Synthesis, spectroscopy and computational studies of selected hydroxyquinolines and their analogues

Article abstract of DOI:10.1016/j.saa.2013.08.031

Synthetic, spectroscopy and mechanistic aspects of preparation of selected hydroxyquinolines and their analogues or derivatives contained methoxy, fluoro, chloro, carboxylic, carbodithioic and phosphinate or dioxaphosphinane groups were elaborated. The mu

Full text of DOI:10.1016/j.saa.2013.08.031

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 117 (2014) 351–359
Contents lists available at ScienceDirect
Spectrochimica Acta Part A: Molecular and
Biomolecular Spectroscopy
journal homepage: www.elsevier.com/locate/saa
Synthesis, spectroscopy and computational studies of selected
hydroxyquinolines and their analogues
Jacek E. Nycz a, , Marcin Szala , Grzegorz J. Malecki , Maria Nowak , Joachim Kusz
⇑
a
a
b
b
a
Institute of Chemistry, University of Silesia, ul. Szkolna 9, PL-40007 Katowice, Poland
Institute of Physic, University of Silesia, ul. Uniwersytecka 4, PL-40007 Katowice, Poland
b
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
ꢀ
ꢀ
ꢀ
Five of hydroxyquinolines have been
characterized by single crystal X-ray
diffraction method.
The NBO analysis of the quinoline
ring indicates the charges on chlorine
and bromine are nearly zero.
The X-ray and NMR’s indicate the
anomeric effect for quinoline esters
with dioxaphosphinane group.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 June 2013
Received in revised form 26 July 2013
Accepted 2 August 2013
Available online 15 August 2013
Synthetic, spectroscopy and mechanistic aspects of preparation of selected hydroxyquinolines and their
analogues or derivatives contained methoxy, fluoro, chloro, carboxylic, carbodithioic and phosphinate or
dioxaphosphinane groups were elaborated. The multinuclear NMR and five single crystal X-ray character-
istics of the series of quinolines have been determined. The molecular orbitals of the selected hydroxy-
quinolines have been calculated by density functional theory. The X-ray and NMR studies of 8-[(5,5-
dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)oxy]-5,7-dibromo-2-methylquinoline
dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)oxy]-5-fluoro-2-methylquinoline indicate the appearance
of anomeric effect.
and
8-[(5,5-
Keywords:
Skraup–Doebner–Miller
Quinoline
Hydroxyquinoline
Halogen
Ó 2013 Elsevier B.V. All rights reserved.
Carboxylic acid
Anomeric effect
Introduction
anti-inflammatory, and trichomonal [2–12]. They are also impor-
tant synthetic intermediates in preparing a variety of biologically
The quinolines are part of the most important compounds
among N-heterocycles found their broad application in pharma-
ceutical and agrochemical industries [1]. They are widely seen in
a number of natural products and have attracted considerable
attention due to their biological activities such as anti-malarial,
anti-fungal, anti-bacterial, anti-asthmatic, anti-hypertensive,
active compounds [6,11–14]. Many of them are ligands in coordi-
nation chemistry as a N and/or O atom donors for chelating with
metals, such as ruthenium metalloantimalarials and are used for
the identification of metals [15–17]. Additionally quinolines have
been used in components for molecular electronic devices [18].
We are particularly interested in the functionalization of ben-
zene or phenol ring in quinoline constitution. Compounds with
hydroxyquinoline carboxylic acid groups carrying carboxylic and
hydroxyl function on benzene ring attracted increasing attentions
⇑
Corresponding author. Tel.: +48 323591206; fax: +48 322599978.
E-mail address: jnycz@us.edu.pl (J.E. Nycz).
1
386-1425/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.saa.2013.08.031

3
52
J.E. Nycz et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 117 (2014) 351–359
1
3
1
due to their analogy to the precursor of a promising HIV-1 integr-
3
C{ H} NMR (CDCl ; 125.78 MHz) d = 24.86, 110.03, 120.45,
ase inhibitor, 2-[(E)-2-(3,4-dihydroxy-5-methoxyphenyl)ethenyl]-
123.57, 124.68, 126.56, 133.59, 138.25, 151.03, 157.77; MS: (ESI)
[M+H] = 194 (100%); CCDC 933796.
+
8
-hydroxyquinoline-7-carboxylic acid (shortly named FZ-41)
which has been demonstrated to block the replication of HIV-1
in cell cultures at nontoxic concentrations [13,19].
