Synthesis, spectroscopy and computational studies of some biologically important hydroxyhaloquinolines and their novel derivatives

Article abstract of DOI:10.1016/j.molstruc.2010.01.054

A series crystalline compounds of methyl and phosphinyl derivatives of 2-methylquinolin-8-ol (1a) and related 5,7-dichloro-2-methylquinolin-8-ol (1b) were quantitatively prepared and characterized by microanalysis, IR, UV-vis and multinuclear NMR spectroscopy. Five of them have been characterized by single crystal X-ray diffraction method. The known compounds, 8-methoxy-2-methylquinoline (2a) and 8-methoxyquinoline (2d), were synthesised by a new route. NMR solution spectra at ambient temperature, showed readily diagnostic H-1 and C-13 signals from methyl groups. The geometries of the studied compounds were optimized in singlet states using the density functional theory (DFT) method with B3LYP functional. In general, the predicted bond lengths and angles are in a good agreement with the values based on the X-ray crystal structure data. Electronic spectra were calculated by TDDFT method. Crown Copyright

Full text of DOI:10.1016/j.molstruc.2010.01.054

Journal of Molecular Structure 969 (2010) 130–138
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, spectroscopy and computational studies of some biologically important
hydroxyhaloquinolines and their novel derivatives
a
c
b
b
Grzegorz Malecki a, Jacek E. Nycz a, , Ewa Ryrych , Lukasz Ponikiewski , Maria Nowak , Joachim Kusz ,
*
Jerzy Pikies c
a Institute of Chemistry, University of Silesia, ul. Szkolna 9, PL-40006 Katowice, Poland
b Institute of Physic, University of Silesia, ul. Uniwersytecka 4, PL-40006 Katowice, Poland
c Department of Inorganic Chemistry, Faculty of Chemistry, Gdan´sk University of Technology, 11/12G. Narutowicz St., PL-80233 Gdan´sk, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A series crystalline compounds of methyl and phosphinyl derivatives of 2-methylquinolin-8-ol (1a) and
related 5,7-dichloro-2-methylquinolin-8-ol (1b) were quantitatively prepared and characterized by
microanalysis, IR, UV–vis and multinuclear NMR spectroscopy. Five of them have been characterized
by single crystal X-ray diffraction method. The known compounds, 8-methoxy-2-methylquinoline (2a)
and 8-methoxyquinoline (2d), were synthesised by a new route. NMR solution spectra at ambient tem-
perature, showed readily diagnostic H-1 and C-13 signals from methyl groups. The geometries of the
studied compounds were optimized in singlet states using the density functional theory (DFT) method
with B3LYP functional. In general, the predicted bond lengths and angles are in a good agreement with
the values based on the X-ray crystal structure data. Electronic spectra were calculated by TDDFT
method.
Received 15 December 2009
Received in revised form 20 January 2010
Accepted 20 January 2010
Available online 1 February 2010
Keywords:
Quinoline
Haloquinoline
DFT
Phosphorylation
HIV
Crown Copyright Ó 2010 Published by Elsevier B.V. All rights reserved.
Anti-malarial
1. Introduction
They are a family of polar ligands with peculiar properties since
they may change either their hydrogen-bond donating or accepting
Compounds containing quinoline structure have been exten-
sively studied and widely used for the design and development
of large variety of medical drugs, especially since the discovery of
Cinchona alkaloids as antimalarial agents. In particular, chloroqui-
nine, quinine and amodiaquine have proved to be among the most
effective anti-malarial drugs [1–3]. Systematic modification of qui-
nine led to diverse quinoline anti-malarial drugs with diverse sub-
stitutions around the quinoline rings. One of the first drugs to be
prepared was the potent and inexpensive chloroquinine [4], which
is a 7-chloroquinoline with an amino substituent in position 4.
2-Methylquinolin-8-ol (1a) and related 5,7-dichloro-2-methyl-
quinolin-8-ol (1b) have received significant attention, as evident
from ca. 600 papers on this topic published only in 1990–2009 [Sci-
finder]. Surprisingly, there are no single crystal X-ray structures re-
ported so far. The persistent interest is not only from the fact that
these compounds have attracted special attention due to its strong
antibacterial, antifungal, trichomonal and keratoplastic effect [5–
9], but also because they are important synthetic intermediates for
the preparation of a variety of biologically active compounds [9].
sites through the protonation/deprotonation processes [10].
Herein, we report full spectroscopic characterization and X-ray
analysis of single crystal structures for five hydroxy-2-methylquin-
olines derivatives.
2. Experimental
2.1. General
All experiments were carried out in an atmosphere of dry argon.
Solvents were dried by usual methods (benzene and THF over ben-
zophenone ketyl, CHCl3 and CH2Cl2 over P2O5, hexane over so-
dium–potassium alloy), distilled and degassed. Chromatography
was carried out on Silica Gel 60 (0.15–0.30 mm) Machery Nagel.
