7.5 Hz, 7-H), 7.52
(1H, d, J 8.2 Hz, 8-H), 7.68 (1H, dt, J 1.5 and 7.8 Hz, 6-H)
and 8.47 (1H, dd, J 1.5 and 8.1 Hz, 5-H).
N-Methyl 2-phenyl derivatives (R0, R00 ¼ OCH2O): 6e
Solid (17%); m.p. 178–181 8C (EtOH) and dH (300 MHz,
CDCl3) 1.80 (3H, s, COCH3), 3.37 (3H, s, CH3), 6.04 (2H, s,
CH2O2), 6.85 (1H, s, 3-H), 7.24 (2H, dd, J 1.8 and 7.9 Hz,
20-H and 60-H), 7.48 (3H, m, 20-H, 30-H and 50-H) and 7.84
(1H, s, 6-H); and 7e Solid (60%); m.p. 210-212 8C (EtOH)
and dH (300 MHz, CDCl3) 3.52 (3H, s, CH3), 6.08 (2H, s,
CH2O2), 6.20 (1H, s, 3-H), 6.93 (1H, s, 8-H), 7.35–7.48
(5-H, m, C6H5) and 7.81 (1H, s, 5-H).
N-Methyl 2-( p-fluorophenyl) derivatives (R0, R00 ¼
OCH2O): 6f Solid (10%); m.p. 226–228 8C (EtOH) and
dH (300 MHz, CDCl3) 1.80 (3H, s, COCH3), 3.38 (3H, s,
NCH3), 6.07 (2H, s, CH2O2), 6.86 (1H, s, 3-H), 7.21 (2H, d,
J 8.4 Hz, 20-H and 60-H), 7.51 (2H, d, J 8.4 Hz, 30-H and
50-H) and 7.84 (1H, s, 6-H); and 7f Solid (70%); m.p.
240-242 8C (EtOH) and dH (300 MHz, CDCl3) 3.52 (3H, s,
CH3), 6.09 (2H, s, OCH2O), 6.18 (1H, s, 3-H), 6.92 (1H, s,
8-H), 7.18 (2H, t, J 8.4 Hz, 20-H and 60-H), 7.38 (2H, t, J
8.4 Hz, 30-H and 50-H) and 7.80 (1H, s, 5-H).
Intensity data were collected on a Bruker SMART 1K
CCD area detector diffractometer with graphite monochro-
mated Mo Ka radiation (50 kV, 30 mA). The collection
method involved v-scans of width 0.38. Data reduction was
carried out using the program SAINT þ [21a] and absorp-
tion corrections were made using the program SADABS
[21b]. The crystal structure was solved by direct methods
using SHELXTL [21c]. Non-hydrogen atoms were first
refined isotropically followed by anisotropic refinement by
full matrix least-squares calculation based on F 2 using
SHELXTL. With the exception of H1, atoms were located
from the difference map then positioned geometrically and
allowed to ride on their respective parent atoms. H1 was
located from the difference map and refined isotropically
without restraints. Diagrams and publication material were
generated using SHELXTL and PLATON [21d]. Crystal data
˚
for 4b, C15H10NOF, Mr ¼ 239.24, monoclinic, a/A
˚
˚
11.776(2), b/A 7.2064(14), c/A 13.322(3), a ¼ g ¼ 908;
˚
b ¼ 92:263ð4Þ8; V/A [3] 1129.6(4), temperature (K) 293(2),
P21/c, Z ¼ 4; m/mm21 0.100, number of reflections
measured ¼ 7298 and number of independent
reflections ¼ 2790 [R(int) ¼ 0.0238]. Supplementary
crystallographic data have been deposited at the Cambridge
Crystallographic Data Centre (CCDC reference number
210421).
Acknowledgements
We are grateful to the Wellcome Trust (UK) for
Equipment Grant [060968/Z/00/Z/JC/SRD] in the form of
Varian Mercury 300 MHz NMR spectrometer. We also
thank Ms Linda Prinsloo of the University of Pretoria and
Mr. Manuel A. Fernandes of University of the Witwaters-
rand for FT-IR and X-ray data, respectively.
References
[1] M.J. Mphahlele, J. Chem. Res. (S) (2002) 196.
[2] M.J. Mphahlele, M.A. Fernandes, A.M. El-Nahas, H. Ottosson, S.M.
Ndlovu, H.M. Sithole, B.S. Dladla, D. De Waal, J. Chem. Soc. Perkin
Trans. 2 (2002) 2159.

136
M.J. Mphahlele, A.M. El-Nahas / Journal of Molecular Structure 688 (2004) 129–136
[3] J. Elguero, J. Marzin, A.R. Katritzky, P. Linda, The Tautomerism of
[16] A.D. Becke, J. Chem. Phys. 98 (1993) 5648.
C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37 (1988) 785.
[17] C. Moller, M.S. Plesset, Phys. Rev. 46 (1934) 618.
Heterocycles, Academic Press, New York, 1976, p. 71. A.R.
