Synthesis, spectroscopic characterization and X-ray structure of novel 7-methoxy-4-oxo-N-phenyl-4H-chromene-2-carboxamides

Article abstract of DOI:10.1016/j.molstruc.2013.09.024

The chromone scaffold has been found to be an important tool in the drug discovery process through its relevant pharmacological activities. Chromone carboxamide derivatives synthesized within our group have shown noteworthy results as inhibitors of monoam

Full text of DOI:10.1016/j.molstruc.2013.09.024

Journal of Molecular Structure 1056–1057 (2014) 31–37
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, spectroscopic characterization and X-ray structure of novel
7-methoxy-4-oxo-N-phenyl-4H-chromene-2-carboxamides
b
c
Joana Reis a, Alexandra Gaspar a, Fernanda Borges a, , Ligia Rebelo Gomes , John Nicolson Low
⇑
a CIQUP/Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, 4169-007 Porto, Portugal
b REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências da Universidade do Porto, Rua Campo Alegre, 687, P-4169-007, Porto P-4200-150, Portugal
c Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, United Kingdom
h i g h l i g h t s
ꢀ
ꢀ
ꢀ
Novel 7-substitued chromone carboxamides have been synthesized.
The structural characterization was performed by FTIR, NMR and X-ray.
The data provide a better understanding of the structure–activity (A3AR) relationships.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 July 2013
Received in revised form 10 September
2013
Accepted 18 September 2013
Available online 12 October 2013
The chromone scaffold has been found to be an important tool in the drug discovery process through its
relevant pharmacological activities. Chromone carboxamide derivatives synthesized within our group
have shown noteworthy results as inhibitors of monoamino oxidase-B and as ligands for adesonine
receptors. Specifically, chromone-2-carboxamide has been shown to be a privileged structure for the
development of selective A3 adenosine receptor ligands. In this work two novel substituted 4-oxo-N-phe-
nyl-4H-chromene-2-carboxamides have been synthesized and a complete structural characterization
was performed using Fourier Transform Infrared Spectroscopy, one-dimensional and two-dimensional
Nuclear Magnetic Resonance techniques and Mass Spectroscopy. Finally, the molecular and supramolec-
ular structures were determined by X-ray analysis. The X-ray crystallographic analysis describes in detail
the molecular conformation and supramolecular structure of a hemihydrate of 7-methoxy-4-oxo-N-phe-
nyl-4H-chromene-2-carboxamide.
Keywords:
Chromone scaffold
Chromone carboxamides
Adenosine receptor ligands
FTIR
NMR
X-ray
The data acquired from this study add valuable information to our chromone database. The unambig-
uous identification of the compounds will support the understanding of the structure–activity relation-
ships of these compounds.
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
Recently our research group reported chromone derivatives as
suitable lead compounds for the development of novel monoamino
Chromones have a 4H-1-benzopyran-4-one nucleus and are an
important class of oxygenated heterocycles. They have emerged as
a fruitful tool for the discovery of novel biologically active com-
pounds and so they have been engaged in diverse medicinal chem-
istry programs [1–5].
The chromone moiety is synthetically versatile and represents a
useful building block, the Claisen condensation, Baker–Venkatam-
aran rearrangement and Vilsmeier–Haack reaction being the most
recognized methods used for chromone core construction. [6,7]
This type of compounds have also a great significance in organic
synthesis due to their reactivity towards nucleophiles that allow
the synthesis of a wide variety of heterocycles.
oxidase B (MAO-B) inhibitors [3,8–10] and adenosine receptor li-
gands [4,11–14]. The results obtained so far reveal the importance
of chromone-2-carboxamide as a template for the development of
selective A3 adenosine receptor ligands (A3AR) [13]. The A3 adeno-
sine receptors are under scrutiny in relation to potential therapeu-
tic approaches for treating inflammatory and neurodegenerative
diseases, asthma and cardiac ischaemia [15]. Therefore, in our pro-
ject new chromone-2-carboxamide derivatives 4 and 5 were syn-
thesized following the procedure presented in Scheme 1, in order
to carry out a structure–activity (A3AR) relationship study.
This work presents the synthesis of two novel chromone car-
boxamide derivatives (Scheme 1), their identification by Fourier
Transform Infrared Spectroscopy (FTIR), 1D and 2D Nuclear
Magnetic Resonance (NMR) techniques and Electron Impact Mass
Spectrometry (EIMS) as well as a detailed X-ray structure charac-
⇑
Corresponding author.