Melting points are uncorrected. NMR spectra were obtained with
Bruker Avance 400 operating at 400.13 MHz (1H), 100.5 MHz
(
13C) and 161.9 MHz (31P) at 30 °C; chemical shifts referenced to
ext. TMS (1H, 13C), 85% H3PO4 31P); coupling constants are given
(
in Hz. IR spectra were recorded on a Nicolet Magna 560 spectro-
photometer in the spectral range 4000–400 cmꢀ1 with the samples
in the form of KBr pellets. Electronic spectra were measured on a
spectrophotometer Lab Alliance UV–vis 8500 in the range 1000–
180 nm in CH2Cl2 solution. Mass spectra were obtained with a
* Corresponding author. Tel.: +48 323591206; fax: +48 322599978.
E-mail address: jnycz@us.edu.pl (J.E. Nycz).
0022-2860/$ - see front matter Crown Copyright Ó 2010 Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.01.054

G. Malecki et al. / Journal of Molecular Structure 969 (2010) 130–138
131
Finnigan MAT 95 (Brema, Germany) in EI mode and, where neces-
sary, FAB technique was applied. Elemental analysis: Perkin-Elmer
2400CHSN/O Analyser. Compounds 5,7-dibromo-2-methylquino-
lin-8-ol (1c), 1d were purchased from Sigma–Aldrich, and were
used without further purification.
2.2. Crystal structure determination and refinement
Data for compounds 1a and 3a were collected on a KM4 diffrac-
tometer using Sapphire-2 CCD detector, for 1b and 2a the data
were obtained during the measurement performed on a KM4 dif-
fractometer equipped with Sapphire-3 CCD detector and for 3b
was collected on a STOE IPDS 2-circle diffractometer. For all mea-
surements graphite-monochromated Mo-Ka radiation was used.
The crystals were cooled down by a cold dry nitrogen gas stream
(Oxford Cryosystems equipment). The temperature stability
was 1 K.
The structures 1a, 3a and 3b were solved by direct methods and
refined by full-matrix least-squares on F2 (all data) using the SHEL-
XTL program package [11]. The structures 1b and 2a were first
solved using the direct method with SHELXS-97 software [12]
and then the solutions were refined with SHELXL-97 [12]. All
non-hydrogen atoms were refined anisotropically. Atomic scatter-
ing factors had values incorporated in the computer programs. All
H atoms bound to C atoms were refined using a riding model with
C–H distances of 0.95 Å or 0.98 Å and Uiso(H) values of 1.2 Ueq(C)
or 1.5 Ueq(C), respectively. H atoms, which took part in hydrogen
bond, were permitted to ride at the positions deduced from the dif-
ference maps with Uiso(H) equal to 1.2 Ueq(C) or 1.5 Ueq(O).
CCDC–739462 (1a), CCDC–736932 (1b), CCDC–746254 and
CCDC–746255 (2a), CCDC–739463 (3a), CCDC–739464 (3b) con-
tain the supplementary crystallographic data (excluding structure
factors) for this paper. These data can be obtained free of charge
via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033).
Fig. 1. Molecular structure diagrams of 1a (the thermal ellipsoids are drawn at the
50% probability level).
Compound 1b crystallization (PhCH3); mp = 113–114 °C; 1H
NMR (CDCl3) d = 2.74 (s, 3H, CH3), 7.38 (d, JHH = 8.6 Hz, 1H, H-quin-
oline), 7.47 (s, 1H, H-quinoline), 8.30 (d, JHH = 8.6 Hz, 1H, H-quino-
line); 13C{1H} NMR (CDCl3) 24.71, 115.15, 120.59, 123.10, 123.39,
127.17, 133.55, 137.82, 146.98, 158.77; UV–vis: 318.0 nm.
2.3. Synthesis
Compounds, 1a was purchased from Sigma–Aldrich, 1b was
purchased from ICN Polfa Rzeszow S.A. and were used with further
purification.
Compound 1a sublimation and crystallization (PhH); mp = 74 °C;
1H NMR (CDCl3) d = 2.73 (s, 3H, CH3), 7.19 (dd, JHH = 7.6 Hz,
JHH = 1.1 Hz, 1H, H-quinoline), 7.29 (d, JHH = 8.5 Hz, 1H, H-quino-
line), 7.29 (d, JHH = 8.2 Hz, 1H, H-quinoline), 7.40 (t, JHH = 7.9 Hz,
1H, H-quinoline), 8.02 (d, JHH = 8.4 Hz, 1H, H-quinoline); 13C{1H}
NMR (CDCl3) 24.75, 109.87, 117.49, 122.60, 126.53, 126.57, 136.11,
137.51, 151.61, 156.77; UV–vis: 306.0 nm.
2.4. Synthesis of 2a, 2b and 2d
Into the solution of 1a or 1b (5.0 mmol) in THF (25 mL), tBuOK
(0.616 g, 5.5 mmol) was added. The reaction was carried out for 3 h
under reflux. Subsequently at r.t., CH3I (5.0 mmol) was added. The
reaction was carried out for 6 h at r.t. Next, CH2Cl2 KHSO4 water
X
X
X
i, ii
i, iii
THF
THF
X
N
1
R
X
N
2
R
X
N
3
R
OH
R
OCH3
O
P
Ph
O
Yield (%)
2
CH3 97 95
Cl CH3 94 96
tBu
X
H
3
a
b
c
Br CH3
-
97
95
-
d
H
H
Scheme 1. Reagents and conditions: i – ButOK, reflux; ii – CH3I, r.t.; iii – Ph(But)P(O)Cl, reflux.