Katritzky, J.M. Lagowski, Advances in Heterocyclic Chemistry,
Academic Press, New York, 1963, p. 339. N. Tokay, C. Ogretir,
J. Mol. Struct. Theochem., 594 (2002) 185.
[18] S. Miertus, E. Scrocco, J. Tomasi, J. Chem. Phys 55 (1981) 117.
J. Tomasi, M. Persico, Chem. Rev. 94 (1994) 2027.
R. Cammi, J. Tomasi, J. Comput. Chem. 16 (1995) 1449.
M. Cossi, V. Barone, R. Cammi, J. Tomasi, J. Chem. Phys. Lett. 255
(1996) 327.
[4] A. de la Cruz, J. Elguero, P. Goya, A. Martinez, W. Pfeiderer,
Tetrahedron 48 (1992) 6135.
E. Murguly, T.B. Nortsten, N. Branda, J. Chem. Soc. Perkin Trans. 2
(1999) 2789.
[19] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb,
J.R. Cheeseman, V.G. Zakrzewski, J.A. Montgomery, Jr., R.E.
Stratmann, J.C. Burant, S. Dapprich, J.M. Millam, A.D. Daniels,
K.N. Kudin, M.C. Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi,
R. Cammi, B. Mennucci, C. Pomelli, C. Adamo, S. Clifford, J.
Ochterski, G.A. Petersson, P.Y. Ayala, Q. Cui, K. Morokuma, D.K.
Malick, A.D. Rabuck, K. Raghavachari, J.B. Foresman, J. Cioslowski,
J.V. Ortiz, A.G. Baboul, B.B. Stefanov, G. Liu, A. Liashenko,
P. Piskorz, I. Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T.
Keith, M. A. Al-Laham, C.Y. Peng, A. Nanayakkara, C. Gonzalez,
M. Challacombe, P.M.W. Gill, B.G. Johnson, W. Chen, M.W. Wong,
J.L. Andres, M. Head-Gordon, E.S. Replogle, J.A. Pople, Gaussian,
Inc., Pittsburgh PA, 1998.
[5] S. Kuo, H. Lee, J. Juang, Y. Lin, T. Wu, J. Chang, D. Lednicer,
K.D. Paull, C.M. Lin, E. Hamel, K. Lee, J. Med. Chem. 36
(1993) 1146.
L. Li, H. Wang, S. Kuo, T. Wu, A. Mauger, C.M. Lin, E. Hamel,
K. Lee, J. Med. Chem. 37 (1994) 3400.
[6] S. Torii, H. Okumoto, L.H. Xu, Tetrahedron Lett. 32 (1991) 237.
[7] S. Sato, Y. Kubota, H. Kumagai, T. Kumazawa, S. Matsuba, J.
Onodera, M. Suzuki, Heterocycles 53 (2000) 1523.
[8] G.M. Cappola, J. Heterocyclic Chem. 19 (1982) 727.
[9] R. Somanathan, K.M. Smith, J. Heterocyclic Chem 18 (1981) 1077.
[10] R. Annunziata, S. Cenini, G. Palmisano, S. Tollari, Synth. Commun.
26 (1996) 495.
[20] (a) A.A. Granovsky, www http://classic.chem.msu.su/gran/gamess/
index.html (b) M.W. Schmidt, K.K. Baldridge, J.A. Boatz,
S.T. Elbert, M.S. Gordon, J.J. Jensen, S. Koseki, N. Matsunaga,
K.A. Nguyen, S. Su, T.L. Windus, M. Dupuis, J.A. Montgomery
J. Comput. Chem. 14 (1993) 1347.
[11] S. Sato, T. Watanabe, H. Kumagai, N. Kitamura, S. Matsuba, T.
Kumazawa, J. Onodera, M. Suzuki, J. Heterocyclic Chem. 36
(1999) 1189.
[12] E.J. Niedzinski, M.R. Leshley, M.H. Nantz, Heterocycles 55
(2001) 623.
[21] (a) Bruker, (1999). SAINTþ, Version 6.02 (includes XPREP and
SADABS), Bruker AXS Inc., Madison, Wisconsin, USA;
¨
(b) Sheldrick, G.M. (1996). SADABS, University of Gottingen,
[13] O.V. Singh, S. Kapil, Synlett. (1992) 751.
R.S. Varma, D. Kumar, Tetrahedron Lett. 39 (1998) 9113.
[14] M.J. Mphahlele, F.K. Mogamisi, M. Tsanwani, S.M. Hlatshwayo,
R.M. Mampa, J. Chem. Res. (S) (1999) 706.
Germany; (c) Bruker, (1999). SHELXTL. Version 5.1. (includes XS,
XL, XP, XSHELL) Bruker AXS Inc., Madison, Wisconsin, USA;
(d) A.L. Spek, Acta Cryst. A46 (1990) C-34.
[15] Alchemy32 version 2.0 [9/21/97], Tripos inc, St. Louis, MO, USA.