6-Chloro-2-methylquinolin-8-ol (3b) (white); 43% mp = 124.6 °C;
H NMR (CDCl ; 400.2 MHz) d = 2.71 (s, 3H, CH ), 7.11 (d, J = 2.1 Hz,
3 3
1
The fluoride derivatives of quinolines or related compounds, in
which the hydrogen atom is replaced by a fluoride, should be con-
1H, aromatic), 7.25 (d, J = 2.1 Hz, 1H, aromatic), 7.31 (d, J = 8.5 Hz,
1
3
1
1H, aromatic), 7.93 (d, J = 8.5 Hz, 1H, aromatic); C{ H} NMR
(CDCl ; 100.5 MHz) d = 24.85, 111.54, 116.56, 123.90, 126.99,
1
9
veniently monitored by F NMR techniques and provide so called
‘NMR probes’’ to enhance the mechanistic understanding of phys-
3
+
‘
132.47, 135.62, 136.28, 152.56, 157.25; MS: (ESI) [M+H] = 194
(100%); CCDC 933797.
iological processes, thus to facilitate and rationalize the design of
more biologically active compounds and new drugs. Our studies
of biological activity of thioanalogue of hydroxyquinolines are in
progress.
In this paper, we reported new quinoline compounds with in-
depth spectroscopic characterization. Computational and spectro-
scopic studies were carried out to compare selected hydroxyquin-
olines and their methoxy, fluoro, chloro, carboxylic, carbodithioic
and phosphinate or dioxaphosphinane derivatives which have
not been reported by previous studies.
2,5-Dimethylquinolin-8-ol (3d) (light green); 36%; mp = 86.6 °C;
1
H NMR (CDCl
), 7.03 (d, J = 7.7 Hz, 1H, aromatic), 7.18 (dd, J = 7.7,
0.9 Hz, 1H, aromatic), 7.32 (d, J = 8.6 Hz, 1H, aromatic), 8.16 (d,
3 3
; 400.2 MHz) d = 2.56 (d, J = 0.9 Hz, 3H, CH ), 2.73
(s, 3H, CH
3
1
3
1
J = 8.6 Hz, 1H, aromatic);
3
C{ H} NMR (CDCl ; 100.5 MHz)
d = 17.92, 24.88, 109.33, 122.30, 124.24, 125.84, 126.71, 133.29,
+
137.99, 150.07, 156.38; MS: (ESI) [M+H] = 174 (100%); CCDC
933795.
Diethyl-(2-methyl-[6]quinolyl)-amine
(4)
; 500.18 MHz) d = 1.01 (t,
), 3.22 (q, J = 7.1 Hz, 4H, CH ),
6.57 (d, J = 2.9 Hz, 1H, aromatic), 6.92 (d, J = 8.4 Hz, 1H, aromatic),
.09 (dd, J = 9.3, 2.9 Hz, 1H, aromatic), 7.63 (d, J = 8.4 Hz, 1H, aro-
(yellow);
46%;
1
bp = 153/32 mmHg; H NMR (CDCl
J = 7.1 Hz, 6H, CH ), 2.51 (s, 3H, CH
3
3
3
2
Experimental
7
1
3
1
General
matic), 7.76 (d, J = 9.3 Hz, 1H, aromatic); C{ H} NMR (CDCl
3
;
1
25.78 MHz) d = 12.10, 24.21, 43.98, 103.79, 118.38, 121.51,
NMR spectra were obtained with Bruker Avance 400 and 500
127.74, 128.59, 133.82, 140.66, 144.93, 153.14.
1
operating at 500.18 or 400.13 MHz ( H), 125.78 or 100.5 MHz
1
3
31
19
(
C), 202.47 or 162.0 MHz ( P) and 470.5 MHz ( F) at 21 °C.
Synthesis of ester 3c
1
13
1
13
Chemical shifts referenced to ext. TMS ( H, C) or DSS ( H, C),
A solution of 2b (10.4 g, 0.050 mol) in 48% HBr (50 mL) was
heated at 100 °C for 48 h and cooled to room temperature. The
water solution was alkalified by aqueous solution of KOH (10%).
Reagents were shaken for a few minutes. The mixture was poured
3
1
19
8
3 4 3
5% H PO ( P) and CFCl ( F). Coupling constants are given in
Hz. Mass spectra were obtained with a Varian 500 MS with applied
ESI technique. Chromatography was carried out on Silica Gel 60
(
0.15–0.3 mm) Machery Nagel. Melting points were determined
2 2 4
into CH Cl . The organic phase was separated and dried by MgSO .
on MPA100 OptiMelt melting point apparatus and uncorrected.
After the solvent was evaporated, the residue was purified by
chromatography:
5
1
,7-Dibromo-2-methylquinolin-8-ol (1a), N,N-diethylbenzene-
,4-diamine (1b), 2-amino-4-fluorophenol (1c), 3-fluoro-2-
7-Chloro-2-methylquinolin-8-ol (3c) (white); 98% (9.5 g,
1
methoxyaniline (1d), 3-chloro-2-methoxyaniline (1e), 2-amino-4-
chlorophenol (1f), 2-amino-5-chlorophenol (1g) and 2-amino-4-
methylphenol (1h) were purchased from Sigma–Aldrich, and were
used without further purification. 5-Fluoro-2-methylquinolin-8-ol
0.049 mol); mp = 108.9 °C; H NMR (CDCl
3
; 400.2 MHz) d = 2.75
3
(s, 3H, CH ), 7.24 (d, J = 8.8 Hz, 1H, aromatic), 7.31 (d, J = 8.4 Hz,
1H, aromatic), 7.41 (d, J = 8.8 Hz, 1H, aromatic), 8.04 (d, J = 8.4 Hz,
1
3
1
1H, aromatic);
3
C{ H} NMR (CDCl ; 100.5 MHz) d = 24.83,
(
1i) was synthesized according to procedure described in the liter-
ature [20].