E-mail address: fborges@fc.up.pt (F. Borges).
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.09.024

32
J. Reis et al. / Journal of Molecular Structure 1056–1057 (2014) 31–37
O
O
COOEt
H3CO
H3CO
OH
a)
O
2
1
b)
c)
O
O
COOH
H3CO
H3CO
O
O
CONH
R
3
4 R = CH3
5 R = H
Scheme 1. Synthesis of 7-methoxy-4-oxo-N-phenyl-4H-chromene-2-carboxamides Reagents and conditions: (a) C2H5OCOCOOC2H5, EtONa/EtOH, HCl, EtOH, (b) NaHCO3 and
(c) POCl3, NH2-Ph-R.
terization. The characterization of those compounds is of the ut-
most importance as it allows data extrapolation, speeding up the
structure–activity studies of the medicinal chemistry program.
J = 9.2; 2.4, H(6)); 7.23 (1H, d, J = 2.4, H(8)); 7.95 (1H, d, J = 9.2, H
(5)).
13C NMR: d = 14.4 COOCH2CH3; 56.8 OCH3; 63.1 COOCH2CH3;
101.5 C(8); 114.4 C(6); 116.2 C(3); 118.1 C(4a); 126.8 C(5); 157.8
C(8a); 160.5 C(2); 161.4 COOCH2CH3); 165.1 C(7); 176.8 C(4).
EIMS (m/z): 248 (M+Å, 100), 220 (32), 203 (10), 192 (49), 177
(25), 148 (16), 119 (27).
2. Experimental
2.1. Materials
2.2.2. Synthesis of 7-methoxy-4-oxo-4H-chromene-2-carboxylic acid
(3)
Chemicals were purchased from Sigma–Aldrich Química S.A.
(Sintra, Portugal). All the solvents were pro analysis grade and used
without additional purification.
Thin-layer chromatography (TLC) was carried out on precoated
silica gel 60 F254 (Merck) with layer thickness of 0.2 mm. For ana-
lytical control the following systems were used: ethyl acetate/
dichloromethane and dichloromethane/methanol in diverse pro-
portions. The spots were visualized under UV detection (254 and
366 nm). Flash chromatography was performed using silica gel
60, 0.040–0.063 mm (Merck, Lisbon, Portugal).
The chromone (2) was dissolved in a solution of NaHCO3 (5 mL,
20% in H2O) and heated at 80 °C for 3 h. After cooling, the solution
was acidified (concentrated HCl) and extracted with CH2Cl2
(3 ꢁ 50 mL). The organic layer was washed with water, dried over
Na2SO4, and evaporated [17]. The product was filtered and purified
by recrystallization (CH2Cl2/n-hexane); Yield = 62%.
1H NMR: d = 3.93 (3H, s, OCH3); 6.86 (1H, s, H(3)); 7.11 (1H, dd,
J = 9.2; 2.4, H(6)); 7.22 (1H, d, J = 2.4, H(8)); 7.95 (1H, d, J = 9.2, H
(5)).
13C NMR: d = 56.7 OCH3; 101.5 C(8); 114.1 C(6); 116.0 C(3);
118.1 C(4a); 126.8 C(5); 153.4 C(8a); 157.9 C(2); 161.9 COOH;
165.0 C(7); 177.1 C(4).
2.2. Synthesis
2.2.1. Synthesis of ethyl 7-methoxy-4-oxo-4H-chromene-2-
EIMS (m/z): 221 (13), 220 (M+Å, 99), 192 (62), 191 (11), 177 (64),
176 (10), 149 (10), 122 (22), 107 (16), 63 (14).
carboxylate (2)
To
a
solution of 20-hydroxy-40-methoxyacetophenone
(12 mmol) in sodium ethoxide (21% in ethanol, 10 mL) diethyloxa-
late (28 mmol, 5 mL) was added. The reaction was refluxed for 1 h.
After reaction, concentrated HCl was added dropwise until the
reaction was acidic and a white precipitate was formed. The prod-
uct was filtered and the yellow solution concentrated. The slurry
obtained was extracted with CH2Cl2 (3 ꢁ 50 mL), washed with
water, dried over Na2SO4 and evaporated [16]. The light yellow so-
lid was filtered and purified by recrystallization (CH2Cl2/n-hex-
ane); Yield = 72%.