132
G. Malecki et al. / Journal of Molecular Structure 969 (2010) 130–138
solution was added. The organic phase was dried (MgSO4), and the
solvent was evaporated and the crude product was purified by sub-
limation, chromatography and crystallization.
8-Methoxy-2-methylquinoline (2a) 0.839 g (4.85 mmol, 97%);
mp = 126 °C; bp = 118–119 °C/1.0 mm Hg; 1H NMR (CDCl3)
d = 2.77 (s, 3H, CH3), 4.05 (s, 3H, CH3), 7.00 (dd, JHH = 7.2 Hz,
JHH = 1.8 Hz, 1H, H-quinoline), 7.27 (d, JHH = 8.5 Hz, 1H, H-quino-
line), 7.28–7.39 (m, 2H, H-quinoline) 7.98 (d, JHH = 8.1 Hz, 1H, H-
quinoline); 13C{1H} NMR (CDCl3) 25.70, 55.96, 107.58, 119.38,
122.54, 125.63, 127.55, 136.050, 139.71, 154.82, 158.09; E.A.
[Found C, 76.02; H, 6.39; N, 8.13; C11H11NO requires C, 76.28; H,
6.40; N, 8.29%]; UV–vis: 300.0 nm.
5,7-Dichloro-8-methoxy-2-methylquinoline (2b) crystallization
(CH2Cl2 hexane) 2.148 g (4.7 mmol, 94%); mp = 110 °C; 1H NMR
(CDCl3) d = 2.80 (s, 3H, CH3), 4.17 (s, 3H, CH3), 7.38 (d, JHH = 8.7 Hz,
1H, H-quinoline), 7.56 (s, 1H, H-quinoline), 8.38 (d, JHH = 8.7 Hz,
1H, H-quinoline); 13C{1H} NMR (CDCl3) 25.55, 62.27, 122.89,
124.59, 126.09, 126.55, 126.80, 133.30, 143.29, 151.05, 160.14;
E.A. [Found C, 54.53; H, 3.58; N, 5.49; C11H9Cl2NO requires C,
54.57; H, 3.75; N, 5.79%]; UV–vis: 326.4, 300.8 nm.
8-Methoxyquinoline (2d) 0.771 g (4.8 mmol, 97%); mp = 48 °C;
bp = 175–176 °C/17 mm Hg; 1H NMR (CDCl3) d = 4.06 (s, 3H,
CH3), 7.02 (dd, JHH = 7.5 Hz, JHH = 1.3 Hz, 1H, H-quinoline), 7.33–
7.46 (m, 3H, H-quinoline), 8.08 (dd, JHH = 8.3 Hz, JHH = 1.7 Hz, 1H,
H-quinoline), 8.89 (dd, JHH = 4.2 Hz, JHH = 1.73 Hz, 1H, H-quino-
line); 13C{1H} NMR (CDCl3) 55.93, 107.51, 119.51, 121.63, 126.66,
129.34, 135.80, 140.23, 149.22, 155.42; E.A. [Found C, 74.93; H,
5.65; N, 8.80; C10H9NO requires C, 75.45; H, 5.70; N, 8.80%]; UV–
vis: 303.2 nm.
2.5. Synthesis of 3a–c
Ph(But)P(O)Cl (5.0 mmol) was added to the suspension of NaH
(0.133 g, 5.5 mmol) in THF (25 mL). Subsequently, 1a (or 1b or
1c) (5.0 mmol), was added. The reaction was carried out for 24 h
under reflux. Next, CH2Cl2 KHSO4 water solution was added. The
organic phase was dried (MgSO4), and the solvent was evaporated
Fig. 2. Molecular structure diagrams of 1b (the thermal ellipsoids are drawn at the
50% probability level).
Table 1
Selected bond lengths and angles for 1a.
Bond lengths (Å)
C7–O1
1.3520(15)
1.3592(15)
1.5007(18)
1.4967(18)
1.4065(18)
C15–C16
N1–C1
N1–C8
N2–C11
N2–C18
1.4087(19)
1.3211(16)
1.3694(16)
1.3197(16)
1.3711(16)
C17–O2
C1–C10
C11–C20
C5–C6
Hydrogen-bond geometry (Å, °)
D–HꢁꢁꢁA
D–H
HꢁꢁꢁA
DꢁꢁꢁA
D–HꢁꢁꢁA
Fig. 3. Molecular structure diagrams of 2a (the thermal ellipsoids are drawn at the
50% probability level).
O1–H1AꢁꢁꢁN1
0.86(2)
0.86(2)
0.86(2)
0.86(2)
2.330(19)
2.132(19)
2.160(2)
2.330(2)
2.7695(14)
2.8261(15)
2.8700(15)
2.7729(14)
112.2(15)
138.0(16)
139.1(19)
111.7(17)
O1–H1AꢁꢁꢁN2A
O2A–H1BAꢁꢁꢁN1
O2A–H1ABꢁꢁꢁN2A
Table 3
Selected bond lengths and angles for 2a. Cg denotes the centroid of the quinoline ring.