The synthesis of quinolines 2, 3 and 4 followed our procedure
described in the literature [20]:
-Fluoro-8-methoxy-2-methylquinoline (2a) (brown oil); 21%; H
NMR (CDCl ; 400.2 MHz) d = 2.78 (s, 3H, CH ), 4.23 (d, J = 1.8 Hz,
), 7.23 (d, J = 8.3 Hz, 1H, aromatic), 7.26 (dd, J = 10.8,
.1 Hz, 1H, aromatic), 7.43 (dd, J = 9.0, 5.4 Hz, 1H, aromatic), 7.99
116.18, 118.02, 122.88, 125.25, 128.14, 136.78, 137.65, 147.80,
158.07; MS: (ESI) [M+H] = 194 (100%).
+
0
0
Synthesis of esters 5a, 5b, 5b , 5c and 5c
1
t
7
Ph(Bu )P(O)Cl or 2-chloro-5,5-dimethyl-1,3,2-dioxaphosph-
inane 2-oxide (5.0 mmol) was added to the suspension of NaH
(0.133 g, 5.5 mmol) in THF (25 mL). Subsequently, 5,7-dibromo-
2-methylquinolin-8-ol (1a), 5-fluoro-2-methylquinolin-8-ol (1i)
(5.0 mmol) in THF (5 mL), was added. The reaction was carried
out for 24 h under reflux. The mixture was allowed to cool to room
temperature. The reaction was neutralized with aqueous solution
3
3
3
9
(
H, OCH
3
d, J = 8.4 Hz, 1H, aromatic); 13C{ H} NMR (CDCl
1
; 100.5 MHz)
3
), 116.81 (d, J = 23.5 Hz),
3
d = 25.76, 62.33 (d, J = 5.1 Hz, OCH
1
21.67 (d, J = 2.6 Hz), 122.50 (d, J = 9.4 Hz), 124.49, 136.37,
1
41.56 (d, J = 9.7 Hz), 143.13 (d, J = 6.2 Hz), 154.20 (d,
of KHSO
phase was dried over MgSO
evaporation. The crude product was purified by chromatography
and crystallization:
4
. After extraction with CH
2
Cl
2
(3 ꢂ 50 mL), the organic
19
1
J = 247.0 Hz), 159.53;
d = ꢁ129.07; MS: (ESI) [M+H] = 192 (100%).
F{ H} NMR (CDCl
3
;
470.5 MHz)
4
, followed by filtration and solvent
+
1
7
-Chloro-8-methoxy-2-methylquinoline (2b) (brown oil); 24%; H
NMR (CDCl
7
8
3
; 400.2 MHz) d = 2.78 (s, 3H, CH
.28 (d, J = 8.4 Hz, 1H, aromatic), 7.44 (2d, J = 0.5 Hz, 2H, aromatic),
.01 (d, J = 8.4 Hz, 1H, aromatic); 1H NMR (CDCl
; 500.18 MHz)
), 4.18 (s, 3H, OCH ), 7.28 (d, J = 8.4 Hz, 1H, aro-
matic), 7.44 (d, J = 0.6 Hz, 2H, aromatic), 8.01 (d, J = 8.4 Hz, 1H, aro-
3
), 4.18 (s, 3H, OCH
3
),
5-Fluoro-2-methylquinolin-8-yl
(5a) (brown); 78%; mpdec. = 176 °C;
3
500.2 MHz) d = 1.26 (d, J = 16.0 Hz, 9H, t-Bu), 2.67 (s, 3H, CH ),
tert-butyl(phenyl)phosphinate
1
H
6
NMR (DMSO-d ;
3
d = 2.78 (s, 3H, CH
3
3
7.20 (dd, J = 9.1 Hz, 1H, aromatic), 7.47 (dd, J = 7.6, 4.5 Hz, 3H, aro-
matic), 7.54 (dt, J = 14.3, 8.7 Hz, 2H, aromatic), 7.90 (ddd, J = 9.7,
7.6, 3.2 Hz, 2H, aromatic), 8.33 (d, J = 8.6 Hz, 1H, aromatic);
1
3
1
matic); C{ H} NMR (CDCl
23.49, 126.81, 127.25, 127.46, 136.49, 142.94, 151.75, 159.49.