2.2.3. Synthesis of 7-methoxy-4-oxo-N-p-tolyl-4H-chromene-2-
carboxamide (4) and 7-methoxy-4-oxo-N-phenyl-4H-chromene-2-
carboxamide (5)
To a solution of chromone-2-carboxylic acid (1.1 mmol) in DMF
(1.5 mL), phosphoryl trichloride (POCl3) (1 mmol) was added. The
mixture was stirred at room temperature for 30 min, with the for-
mation in situ of the corresponding acyl chloride. Then, the corre-
sponding aromatic amine (1.1 mmol) was added. The system was
heated 160 °C for 5 min in a microwave apparatus. After, the
mixtures were poured in a beaker and water was added (20 mL).
1H NMR: d = 1.35 (3H, t, J = 6.8, COOCH2CH3); 3.93 (3H, s, OCH3);
4.40 (2H, d, J = 7.2, COOCH2CH3) 6.89 (1H, s, H(3)); 7.11 (1H, dd,

J. Reis et al. / Journal of Molecular Structure 1056–1057 (2014) 31–37
33
Table 1
Table 3
1H and 13C chemical shifts and HMBC correlations for compound 4.
Details of data acquisition, structural solution and refinement for compound (5).
3'
2'
Crystal data
Compound 5
9
Chemical formula
Mr
Crystal system, space group
2(C17H12NO4)ꢂH2O
1'
4'
8
5
1
H3CO
O
O
CONH
CH3
304.29
8a
4a
2
7
Monoclinic, C2/c
100
13.1865 (10), 8.173 (6), 26.602 (19)
96.644 (12)
2848 (3)
8
Temperature (K)
a, b, c (Å)
b (°)
5'
6'
6
3
4
V (Å3)
Z
F(000)
1272
Mo K
0.10
Plate
Colourless
0.21 ꢁ 0.15 ꢁ 0.05
Compound 4
Radiation type
a
1Ha
–
6.89(s)
–
–
7.98(d, 8.8)
7.13(dd. RQ 8.8, 2.4)
–
13C
HMBCb
l
(mmꢃ1
)
Crystal shape
Colour
Crystal size (mm)
2
3
4
4a
5
6
7
8
157.47
111.05
176.37
117.56
126.37
115.40
164.29
101.09
157.01
155.38
134.98
121.02
129.20
134.07
129.20
121.02
56.14
–
C4a, C5, C9, C2, C4
–
–
C8, C6, C8a, C7, C4
C8, C4a, C8a, C7
–
Data collection
Diffractometer
Rigaku Saturn724+(2 ꢁ 2 bin mode)
diffractometer
Rotating anode
Radiation source
Monochromator
Absorption correction
7.30(d, 2.4)
–
–
C6, C4a, C8a, C7
–
–
–
Confocal
8a
9
Multi-scan CrystalClear-SM Expert 2.0
r13 (Rigaku, 2011)
10
–
Tmin, Tmax
No. of measured, independent and
observed [I > 2
Rint
(sinh/k)max (Åꢃ1
0.979, 0.995
20
7.68(d, 8.4)
7.22(d, 8.4)
–
7.22(d, 8.4)
7.68(d, 8.4)
3.95(s)
10.60(s)
2,31(s)
C30, C50, C40, C10, C60
C20, C60, C40, C50
–
30
r
(I)] reflections
13494, 3230, 3011
0.107
0.649
40
50
C20, C60, C40, C50, C30
C30, C50, C40, C10, C20
C7, C8
)
60
Range of h, k, l
h = ꢃ13 ? 17, k = ꢃ10 ? 10,
OCH3
NH
CH3
l = ꢃ33 ? 34
–
C2, C20,C60
20.52
C20, C60, C30, C50, C40
Refinement
R[F2 > 2
r
(F2)], wR(F2), S
0.094, 0.266, 1.19
3230
205
0
a
Chemical shifts d in ppm (multiplicity, J in Hz).
Carbons coupled to the corresponding H atom.