Bond lengths (Å)
Table 2
C7–O1
1.353(3)
1.434(3)
1.499(3)
1.497(3)
1.381(3)
1.405(3)
C4–C5
C4–C9
N1–C1
N1–C8
C26–C27
1.367(3)
1.403(3)
1.302(3)
1.367(3)
1.414(3)
Selected bond lengths and angles for 1b.
O1–C11
C1–C10
C22–C31
C6–C7
Bond lengths (Å)
C7–O1
C6–Cl2
C4–Cl1
C4–C9
C1–Cl0
1.348(10)
1.734(16)
1.752(16)
1.418(2)
N1–C1
1.330(12)
1.371(19)
1.387(19)
1.365(12)
1.413(13)
N1–C8
C6–C7
C4–C5
C6–C5
C5–C6
Bond angles (°)
C7–O1–C11
1.507(20)
116.57(17)
C27–O2–C31
117.26(16)
Hydrogen-bond geometry (Å, °)
Hydrogen-bond geometry (Å, °)
D–HꢁꢁꢁA
O1–H1AꢁꢁꢁN1A
D–H
HꢁꢁꢁA
1.92(2)
DꢁꢁꢁA
2.6967(13)
D–HꢁꢁꢁA
165.2(19)°
D–HꢁꢁꢁA
C11–H11A ꢁꢁꢁ Cg
D–H
HꢁꢁꢁA
2.85(3)
DꢁꢁꢁA
3.757(11)
D–HꢁꢁꢁA
159.71 (1.93)
0.80(2)
0.95(2)

G. Malecki et al. / Journal of Molecular Structure 969 (2010) 130–138
133
Fig. 4. Molecular structure diagrams of 3a (the thermal ellipsoids are drawn at the 50% probability level).
and the crude product was purified by chromatography and
crystallization:
2-Methylquinolin-8-yl tert-butyl(phenyl)phosphinate (3a) crystal-
lization (CH2Cl2: hexane); 1.610 g (4.8 mmol, 95%); mp = 112 °C;
3
1H NMR (CDCl3) d = 1.36 (d, JPH = 16.0 Hz, 9H, But), 2.71 (s, 3H,
CH3), 7.24 (d, JHH = 8.3 Hz, 1H, aromatic-Q), 7.29 – 7.38 (m, 2H, aro-
matic), 7.42 (2dd, JHH = 1.4 Hz, JHH = 7.6 Hz, 2H, aromatic-Q), 7.65
(td, JHH = 1.4 Hz, JHH = 7.7 Hz, 1H, aromatic-Q), 7.93 (d, JHH = 8.4 Hz,
1H, aromatic-Q), 8.02–8.05 (m, 2H, aromatic), 8.04 (dd, JHH = 1.4 Hz,
3JP-H = 17.4 Hz, 1H, aromatic); 13C{1H} NMR (CDCl3) 24.38, 25.49,
Table 4
Selected bond lengths and angles for 3a. Symmetry codes: (i) 1 ꢀ x, ꢀ1/2 + y, 1/2 ꢀ z,
(ii) x, 1.5 ꢀ y, ꢀ1/2 + z.
Bond lengths (Å)
C7–O1
P1–O1
P1–O2
C4–C5
C5–C6
1.3920(2)
1.6042(18)
1.4740(13)
1.3630(4)
1.4090(3)
C6–C7
C4–C9
N1–C1
N1–C8
1.3680(3)
1.4140(3)
1.3200(2)
1.3680(2)
Bond angles [°]
C7–O1–P2
125.79(11)
O1–P1–O2
115.70(7)
Hydrogen-bond geometry (Å, °)
D–HꢁꢁꢁA
D–H
HꢁꢁꢁA
2.38(2)
2.60(2)
DꢁꢁꢁA
3.180(2)
3.419(2)
D–HꢁꢁꢁA
143.2(19)
139.9(18)
C15–H15AꢁꢁꢁO2(i)
0.94(2)
1.00(3)
Fig. 5. Molecular structure diagram of 3b (the thermal ellipsoids are drawn at the
50% probability level).
C18–H18AꢁꢁꢁO2(ii)

134
G. Malecki et al. / Journal of Molecular Structure 969 (2010) 130–138
33.96 (JCP = 100 Hz), 119.50 (JCP = 4 Hz), 122.20, 123.27, 125.37
(JCP = 1 Hz), 127.66 (JCP = 18 Hz), 127.83 (JCP = 12 Hz), 129.37,
131.96 (JCP = 3 Hz), 133.56 (JCP = 9 Hz), 130.72, 140.73 (JCP = 4 Hz),
147.23 (JCP = 10 Hz), 158.48; 31P{1H} NMR (CDCl3) d = 51.54; EI-MS
(m/z, %) 340.3 (6, [M]+1)+, 282.2 (100, [M]ꢀBu t)+; E.A. [Found C,
70.50; H, 6.57; N, 4.10; C20H22NO2P requires C, 70.78; H, 6.53; N,
4.13%]; UV–vis: 319.3, 283.4, 272.9 nm.
reaction was carried out for 6 h at room temperature. Ph(But)-
P(O)Cl was found less reactive and required heating because of ste-
ric and electronic reasons. All products, 2a, 2b, 2d and 3a–c were
isolated with high yields (94–97%).