-Chloro-2-methylquinolin-8-ol (3a) (light yellow); 41%;
3
; 100.5 MHz) d = 25.75, 62.22, 122.41,
1
3
1
1
6
C{ H} NMR (DMSO-d ; 100.6 MHz) d = 24.47, 25.54, 33.99 (d,
5
J = 99.9 Hz), 117.98 (bs), 122.43 (bs), 127.94 (bs), 129.13 (bs),
1
mp = 67.4 °C; H NMR (CDCl
3
; 500.18 MHz) d = 2.74 (s, 3H, CH
.06 (d, J = 8.2 Hz, 1H, aromatic), 7.39 (d, J = 8.6 Hz, 1H, aromatic),
.42 (d, J = 8.2 Hz, 1H, aromatic), 8.37 (d, J = 8.6 Hz, 1H, aromatic);
3
),
132.20 (bs), 133.58 (bs), 139.56 (bs), 143.32 (bs), 158.86 (bs);
3
1
1
19
7
7
P{ H} NMR (DMSO-d
6
; 202.5 MHz) d = 51.19; F NMR (CDCl
3
;
+
470.5 MHz) d = ꢁ127.44; MS: (ESI) [M+H] = 358 (56%).

J.E. Nycz et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 117 (2014) 351–359
353
Fig. 1. ORTEP drawing of 3a, 3b, 3d, 5c and 6b molecules with 50% probability displacement ellipsoids.
8
-[(5,5-Dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)oxy]-5-fluoro-
3
(s, 3H, CH ), 3.94 (m, 2H, CH2e), 4.82 (bd, J = 10.4 Hz, 2H, CH2a),
7.08 (pseudo-t, J = 8.6 Hz, 1H, aromatic), 7.37 (d, J = 8.6 Hz, 1H, aro-
matic), 7.71 (ddd, J = 8.5, 5.0, 1.7 Hz, 1H, aromatic), 8.28 (d,
0
1
2
-methylquinoline (5b and 5b ) (brown); 76%; mpdec. = 190.1 °C;
NMR (CDCl ; 400.2 MHz) d = 0.92 (s, 3H, CH ), 1.32 (s, 3H, CH ), 2.71
H
3
3
3

3
54
J.E. Nycz et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 117 (2014) 351–359
Fig. 1 (continued)
J = 8.6 Hz, 1H, aromatic); 13C{ H} NMR (DMSO-d
1
; 100.6 MHz)
aromatic), 7.37 (d, J = 8.6 Hz, 1H, aromatic); 1H NMR (D
DMSO-d ; 400.2 MHz; 70 °C) d = 2.37 (s, 3H, CH ), 2.81 (s, 3H,
CH ), 7.53 (s, 1H, aromatic), 7.81 (d, J = 8.8 Hz, 1H, aromatic),
8.75 (d, J = 8.7 Hz, 1H, aromatic);
125.78 MHz) d = 16.80, 23.23, 113.57, 122.81, 123.04, 124.80,
127.79, 132.76, 137.34, 154.83, 157.11, 175.69; CCDC 939809.
6
2 4 2
SO /D O/
d = 19.28, 21.03, 24.97, 31.79 (d, J = 5.8 Hz), 78.27 (d, J = 6.9 Hz),
09.24 (d, J = 17.8 Hz), 117.51 (d, J = 18.0 Hz), 119.28 (d,
J = 9.4 Hz), 123.58, 129.45, 139.33 (d, J = 114.3 Hz), 141.18 (d,
6
3
1
3
1
3
1
2
C{ H} NMR (KOD/D O;
31
1
J = 4.0 Hz), 155.29, 160.47; P{ H} NMR (CDCl
3
; 162.0 MHz) de,a = -
; 470.5 MHz) de,a = ꢁ125.55
; 470.5 MHz) de,a = ꢁ125.55 (ddd,
1
9
1
ꢁ
12.93 and ꢁ13.10; F{ H} NMR (CDCl
3
1
9
and ꢁ125.56; F NMR (CDCl
J = 7.1, 4.7, 1.9 Hz); MS: (ESI) [M+H] = 326 (100%).
-[(5,5-Dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)oxy]-5,7-
3
5-Chloro-8-hydroxy-2-methylquinoline-7-carbodithioic acid (6c)
+
1
(brick red); 23%; mpdec. = 164.3 °C;
400.2 MHz) d = 2.61 (s, 3H, CH
7.30 (d, J = 8.4 Hz, 1H, aromatic), 7.36 (d, J = 8.7 Hz, 1H, aromatic),
H
2 3 2
NMR (K CO /D O;
8
3
), 6.66 (d, J = 8.4 Hz, 1H, aromatic),
1
dibromo-2-methylquinoline (5c) (white); 89%; mpdec. = 186.7 °C; H
NMR (CDCl ; 400.2 MHz) d = 0.96 (s, 3H, CH ), 1.37 (s, 3H, CH ),
.73 (s, 3H, CH ), 4.08 (dd, J = 23.2, 11.1 Hz, 2H, CH2e), 4.73 (d,
J = 10.7 Hz, 2H, CH2a), 7.36 (d, J = 8.7 Hz, 1H, aromatic), 7.88 (s,
1
3
1
3
3
3
8.30 (d, J = 8.7 Hz, 1H, aromatic); C{ H} NMR (KOD/D
125.78 MHz) d = 23.68, 112.28, 113.73, 122.74, 125.57,
127.47, 133.45, 142.94, 156.49, 167.94, 242.34.