No. of reflections
No. of parameters
No. of restraints
H-atom treatment
Weighting scheme
b
H-atom parameters constrained
2
Table 2
1H and 13C chemical shifts and HMBC correlations for compound 5.
w ¼ 1=½r2ðF2oÞ þ ð0:1329PÞ þ 5:9064Pꢄ
where P ¼ ðF2o þ 2Fc2Þ=3
0.001
(D/r)
max
3'
2'
D
qmax
,
D
qmin (eꢂÅꢃ3
)
0.58, ꢃ0.58
9
1'
8
5
1
H3CO
O
O
CONH
4'
8a
4a
2
7
5'
6'
7-Methoxy-4-oxo-N-p-tolyl-4H-chromene-2-carboxamide
(4): Yield 78%; 1H and 13C NMR data (Table 1).
6
3
4
EIMS (m/z): 295 (49), 294 (M+Å, 99), 266 (11), 172 (13), 151 (13),
119 (56), 118(11).
Compound 5
7-Methoxy-4-oxo-N-phenyl-4H-chromene-2-carboxamide
(5): Yield 74%; 1H and 13C NMR data (Table 2).
1Ha
–
6.89(s)
–
–
7.98(d, 8.8)
7.13(dd, RQ 8.8, 2.4)
–
7.30(d, 2.4)
–
–
–
7.80(dd, 8.6, 1.1)
7.43(dd, 8.6, 7.6)
7.21(m)
7.43(dd, 8.6, 7.6)
7.80(dd, 8.6, 1.1)
3.95(s)
13C
HMBCb
EIMS (m/z): 310 (15), 309 (74), 308 (M+Å, 99), 292 (12), 280 (10),
186 (14), 151 (13), 131 (17), 119 (59), 107 (12), 106 (33), 77 (15).
2
3
4
4a
5
6
7
8
158.16
111.64
176.84
118.05
126.85
115.89
164.78
101.57
157.49
155.76
137.99
121.57
129.29
125.40
129.29
121.57
56.52
–
C4a, C5, C9, C2, C4
–
–
C8, C6, C8a, C7, C4
C8, C4a, C8a, C7
–
C6, C4a, C8a, C7
–
–
–
2.3. Measurements and characterization
2.3.1. Apparatus
Microwave-assisted synthesis was performed in a BiotageÒ Ini-
tiator Microwave Synthesizer.
8a
9
Infrared absorption spectra were recorded on a Bruker Tensor
27 FTIR using a single reflection ATR accessory with a germanium
crystal. Approximately 1 mg from each sample was mixed with
100 mg potassium bromide (KBr) powder. After mixing, the pow-
der was pressed into a ½-inch diameter pellet and compacted.
1H and 13C NMR spectra of samples (approximately 10% solu-
tions in DMSO-d6), were recorded, at room temperature in 5 mm
outside diameter (o.d.) tubes. Tetramethylsilane (TMS) was used
as internal standard, chemical shifts are expressed in ppm (d)
and J in Hz. One-dimensional 13C NMR was recorded on a Bruker
AMX 400 NMR spectrometer operating at 125.77 MHz, typically
with a 30° pulse flip angle, a pulse repetition time of 4.8 s, and a
spectral width of 31 250 Hz with 32 K data points. For the DEPT se-
10
20
C30, C50, C40, C10, C60
C20, C60, C40, C50, C10
C20, C60, C30, C50
C20, C60, C40, C50, C30
C30, C50, C40, C10, C20
C7, C8
30
40
50
60
OCH3
NH
CH3
10.66(s)
–
–
–
C2, C20,C60
–
a
Chemical shifts d in ppm (multiplicity, J in Hz).
Carbons coupled to the corresponding H atom.
b
The formed solids were filtered and purified by recrystallization
[9,18].

34
J. Reis et al. / Journal of Molecular Structure 1056–1057 (2014) 31–37
Fig. 1. A view of the asymmetric unit of 5 with the atom numbering scheme. Displacement ellipsoids are drawn at the 70% probability level. The dashed bonds show the
intramolecular hydrogen bonds and the hydrogen bond between N2 and the water molecule.
0.95 Å, with Uiso = 1.2Ueq(C). C---H(methyl) 0.98Å with Uiso = 1.5-
Ueq(C). The H attached to amido N atom and those attached to the
Table 4
water oxygen were allowed to ride at positions derived from a dif-
ference map and their positions and those of the methyl H atoms
were checked on a final difference Fourier map.
The complete set of structural parameters in CIF format is avail-
able as an Electronic Supplementary Publication from the Cam-
bridge Crystallographic Data Centre (CCDC 939914).
Selected hydrogen-bond and short contact parameters for 5.