The reagents 1a and 1b were chosen as model compounds, and
were characterised by X - ray crystal structure analysis (Figs. 1 and
2; Tables 1 and 2), which showed the presence of hydrogen-bond
5,7-Dichloro-2-methylquinolin-8-yl tert-butyl(phenyl)phosphinate
(3b) crystallization (CH2Cl2: hexane); 1.958 g (4.8 mmol, 96%);
3
mp = 205–206 °C; 1H NMR (CDCl3) d = 1.37 (d, JPH = 16.1 Hz, 9H,
But), 2.04 (s, 3H, CH3), 7.19 (d, JHH = 8.7 Hz, 1H, aromatic-Q), 7.47
3
(dt, JHH = 3.6 Hz, JPH = 7.4 Hz, 2H, P-Ph-o), 7.54 (dd, JHH = 1.3 Hz,
3JPH = 7.1 Hz, 1H, P-Ph-p), 7.56 (s, 1H, aromatic-Q), 7.93 (ddd,
JPH = 10.9 Hz, JHH = 8.2 Hz, JHH = 1.6 Hz, 2H, P-Ph-m); 8.24 (d,
JHH = 8.7 Hz, 1H, aromatic-Q); 13C{1H} NMR (CDCl3) 23.59, 24.18,
34.75 (JCP = 98 Hz), 123.13, 124.13, 124.46 (JCP = 5 Hz), 126.37,
126.63 (JCP = 1 Hz), 127.59 (JCP = 12 Hz), 130.86, 131.03 (JCP = 3 Hz),
132.19 (JCP = 9 Hz), 132,41, 132.82, 141.17 (JCP = 2 Hz), 143.88
(JCP = 12 Hz), 159.44; 31P{1H} NMR (CDCl3) d = 53.17; MS (FAB)
(m/z, %) 408 (100%, [M])+; HRMS: m/z Calcd for C20H21NPO2Cl2
(M + H)+: 408.06886 Found 408.068699; E.A. [Found C, 58.75; H,
5.13; N, 3.43; C20H20Cl2NO2P requires C, 58.84; H, 4.94; N,
3.43%]; UV–vis: 300.2 nm.
5,7-Dibromo-2-methylquinolin-8-yl
tert-butyl(phenyl)phosphi-
nate (3c) crystallization (CHCl3: hexane); 2.361 g (4.8 mmol,
3
95%); mp = 203 °C; 1H NMR (CDCl3) d = 1.35 (d, JPH = 16.0 Hz, 9H,
But), 1.99 (s, 3H, CH3), 7.15 (d, JHH = 8.7 Hz, 1H, aromatic-Q),
7.37–7.54 (m, 3H, aromatic-Q), 7.84–7.92 (m, 3H, aromatic-Q),
8.16 (d, JHH = 8.7 Hz, 1H, aromatic-Q); 13C{1H} NMR (CDCl3)
23.30, 24.87, 34.78 (JCP = 99 Hz), 113.50, 119.15, 123.65, 125.92,
127.51, 127.71, 130.90, 130.94, 131.93, 132.07, 132.40, 134.95,
159.22; 31P{1H} NMR (CDCl3) d = 52.70; EI-MS (m/z, %) 496.9 (17,
[M])+; E.A. [Found C, 49.44; H, 4.16; N, 2.78; C20H20Br2NO2P re-
quires C, 48.32; H, 4.05; N, 2.82%]; UV–vis: 300.2 nm.
3. Results and discussion
The reactions of hydroxyhaloquinolines 1a–d with ButOK were
carried out under reflux with a set of identical reaction conditions
(Scheme 1). Subsequently electrophiles were added. For CH3I the
Table 5
Selected bond lengths and angles for 3b. Symmetry codes: (i) x, ꢀ1/2 ꢀ y, 1/2 + z, (ii)
2 ꢀ x, ꢀy, ꢀz.
Bond lengths (Å)
C7–O1
O1–P1
P1–O2
C4–Cl1
C6–Cl2
C4–C5
1.3762(15)
1.6231(10)
1.4745(10)
1.7409(14)
1.7272(14)
1.3600(9)
C5–C6
C6–C7
C4–C9
N1–C1
N1–C8
1.4106(16)
1.378(18)
1.4140(18)
1.3194(18)
1.3547(17)
Bond angles (°)
C7–O1–P1
125.20(7)
O1–P1–O2
114.85(5)
Hydrogen-bond geometry (Å, °)
D–HꢁꢁꢁA
D–H
HꢁꢁꢁA
2.369(18)
2.348(18)
DꢁꢁꢁA
3.2695(17)
3.266(2)
D–HꢁꢁꢁA
158.3(15)
169.5(15)
C2–H2ꢁꢁꢁO2(i)
0.949(18)
0.929(18)
C12–H12AꢁꢁꢁO2(ii)
Table 6
The 1H and 13C chemical shifts of methyl group in DMSO-d6.