2
O/DMSO-
2
3
6
d ;
13
1
1
H, aromatic), 8.24 (d, J = 8.7 Hz, 1H, aromatic); C{ H} NMR
(
DMSO-d 100.6 MHz) d = 20.37, 22.20, 25.15, 32.21 (d,
6
;
J = 5.7 Hz), 78.59 (d, J = 7.2 Hz), 115.56 (d, J = 5.9 Hz), 117.96 (d,
J = 2.6 Hz), 123.92, 126.10, 132.24 (d, J = 1.8 Hz), 135.50, 141.76
3
1
1
(
1
3
d, J = 2.5 Hz), 144.79 (d, J = 8.5 Hz), 160.75; P{ H} NMR (CDCl ;
3
1
62.0 MHz) d = ꢁ14.29; P NMR (CDCl ; 162.0 MHz) d = ꢁ14.29
3
+
+
(
(
t, J = 23.1 Hz); MS: (ESI) [M+H] = 467 (100%), [M+Na] = 488
18%); CCDC 940334.
0
1
(
5c ) H NMR (CDCl
3
; 400.2 MHz) d = 0.89 (s, 3H, CH
3
), 1.31 (s,
3
H, CH ), 2.74 (s, 3H, CH
3
3
), 3.98 (ddd, J = 24.4, 9.8, 1.4 Hz, 2H,
CH2e), 4.47 (d, J = 10.7 Hz, 2H, CH2a), 7.37 (d, J = 8.7 Hz, 1H, aro-
matic), 7.88 (s, 1H, aromatic), 8.25 (d, J = 8.6 Hz, 1H, aromatic);
3
1
1
P{ H} NMR (CDCl
Quinoline-7-carboxylic(carbodithioic) acids 6 were synthesized
according to our procedure described in the literature [20].
-Chloro-8-hydroxy-2-methylquinoline-7-carboxylic acid (6a)
3
; 162.0 MHz) d = ꢁ21.12.
5
1
(
yellow); 9%; mp = 206 °C;
H
2 6
NMR (KOD/D O/DMSO-d ;
4
7
00.2 MHz) d = 2.52 (s, 3H, CH
.49 (s, 1H, aromatic), 8.13 (d, J = 8.5 Hz, 1H, aromatic); H NMR
SO /D O/DMSO-d ; 400.2 MHz) d = 2.85 (s, 3H, CH ), 7.50 (s,
H, aromatic), 7.90 (d, J = 8.9 Hz, 1H, aromatic), 8.73 (d, J = 8.9 Hz,
3
), 7.30 (d, J = 8.6 Hz, 1H, aromatic),
1
(
D
2
4
2
6
3
1
1
1
3
1
2 6
H, aromatic); C{ H} NMR (KOD/D O/DMSO-d ; 125.78 MHz)
d = 25.13, 110.86, 122.74, 124.64, 127.54, 129.33, 134.24, 145.58,
ꢁ
1
57.17, 164.05, 177.32; MS: (ESI) M = 237 (40%).
8
-Hydroxy-2,5-dimethylquinoline-7-carboxylic acid (6b) (yellow);
1
6
8%; mp = 222.2 °C; H NMR (KOD/D
2
O; 400.2 MHz) d = 1.92 (s, 3H,
CH
3
), 2.36 (s, 3H, CH ), 6.82 (d, J = 8.6 Hz, 1H, aromatic), 6.97 (s, 1H,
3
Fig. 2. p-Stacking interaction in the molecular structure of 6b.

J.E. Nycz et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 117 (2014) 351–359
355
Fig. 3. The electrostatic potential (ESP) surfaces on molecules 3a, 3b, 3d, 5c and 6b.
8
-Hydroxy-2,5-dimethylquinoline-7-carbodithioic acid (6d) (brick
DFT calculations
1
red); 64%; mpdec. = 206.7 °C; H NMR (K
2 3 2
CO /D O; 400.2 MHz)
d = 2.49 (s, 3H, CH ), 2.67 (s, 3H, CH ), 6.77 (d, J = 7.7 Hz, 1H, aro-
3
3
The calculations were carried out by using Gaussian 09 program
[21]. The DFT/B3LYP method was used for the geometry optimiza-
tion and electronic structure determination [22]. The geometry
optimization was made for gas phase molecule and a frequency cal-
culation was carried out, verifying that the optimized molecular
structure obtained corresponds to energy minimum, thus only po-
sitive frequencies were expected. The absence of the imaginary fre-
quencies, as well as of negative eigenvalues of the second derivative
matrix has been obtained in geometry optimization of all com-
pounds. The calculations were performed using the polarization
matic), 7.17 (d, J = 7.8 Hz, 1H, aromatic), 7.39 (d, J = 8.6 Hz, 1H, aro-
ꢁ
matic), 8.26 (d, J = 8.6 Hz, 1H, aromatic); MS: (ESI) [MꢁH] = 216
(
30%).