DAHꢂ ꢂ ꢂA
DAH (Å)
Hꢂ ꢂ ꢂA (Å)
Dꢂ ꢂ ꢂA (Å)
DAHꢂ ꢂ ꢂA (°)
N2AH2ꢂ ꢂ ꢂO1
1.00
1.00
0.98
0.95
0.98
0.95
2.21
1.99
1.80
2.26
2.38
2.55
2.669 (3)
2.945 (3)
2.771 (3)
2.873 (4)
3.345 (4)
3.420 (4)
106
160
173
121
170
153
N2AH2ꢂ ꢂ ꢂO3
O3AH3Aꢂ ꢂ ꢂO4i
C216AH216ꢂ ꢂ ꢂO2
C71AH71Aꢂ ꢂ ꢂO2ii
C213AH213ꢂ ꢂ ꢂO2i
3. Results and discussion
Symmetry code(s): (i) x, y + 1, z; (ii) ꢃx + 1/2, y + 1/2, ꢃz + 1/2.
3.1. Chemistry
quence, the width of the 90° pulse for 13Cꢃw1 as 4
l
s, and that of the
90° pulse for 1H was 9.5 s; the delay 2JC;H was set to 3.5 ms. 1H-
l
Chromone carboxamides (4 and 5) were synthesized by the
three-step synthetic strategy described in Scheme 1. The chromone
(2) was obtained by a Claisen condensation using 20-hydroxy-40-
methoxyacetophenone (1) and diethyloxalate in the presence of
sodium ethoxide. The 1,3-dioxophenoxy intermediate formed in
the reaction was cyclized in situ under acidic conditions. The sub-
sequent hydrolysis of the ethyl chromone-2-carboxylate (2), under
base catalysis, gave the intended chromone carboxylic acid (3) that
was used as starting material for the synthesis of chromones 4 and
5. The microwave assisted amidation reactions, previously de-
scribed by our research group [18], were carried out by a conden-
sation reaction, in the presence of POCl3, of the chromone
carboxylic acid and the corresponding aromatic amine via forma-
tion in situ of an acyl chloride intermediate.
detected, one-bond HMQC spectra were recorded on a Bruker
AMX 500 spectrometer using pulse sequence that allowed gradient
selection (Bruker programs INV4GS and INVGSLPLRND). Spectra
were collected in the t1 domain in 256 experiments with 2 K data
points and spectral widths of 5050 and 27 669 Hz in the F2 (1H) and
F1 (
13C) dimensions, respectively. The relaxation delay D1 was set
to 2 s. The data were processed using sine-bell weighting functions
in both dimensions.
Electron impact mass spectra (EIMS) were carried out on a VG
AutoSpec Fison, Ipswich, United Kingdom) instrument; the data
are reported as m/z (percentage of relative intensity of the most
important fragments).
2.3.2. Single crystal X-ray data collection, structure solution and
refinement
3.2. FTIR functional characterization
X-ray quality crystals of 7-methoxy-4-oxo-N-phenyl-4H-chro-
mene-2-carboxamide, 5, were grown from an aqueous methanolic
solution (1%) at room temperature and by slow isothermal evapo-
ration and crystallised as a hemihydrate. Crystallographic data
were collected on a Rigaku Saturn724+, AFC12 Kappa 3 circle dif-
fractometer. The structure was solved using the following com-
puter programs SHELXS [19], OSCAIL [20], SHELXS97 [19], PLATON
[21], MERCURY [22]. Detailed crystal data and structural refine-
ment parameters are summarized in Table 3.
From the infrared spectra of the 2-carboxamide chromone
derivatives a characteristic band correspondent to the NAH str
(stretching) at 3356 cmꢃ1 and 2359–2341 cmꢃ1 was observed for
compounds 4 and 5, respectively. In addition, a NAH bending vibra-
tion representative of the amide group is also detected (1645 cmꢃ1
and 1647 cmꢃ1 for compounds 4 and 5, respectively). Finally, the
carbonyl group is confirmed by a C@O str band showing at
1682 cmꢃ1 for 2-carboxamide 4 and 1702 cmꢃ1 for 2-carboxamide
5. The CAN bond is similarly present in the spectra with vibrations
of 1157 cmꢃ1 and 1016 cmꢃ1 for compounds 4 and 5 respectively.