1a
1b
2a
2b
3a
3b
3c
1H
2.73
24.75
2.74
24.71
2.77
25.70
2.80
25.55
2.71
25.49
2.04
24.18
1.99
24.87
13C
Fig. 6. Contours of HOMO and LUMO orbitals of studied compounds.

G. Malecki et al. / Journal of Molecular Structure 969 (2010) 130–138
135
their reactivity we compared selected geometric parameters such
as bond lengths and bond angles presented on Tables 1–5.
Comparing the structural parameters of hydroxyhaloquinolines
1a and 1b with the data of their derivatives, such as ether 2a, esters
3a and 3b shows significant differences. Esters possess much long-
er C7–O1 bond lengths because of the electron withdrawing ability
of P@O group. For the same reason the P@O group could induce
shortened C4–Cl1 and C6–Cl2 bonds. Meanwhile, the existence of
halogen atoms could cause an abridgement of C7–O1 bond. We
also observed the electronic influence of oxygen from C7–O1 on
both bond lengths C4–Cl1 and C6–Cl2 of compounds 1b and 3b
(see Table 6).
3.1. NMR
Recently we studied 13C and 15N NMR spectra demonstrating
proton transfer reactions between the pyridine and carboxylic acid
functions of some hydroxyquinoline carboxylic acids [10]. The 1H
and 13C NMR spectra of 1a–c, 2a,b and 3a–c displayed readily diag-
nostic signals from methyl protons and carbon atoms. Analysis of
the trend in 1H chemical shifts revealed that the presence of
P@O, compared to the methyl of ether or H of hydroxylic group,
significantly increased the deshielding effects on proton. Similar
effect in 13C chemical shifts was observed. Halogen (Cl or Br) atoms
at 5 and 7 positions have weaker effects on the 1H and 13C chemical
shifts of methyl group.
3.2. IR
In the studied compounds the bands of C@C and C@N stretching
modes were observed at 1600, 1608, 1603, 1605, 1617, 1604, 1596,
1585 cmꢀ1 for 1a, 1b, 2a, 2b, 2d, 3a, 3b and 3c, respectively. The
mO–H had the maxima at 3278 cmꢀ1 (1a) and 3274 cmꢀ1 (1b),
respectively. The bands at 1263 and 1031 cmꢀ1 indicated the ether
group in the compound 2a. Strong band corresponding to the
stretching vibration of P@O group in 3a and 3b appeared at 1229
and 1244 cmꢀ1, respectively. The maxima at 2960, 2939, 2946
and 3066 cmꢀ1 are related to stretching modes of tert-butyl and
methyl fragments in studied compounds. More details of the vibra-
tional spectra of the compounds are given in the Table S1.
Fig. 6 (continued)
donating and accepting sites between the pyridine and hydroxylic
functions, mimicking previously described behaviors of some
hydroxyquinoline carboxylic acids [10]. Compound 1a crystallises
in space group Pbca (no. 61), compound 1b, in C1 2/c 1 (no. 15).
The molecular ring systems are both essentially planar. The mole-
cules of 1a are linked by weak bifurcated O1–H1AꢁꢁꢁN2A, O1–
H1AꢁꢁꢁN1 and O2AH1BAꢁꢁꢁN2A, O2AH1BAꢁꢁꢁN1 hydrogen bonds.
For 1b it is through strong O1–H1AꢁꢁꢁN1A and O1A–H1AAꢁꢁꢁN1
hydrogen bonds.
3.3. DFT calculations
The calculations were carried out using Gaussian03 [19] pro-
gram. The DFT/B3LYP [20,21] method was used for the geometry
optimization and electronic structure determination. Electronic
spectra were calculated by TDDFT [22] method. The calculations
were performed with polarization functions for all atoms: 6-31g
Compound 2a crystallises in space group C1 2/c 1 (no. 15). The
molecular ring system is essentially planar (see Fig. 3 and Table 3).
The detailed study of peaks on the difference Fourier map
showed that in the position of one of the 2a molecule, there is
one molecule of 2-methylquinolin-8-ol (1a). The lack of the addi-
tional reflections from superstructure is evidence that these mole-
cules are disordered. The refinement showed that the occupancy of
1a is equal to 0.078(2), which caused the decrease of R1 value from
5.59% to 3.04% and the maximum on the difference Fourier map
**
(2d,p) – chlorine, bromine and phosphorus, 6-31g – carbon,
nitrogen and 6-31g(d,p) – hydrogen. The PCM solvent model was
used in the Gaussian calculations with dichloromethane as the sol-
vent. The contribution of molecular orbitals in the electronic tran-
sitions was calculated using Gaussum software [23].
3.4. Optimized geometries
0
0
from 1.03 eÅAꢀ3 to 0.20 eÅAꢀ3. In spite of this, such attempts do
not change the molecular parameters. The high quality crystals
of 2a grew only from the crude product (see Figs. 4 and 5).