Crystallization
The crystals suitable for X-ray analysis were obtained from hot
3
hexane solution for 3a, 3b, 3c, hot CHCl solution for 5c and from
hot DMSO solution ca.100 °C for 6b.

3
56
J.E. Nycz et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 117 (2014) 351–359
t
t
Scheme 1. Synthesis of 2, 3, 4, 5 and 6. Reagents and conditions: (i) CH
3
CHCHCHO, HCl, reflux; (ii) HBr aq., reflux; (iii) Bu OK, RR’P(O)Cl, reflux, (iv) Bu OK, CO
2
or CS
2
.
ꢃꢃ
functions for all atoms: 6-31G – carbon, nitrogen, oxygen, chlorine
The structures of the compounds are stabilized by hydrogen
bonds described in Table S3 (Supplementary data), which form dif-
ꢃꢃ
and hydrogen and 6-311G for phosphorus. Natural bond orbital
analyses were also made for all compounds using the NBO 5.0 pack-
age included in Gaussian 09 [23].
1
1
ferent type of dimers from simply D ð2Þ, intramolecular S ð6Þ to
1
1
2 4 4
cyclic intermolecular R ð10Þ; R ; R ð18Þ. Moreover structures of
2
4
4
these compounds are stabilized by
p-stacking interactions (see
Table S4, Supplementary data); interactions between quinoline
rings create ordered stocks as one can see in Fig. 2.
Crystal structure determination and refinement
The crystals of the quinoline derivatives were mounted in turn
on an Xcalibur, Oxford Diffraction automatic diffractometer
equipped with a CCD detector for data collection. X-ray intensity
data were collected with graphite monochromated Mo K
tion ðk ¼ 0:71073Þ Å at temperature of 100(1) K (3a, 3b, 3c, 6d)
and 295.0(2) K (5c), with scan mode. Ewald sphere reflections
a radia-
x
were collected up to 2h = 50.10. Details of crystal data and refine-
ment are gathered in Table S1 (Supplementary data) and selected
bond lengths and angles for compounds in Table S2 (Supplemen-
tary data). During the data reduction, the decay of the correction
coefficient was taken into account. Lorentz, polarization and
empirical absorption correction using spherical harmonics imple-
mented in SCALE3 ABSPACK scaling algorithm were applied [24].
The structures were solved by direct method. All the non-hydrogen
atoms were refined anisotropically using full-matrix, least-squares
2
technique on F . All the hydrogen atoms were found from the dif-
ference of the Fourier synthesis after four cycles of anisotropic
refinement, and refined as ‘‘riding’’ on the adjacent atom with indi-
vidual isotropic temperature factor equal to 1.2 times the value of
equivalent temperature factor of the parent atom, with geometry
idealization after each cycle. The Olex2 and SHELXS97, SHELXL97
programs were used for all the calculations [25,26]. Atomic scatter-
ing factors were those incorporated in the computer programs.
X-ray and DFT studies
The studied quinoline derivatives 3a, 3b, 3d and 5c crystallize in
monoclinic P2
1
/c and C2/c while 6b in triclinic P ꢁ 1 space groups
and theirs molecular structures are displayed as ORTEP representa-
tions in Fig. 1. As one can see from the Fig. 1 that the compound 3a
has two independent molecules in the asymmetric unit. These two
molecules are twisted, which prevents the existence of higher
crystallographic symmetry.
Fig. 4. The stabilizing hyperconjugation interaction of non-bonding
p oxygen
orbitals via phosphorus with 5,7-dibromo-2-methylquinolin-8-ol antybonding
ꢃ
p
-accepting orbitals.

J.E. Nycz et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 117 (2014) 351–359
357
Scheme 2. The hyperconjugation in 5c (left) and N-{8-[(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)oxy]-5-hydroxy-2-methylquinolin-7-yl}acetamide (right) [31].