The water oxygen, O3, sits on the centre of symmetry at (0,y,1/
4). H atoms were treated as riding atoms with C---H(aromatic),

J. Reis et al. / Journal of Molecular Structure 1056–1057 (2014) 31–37
35
Fig. 2. Part of the crystal structure of 5 showing the hydrogen bonding around the water molecule viewed down the a-axis, 2a. The
p
. . .p
stacking of the pyran rings is also
shown. Hydrogen bonds are indicated by blue dashed lines. Hydrogen atoms not involved in the hydrogen bonding have been omitted for clarity. (For interpretation of the
references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3. Part of the crystal structure of 5 showing the chain formed by molecules linked by the water molecules running parallel to the b-axis. Adjacent chains are linked by a
weak CAH(methyl). . .O hydrogen bond. Hydrogen bonds are indicated by blue dashed lines. Hydrogen atoms not involved in the hydrogen bonding have been omitted for
clarity. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
The FTIR data confirmed the formation of the amide functional
group generated in the amidation reaction of chromone carboxylic
acid (3).
COSY experiments. Furthermore, the direct correlation (HSQC) be-
tween the protons and their direct attached carbons led to a
straightforward identification of C-3, C-5, C-6 and C-8. Based on
the same assumptions, the protons of methoxyl and methyl groups
were assigned at d of 3.95 and 2.31 ppm, respectively. The corre-
sponding carbons were allocated at d = 56.14 and at 20.52 ppm,
respectively. These values were also confirmed by HSQC data. A
long distance correlation (HMBC) between the methoxyl protons
and the quaternary carbon at d = 164.29 ppm was observed, which
was assigned as C-7. The C4a and C8a quaternary carbons were as-
signed based on the HMBC correlations depicted in Table 1. The
quaternary carbon at d = 134.07 ppm was assigned as C-40, essen-
tially based on its long range interaction with the CH3 protons.
3.3. NMR characterization
1H and 13C NMR data are shown in Tables 1 and 2. Unambiguous
assignments for all NMR signals were attained through the com-
bined information of one-dimensional (1D) and homonuclear and
heteronuclear two dimensional (2D) NMR techniques experiments,
namely COSY, HSQC and HMBC. The protons H-3, H-5, H-6 and H-8
of chromone carboxamide (4) (Scheme 1) were easily assigned by
their chemical shifts (d), multiplicity and coupling constants and

36
J. Reis et al. / Journal of Molecular Structure 1056–1057 (2014) 31–37
The unequivocal assignment of C-10 at 134.98 ppm was also per-
formed by HMBC. The long range correlation between H-3 and
the carbon at 155.38 ppm led to its identification as C-9. The two
signals at d = 7.68 and 7.22 ppm present on the 1H NMR were
attributed to the exocyclic ring protons H-20/H60 and H-30/H-50,
respectively, in accordance with their multiplicity, integration
and the long range interaction (Table 1). The HSQC experiments
provide assignment of the carbons: the signal at 121.02 was attrib-
uted to the equivalent carbons C-20/C-60 and the signal at
129.04 ppm to the carbons C-30/C-50.
The structural characterization of chromone carboxamide 5
(Scheme 1) was performed using the same NMR techniques that al-
low the assignment of the protons and carbons of the chromone
carboxamide structure (2, 3, 4, 4a, 5, 6, 7, 8, 8a and 9). The major
differences found in the 1D and 2D NMR data of chromones 4
and 5 are in accordance with their structures. In fact, no signal cor-
responding to the CH3 function in the 1H NMR spectra of com-
pound 5 was detected. In line with this, a new multiplet appears
at d = 7.13 ppm that was ascribed to H-40. HMBC correlations allow
to assign the quaternary carbon at d = 137.99 ppm as C-40. Finally,
the analysis of the HSQC led to the conclusion that C-40 appears at a
d = 125.40 ppm.
and by one weak CAH. . .O interaction. These dipole-dipole interac-
tions are directional and can vary in strength depending on the
type of donor and acceptor involved on the interaction.