Compounds 3a and 3b crystallized in space group P121/c1 (no.
14), and their molecular ring systems (quinoline) are essentially
planar. In both cases the molecules are linked by weak C–HꢁꢁꢁO
hydrogen bonds (Tables 4 and 5).
The geometries of the studied compounds were optimized in
singlet states using the DFT method with the B3LYP functional.
In general, the predicted bond lengths and angles are in a good
agreement with the values based on the X-ray crystal structure
data. The general trends observed in the experimental data were
well reproduced in the calculations.
The development of new and more efficient methodologies to
transform hydroxyhaloquinolines to their derivatives which could
help to look deeper into reasons of HIV inhibition is a subject of
continuous interest in our laboratory [10,13–18]. To understand
The maximum differences between optimized and experimen-
tal geometry of the heteroatoms and carbons in studied com-
pounds are visible in distances: O(1)–C(7) 0.008 Å, O(1)–C(7)
0.017 Å, Cl(1)–C(5) 0.011 Å, P(1)–O(1) 0.048 Å and P(1)–O(1)

136
G. Malecki et al. / Journal of Molecular Structure 969 (2010) 130–138
0.053 Å in compound 1a, 1b, 2a, 3a and 3b, respectively. In the an-
gles differences do not outrun 2°.
the localized molecular orbitals are from HOMO-3, 4, 5 in
compound 3a, and are from HOMO-2 and HOMO-4 in 3b. The virtual
MO LUMO + 2, LUMO + 4 in 3a and LUMO + 2 and LUMO + 3 in 3b are
composed from phosphinate. The eigenvalues of the HOMO and
LUMO molecular orbitals in studied compound are negative (1a –
HOMO ꢀ5.70; LUMO ꢀ1.32; 1b – HOMO ꢀ5.56; LUMO ꢀ1.01; 2a –
HOMO ꢀ5.98; LUMO ꢀ1.67; 2b – HOMO ꢀ5.91; LUMO ꢀ1.63; 2d
– HOMO ꢀ5.65, LUMO ꢀ1.14;3a – HOMO ꢀ6.06, LUMO ꢀ1.34; 3b
– ꢀ6.23, LUMO ꢀ1.71; 3c – HOMO ꢀ6.12, LUMO ꢀ1.69 eV). Never-
theless, the electron acceptor ability of the LUMO may play a greater
role than the electron donation of the HOMO. The LUMO eigenvalues
are far less negative compared to the HOMO eigenvalues whatever
indicating a strong affinity for electrons.
Although the X-ray structures of the compounds 2b, 2d and 3c
were not determined, their geometries, IR frequencies and elec-
tronic transitions were calculated. A good agreement of the
calculated spectroscopic properties of 2b, 2d and 3c with the
experimental ones (Fig. S1) indicates that the calculated geome-
tries correspond well to the real structures. The maximum error
between the calculated and experimental IR frequencies is about
4.3%, 8.2% for 2b, 2d and 7.8% for 3c.
3.5. Electronic structure and NBO analysis
Basing on the NBO theory [24] the stabilization energy [25]
were calculated and shown that the molecules were stabilised by
the donation of charge from N–C to antibonding orbital of C–C
The HOMO and LUMO orbitals of studied compounds are pre-
sented in Fig. 6. The HOMO orbitals of the studied compounds are
composed from pC and pO hydroxyquinoline moiety and in LUMO
p
nitrogen orbitals played a role. The heteroatoms of studied com-
pounds contributed in the low molecular orbitals. The HOMO-6 of
3a is composed of O(P) (56%) and O(quinoline) (18%). HOMO-9 of 3b
is localized mainly on the chlorines. On the phosphinate moiety,
(for example DEij = 120.39 (1a); 261.32 (1b); 168.37 (2b) kcal/
mol). In the molecules 2a, 3a and 3b the stabilisation is visible in
the donation of hydroxyquinoline oxygen to the antibonding orbi-
tal of C–C and phosphorus empty d orbitals.
p
p
Fig. 7. Electrostatic potential densities of the compounds 1a, 1b, 2a, 2d, 3a and 3b at the electron density of 0.005 a.u.

G. Malecki et al. / Journal of Molecular Structure 969 (2010) 130–138
137
The heteroatoms charges of the studied compounds taking from
Natural Population Analysis are as follow: 1a: N ꢀ0.509, O ꢀ0.691;
1b: N ꢀ0.444, O ꢀ0.501; 2a: N ꢀ0.501, O ꢀ0.672, Cl ꢀ0.004, 0.023;
2b: N ꢀ0.426, O ꢀ0.501, Cl ꢀ0.004 2d: N ꢀ0.430, O ꢀ0.499; 3a: P
2.256, Ohydroxyqu ꢀ0.808, Ophosphorus ꢀ1.086, N ꢀ0.467; 3b: Cl 0.001,
0.020, P 2.257, Ohydroxyqu ꢀ0.808, Ophosphorus ꢀ1.067, N ꢀ0.455, 3c:
Br 0.066, 0.089, P 2.257, Ohydroxyqu ꢀ0.807, Ophosphorus ꢀ1.066, N
ꢀ0.453. In this study the chlorine and bromine substituents for
1b, 2b, 3b and 3c are almost neutral, which could explained the
difficulties with the preparation of arylphosphanes using halogen-
oaryls [18]. The charges on the quinoline nitrogen atom increased
in compounds, and the charge on the quinoline oxygen declined.