DFT
The geometry of the compounds 3a, 3b, 3d, 5c and 6b were
optimized in singlet states using the DFT method with the B3LYP
functional. The atomic charge calculations can give a feature for
the relocation of the electron density of the compounds, but the lo-
cal concentration and local depletion of electron charge density al-
low us to determine whether the nucleophile or electrophile can be
attracted.
is the difficulties of isolating complex reaction mixtures, mostly
due to the formation of the target product accompanied by regioi-
somers. Results from our previous studies and literature data
showed that the reaction of various anilines with crotonaldehyde
usually favored the quinoline products with the phosphorus, fluoro
or carboxylic group in 5 position [20,27,28,30]. By applying our pro-
tocol, the previous and present results showed that the syntheses
are fast, general and simple in use, afforded the product in up to
24% for 2, 43% or 98% for 3 and 46% yield for 4 after 4.5 h (Scheme 1),
respectively. Comparing with other methods like Friedländer reac-
tion, our starting reagents are commercially available and cheap.
Our following work was also presented regarding the synthesis
of some hydroxyquinoline carboxylic acids 6a and 6b, and hydroxy-
quinoline carbodithioic acids 6c and 6d, which possess hydroxyl
and carboxylic (carbodithioic) function in vicinal position, by direct
Fig. 3 presents the plots of the electrostatic potential for the
compounds. The isoelectronic contour is plotted at 0.05 a.u.
(
0
3.1 kcal/mol). The color code of the map is in the range of
.05 a.u. (deepest red) to ꢁ0.05 a.u. (deepest blue), 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 potentials
are localized on the oxygen (ꢁ0.7) and nitrogen (ꢁ0.5) atoms.
Chloro and bromo substituents have charges close to zero (simi-
larly to our previous results), but there are some visible differences
depend on position in quinoline ring [27]. Therefore, chloro substi-
tuent in position 5 is more charged (ꢁ0.063) than in position 6
2 2
carboxylation of certain phenols by CO (CS ), respectively [20]. In
order to obtain more understanding about the synthetic abilities
of hydroxyquinoline carboxylic acids (carbodithioic acids), a study
of hydroxyquinolines (Figs. 1 and 3) have been undertaken, includ-
ing both the experimental (from single crystal X-ray diffraction)
and computational analysis of the distribution of electron densities
and electrostatic potentials. Considering our previous results and
the present work, the relation between electron density inside the
quinolines and the yield of products was investigated [20,27]. High-
er yields were observed for 6b 68% and 6d 64% (Scheme 1), where
starting reagent 3d possessed higher electron density. Low yields
were obtained for the syntheses of 6a 9% and 6c 23%, where apply-
ing starting material 3b was electron poorer. The syntheses of 6-
chloro-8-hydroxy-2-methylquinoline-7-carboxylic acid and 6-
chloro-8-hydroxy-2-methylquinoline-7-carbodithioic acid from
(
ꢁ0.054), similarly bromo in position 5 has slightly higher charges
density than in position 7.
Results and discussion
In our previous studies the synthesis and characterization of
some hydroxyquinolines and their derivatives have been reported
[
20,27,28]. X-ray crystal structure analysis showed the presence of
hydrogen-bond donating and accepting sites between the pyridine
and hydroxyl functional groups. The solution and solid state NMR
studies demonstrated that there is a tautomeric equilibrium in the
neutral, cationic and anionic species of hydroxyquinoline carbox-
ylic acids obtained by protonation or deprotonation, which was
3
b were unsuccessful, possibly due to the negative potential value,
ꢁ
0.314 on the C6 carbon atom in 3b (Fig. 2).
The presented phosphorus esters of halogeno-2-methylquino-
lines 5a, 5b and 5c could have potential influence not only on their
chemical reactivity but on biological activity as well.
The X-ray structure of 5c was compared with that obtained for
N-{8-[(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)oxy]-5-
hydroxy-2-methylquinolin-7-yl}acetamide [31].
1
3
15
evaluated by C and N chemical shifts [28]. To the best of our
knowledge about literature data, there are few examples of the
X-ray crystal structures of hydroxyquinoline carboxylic acids or
halogenohydroxyquinolines including our attempts [20,27]. There-
fore, further experiments were carried out in order to obtain a dee-
per understanding of the chemical properties of selected
hydroxyquinolines and their analogues or derivatives contained
methoxy, fluoro, chloro, carboxylic, carbodithioic and phosphinate
or dioxaphosphinane groups (Scheme 1).
Both compounds and 5b attracted our attention due to ob-
served chair conformers. The conformation studies on saturated
1
,3,2-dioxaphosphinane rings were first started by Bentrude and
Hargis [32]. The assignments of conformation were based on
NMR, X-ray and literature analysis [33]. According to the Karplus
equation and taking into consideration of the coupling constant,
In this paper we present the syntheses of two 7-halogeno-
2 a e
the order of chemical shifts for CH protons, d H > d H was
8
8
-methoxy-2-methylquinolines 2a and 2b, four 2-methylquinolin-
-ols 3a, 3b, 3c and 3d, and 4 together with their X-ray structures
determined.