The geometric parameters for those interactions are given in
Table 4. The N2AH2ꢂ ꢂ ꢂO3 (within the selected asymmetric unit)
and the NAH at (ꢃx,y,1/2 ꢃ z) act as hydrogen donors to the water
molecule at (0, y, 1/4) which in turn acts as hydrogen donor via
O3AH3ꢂ ꢂ ꢂO4 (x,1 + y,z) and via the water generated by the two-
fold axis at (0,y,0.1/4), on which the water atom sits, to O4 at
(ꢃx,1 + y,½ + z), Fig. 2. This forms a sandwich type chain structure
which runs parallel to the b-axis, Fig. 3. Adjacent chains are linked
by a weak CAH(methyl) interaction to atom O2 at (ꢃx + 1/2, y + 1/
2, ꢃz + 1/2), Fig. 3.
This structure is reinforced by the weak C213AH213ꢂ ꢂ ꢂO2 (x,
1 + y, z) interaction. Within this chain the pyran rings of the 2-fold
related molecules are
p. . .p stacked above each other with a cen-
troid to centroid distance of 3.872(3)Å, a perpendicular distance
between of 3.5074(10)Å and a slippage of 1.640 Å, Fig. 2.
In 4, which is not hydrated, the molecules are linked into chains
by a hydrogen bond between the amino H and the 4-oxo oxygen
atom reinforced by weak CAH. . .O interactions. CAH. . .
. . . stacking are also present, [23].
p and
p
p
3.4. X-ray structural characterization
4. Conclusion
3.4.1. Molecular dimensions and conformation
The chromone 2-carboxamide derivatives 4 and 5 were ob-
tained in moderate to high yields by either classic or microwave
reactions.
Compound 5 crystallized in the monoclinic space group C2/c as
a hemihydrate. The crystallization was carried out in methanol.
The ORTEP diagram for 5 together with the adopted numbering
scheme is shown in Fig. 1. The X-ray structure of 4 has been al-
ready published [23] and the data will be only used for compara-
tive discussion purpose. The molecule is made up of two
aromatic rings, a chromone ring and a benzyl ring connected by
an amide residue. The bond lengths between atoms of the amide
residue are within the average values obtained for phenylamides
[23].
The configuration of the molecule is thus given by the CAN rot-
amer of the amide that defines the position of the aromatic rings
with respect to one other: the molecule shows an anti-rotamer
configuration in which the oxygen atom of the amide is trans re-
lated with oxygen atom O2 of the chromone ring, allowing for
the establishment of an intramolecular hydrogen bond,
N2AH2ꢂ ꢂ ꢂO1 (geometric parameters given in Table 4), forming a
S(5) pseudo-ring [24]. The nitrogen atom N2 also acts as a donor
to the oxygen atom O3 of the water molecule linking the crystalli-
zation solvent to the chromone. In addition, there is a weak hydro-
gen bond linking the benzyl ring with the carboxamide O2 atom,
C(ortho)AHꢂ ꢂ ꢂO2 forming a pseudo S6 ring [24]. Compound 4 also
exhibits an intramolecular hydrogen bond between N2 and O1 as
well as the C216AH216ꢂ ꢂ ꢂO2 weak contact [23].
The combination of 1D, 2D and EIRS NMR techniques allowed
for full NMR 1H and 13C signal assignments. The compounds were
also characterized by Infrared spectroscopy and XRD.
The X-ray analysis shows the interplay between intramolecular
hydrogen and intermolecular hydrogen bonding in the molecular
conformation, factors which may influence drug effectiveness.
The data acquired from this study make a valuable addition to
our chromone database which will help the unambiguous identifi-
cation of the compounds in our arsenal of chromone compounds
thus providing a better understanding of the structure–activity
relationships of these compounds.
Acknowledgements
The authors thank the Foundation for Science and Technology
(FCT), Portugal (PTDC/QUI-QUI/113687/2009 and Pest/C-QUI/
UI0081/2011) and the grant of A. Gaspar (SFRH/BD/43531/2008).
Thanks are due to the staff at the National Crystallographic Service,
University of Southampton for the data collection, help and advice
[25].
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The dihedral angle between the best planes of the chromone
and the benzyl ring for 5 is 3.71(10)° but the clockwise torsions
of the aromatic rings around the N2AC211 and C2AC21 axis, for
the benzyl and the chromone rings respectively, are significantly
higher [the C3AC2AC21AO2 and the C21AN2AC211AC216 tor-
sion angles are of ꢃ11.9(4) and 11.5(4)°, respectively] showing that
the rings are not co-planar but they lie on nearly parallel planes.
Compound 5 is more planar than compound 4, in which the dihe-
dral angle between mean planes made between the chromone and
the benzyl ring atoms is 11.05(5)°.
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