The atomic charge calculations can be indicative for the relocation
of the electron density of the compounds, but the local concentra-
tion and local depletion of electron charge density allow us to
determine whether the nucleophile or electrophile can be at-
tracted. Because the electron distribution is not apparent from
the partial atomic charges in Fig. 7, it only gives the plots of the
electrostatic potentials for the studied compounds. The isoelec-
tronic contours are plotted at 0.005 a.u. (3.1 kcal/mol). The color
code of these maps is in the range of 0.005 a.u. (deepest red) to
ꢀ0.005 a.u. (deepest blue) in all compounds, where blue indicates
the strongest attraction and red indicates the strongest repulsion.
Regions of negative V(r) are usually associated with the lone pair
of electronegative atoms. The negative potential in the studied
compounds wraps the nitrogen, oxygen and phosphorus atoms.
in Figs. S2–S4.electronic absorption spectra display bands with the
maximums at 1a – 306.0 nm, 1b – 318.0 nm, 2a – 300.0 nm, 2b –
326.4, 300.8 nm, 2d – 303.2 nm, 3a – 319.3, 283.4, 272.9 nm and
3b – 300.2 nm, 3c – 301.8 nm. The first calculated transitions in
the studied compounds were derived from HOMO ? LUMO excita-
tion (1a – 87%, 1b, 2a–c – 86%, 3a,b – 84%, 3c – 85%).
Shoulders on the spectra of compound 3a, 3b and 3c are associ-
ated with the transitions in which heteroatoms (P, O, N)
p orbitals
play significant roles. Molecular orbital coefficients analyses based
on the optimized geometry indicate that the frontier molecular
orbitals are mainly composed of p atomic orbitals, so electronic
transitions corresponding to above electronic spectra are mainly
*
p
*
electronic transitions.
assigned to n ?
and
p
?
p
4. Conclusion
In the present studies, we report the synthesis and characteriza-
tion of some methyl and phosphinyl derivatives of 2-methylquin-
olin-8-ol (1a) and related 5,7-dichloro-2-methylquinolin-8-ol
(1b) using microanalyses (C,H,N), IR, UV–vis, multinuclear NMR
spectroscopic techniques. Five of them have been characterized
by single crystal X-ray diffraction method.
X-ray crystal structure analysis of 1a and 1b showed the pres-
ence of hydrogen-bond donating and accepting sites between the
pyridine and hydroxylic functions.
The 1H and 13C NMR spectra of 1a–c, 2a,b and 3a–c displayed
readily diagnostic signals from methyl protons and carbon atoms.
Analysis of the trend in 1H chemical shifts revealed that the pres-
ence of P@O, compared to the methyl of ether or H of hydroxylic
group, significantly increased the deshielding effects on proton.
Halogen (Cl or Br) atoms at 5 and 7 positions have weaker effects
on the 1H and 13C chemical shifts of methyl group.
The NBO studies showed us that the chlorine and bromine sub-
stituents for 1b, 2b, 3b and 3c are almost neutral. The charges on
the quinoline nitrogen atom increased in compounds, and the
charge on the quinoline oxygen declined. The atomic charge calcu-
lations are the indication of the relocation of the electron density of
the compounds, but the local concentration and local depletion of
electron charge density allow us to determine whether the nucle-
ophile or electrophile can be attracted.
3.6. Electronic spectra
Experimental electronic spectra measured in dichloromethane
solutions along with the theoretical electronic absorption spectra
*
calculated on the B3LYP/6-31G level optimized structures are
listed in Table 7. The calculations of electronic spectra were per-
formed using PCM model. The experimental spectra are presented
Table 7
Experimental and theoretical electronic absorption spectra values for studied
compounds.
Experimental
Calculated
Oscillator
strength
Most important
configurations
1a
306.0
Acknowledgments
325.8
279.5
0.043
0.010
H ? L (87%)
H-1 ? L (42%), H ? L + 1 (57%)
We thank Professor Dietrich Gudat for NMR spectra and the ICN
Polfa Rzeszow S.A. for a sample of 5,7-dichloro-2-methylquinolin-
8-ol.
1b
318.0
307.4
0.076
H ? L (86%)
2a
300.0
327.0
292.0
0.065
0.008
H ? L (86%)
H-1 ? L (38%), H ? L + 1 (62%)
Appendix A. Supplementary data
2b
326.4
300.8
326.7
289.5
285.5
0.103
0.011
0.002
H ? L (86%)
H-1 ? L (35%), H ? L + 1 (65%)
H-2 ? L (94%)
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2010.01.054.
2d
303.2
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278.3
278.1
0.082
0.004
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H ? L (86%)
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