The presence of the anomeric effect for 5b, 5c or
N-{8-[(5,5-dimethyl-2-oxido-1,3,2-dioxaphosphinan-2-yl)oxy]-5-
(Fig. 1). Our protocol was based on Skraup–Doebner–Miller
quinoline synthesis with Matsugi modification [20,29]. One of the
serious drawbacks of the Skraup–Doebner–Miller transformation
hydroxy-2-methylquinolin-7-yl}acetamide,
compounds
with

3
58
J.E. Nycz et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 117 (2014) 351–359
Fig. 5. Short contact interaction and electrostatic potential surface in the molecular structure of 5c dimer.
1
,3,2-dioxaphosphinane rings was evidenced by the results that
The analysis of the trend in 1H chemical shifts revealed that the
deprotonation of molecules (solvents: KOD/D O/DMSO-d ) signifi-
cantly increased the shielding effect (upfield effect, smaller d)
resulting in the decreased chemical shifts of selected H-1 signals
in comparison with in neutral solvent, such as DMSO-d6. The pro-
the preferential axial position of substituents was the one adja-
cent to oxygen [31]. In literature there were several proposed
explanations for the validity of the anomeric effect. One of the
explanation could be a stabilizing hyperconjugation contribution
2
6
between the unshared electron pair on the oxygen atom in a
2 4 2 6
tonation of molecules using solvents: D SO /D O/DMSO-d showed
ꢃ
1
,3,2-dioxaphosphinane ring and the
r
orbital for the PAO bond
opposite effect, the chemical shifts were moved to downfield (lar-
ger d), this trend is elegantly showed particularly for protons from
pyridine ring of 6a and 6b. This is a consequence of simple proton-
ation or deprotonation of pyridine rings in quinoline constitution.
This corresponds well with the electrostatic potential surfaces
(ESP) (Fig. 3). The largest difference in C-13 NMR spectroscopy is
visible by comparing carboxylic group for molecules 6a, 6b and
dithiocarboxylic group for 6c, similarly to previous results [20].
The chemical shifts were moved significantly to downfield (larger
d) for 6c. The deshielding effect (downfield shift) is quite visible
for dithiocarboxylic group for 6c, which can be explained in the
frame of electron density. Sulfur is less electronegative than oxy-
gen and makes the carbon atom less positive than that of oxygen.
Thus, the carbon atom is more deshielded from the applied mag-
in the axial position (Fig. 4).
The anomeric effect is presented in Scheme 2 where the non-
bonding p oxygen orbitals interact with phosphorus and the charge
is transferred through oxygen atom to quinoline part, which pos-
sesses empty
structure of 5c
p
-accepting orbitals. Nevertheless in the molecular
-stacking interactions are associated with inter-
p
molecular short contact interaction between P@O and quinoline
ring, presented in Fig. 5, which has impact on the geometry of
the molecule. In the formed dimer, the anomeric effect may be en-
hanced by electrostatic interactions between quinolone rings.
Moreover reciprocal interaction of quinoline rings in the dimer ex-
erts influence on the charge relocation.
The geometrical data collected in Table S2 (Supplementary
data) for ester 5c show that the compound crystallized as ano-
mer with oxygen atom in the equatorial position. This is in
accordance with the observation of an increased tendency that
adopt an axial position with the electron-withdrawing character
of an anomeric substituent, 5c here the P(1)AO(1) bond. More
electronegative groups tend to preferentially take the axial posi-
tion in the chair conformations of six-membered rings, and the
trend increases if the anomeric substituent has electron-with-
drawing character, due to lowering the energy of the exocyclic
1
3
netic field, B
o
.
C NMR spectra for compound 6d were not obtained
due to their poor solubility. In the case of 2b both aromatic protons
coincidentally have practically the same chemical shift, and very
low coupling constants.
Conclusions
The presented research has been focused on the synthesis of
crystalline hydroxyquinolines and their analogues or derivatives
containing methoxy, fluoro, chloro, carboxylic, carbodithioic and
phosphinate or dioxaphosphinane groups. The compounds were
further characterized by analytical methods and rationalized on
the basis of DFT calculation method with B3LYP functional. After
comparing to the literature methods, our simpler protocols pro-
vides high yield of products. The experimental (from single crystal
X-ray diffraction) and computational analysis of the distribution of
ꢃ
s (PAX) orbital.
NMR studies
The 1H NMR solution spectra of hydroxyquinolines and their
derivatives or analogues showed distinctive H-1 signals from aro-
matic protons and CH group (Table S5, Supplementary data).
3

J.E. Nycz et al. / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 117 (2014) 351–359
359
electron densities and electrostatic potentials revealed the rela-
tionship between the structure factor and the synthesis yields.
The proton transfer reactions between the pyridine and carboxylic
acid functional groups or generally simple protonation or deproto-
nation of pyridine rings in quinoline constitution could be used as a
pH indicator. The largest effect should be visible in the N NMR
spectra which allow distinguishing between species with proton-
ated and deprotonated pyridine rings. Another example of com-
pound with anomeric effect was reported.
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Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.saa.2013.08.031.
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