Synthesis, NMR characterization, X-ray structural analysis and theoretical calculations of amide and ester derivatives of the coumarin scaffold

Article abstract of DOI:10.1016/j.molstruc.2013.03.014

Compounds 1 (4-methyl-N-(coumarin-3-yl)benzamide) and 2 ((coumarin-3-yl)-4-methylbenzoate) were synthesized by linking the coumarin system (3-aminocoumarin or 3-hydroxycoumarin, respectively) to a p-toluoylchloride. ¹H and ¹³C NMR and X-ray diffractometry determined the molecular structures of both derivatives. The X-ray results were compared to those obtained by conformational analysis followed by semiempirical methodologies (AM1 and PM3). The theoretical calculations yielded results reproducing the whole three-dimensional (3D) structure of both molecules in a good agreement with X-ray structural analysis. The global structures of the two compounds are very similar in the two studied environments, meaning that the structural determination in the gas phase can be extrapolated. A comparative study between compounds 1 and 2, based on the structural results, was carried out.

Full text of DOI:10.1016/j.molstruc.2013.03.014

Journal of Molecular Structure 1041 (2013) 144–150
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, NMR characterization, X-ray structural analysis and theoretical
calculations of amide and ester derivatives of the coumarin scaffold
⇑
Maria J. Matos , Eugenio Uriarte, Lourdes Santana, Santiago Vilar
Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
g r a p h i c a l a b s t r a c t
h i g h l i g h t s
ꢀ
Compound 1 (4-Methyl-N-
(coumarin-3-yl)benzamide) was
synthesized.
ꢀ
ꢀ
Compound 2 (coumarin-3-yl)-4-
methylbenzoate was synthesized.
1H and 13C NMR and X-ray
diffractometry determined the
molecular structures.
ꢀ
ꢀ
Semiempirical calculations presented
an alternative to determine the 3D
structures.
AM1 and PM3 yielded results
reproducing the whole 3D structure
of both molecules.
a r t i c l e i n f o
a b s t r a c t
Article history:
Compounds 1 (4-methyl-N-(coumarin-3-yl)benzamide) and 2 ((coumarin-3-yl)-4-methylbenzoate) were
synthesized by linking the coumarin system (3-aminocoumarin or 3-hydroxycoumarin, respectively) to a
p-toluoylchloride. 1H and 13C NMR and X-ray diffractometry determined the molecular structures of both
derivatives. The X-ray results were compared to those obtained by conformational analysis followed by
semiempirical methodologies (AM1 and PM3). The theoretical calculations yielded results reproducing
the whole three-dimensional (3D) structure of both molecules in a good agreement with X-ray structural
analysis. The global structures of the two compounds are very similar in the two studied environments,
meaning that the structural determination in the gas phase can be extrapolated. A comparative study
between compounds 1 and 2, based on the structural results, was carried out.
Received 5 February 2013
Received in revised form 6 March 2013
Accepted 6 March 2013
Available online 19 March 2013
Keywords:
Coumarin derivatives
Synthesis
X-ray structural analysis
NMR analysis
Ó 2013 Elsevier B.V. All rights reserved.
Conformational analysis
Semiempirical calculations
1. Introduction
tives, focusing on those targets. Coumarin (2H-1-benzopyran-2-
one) is a natural compound that can be found in several plants like
The complex etiology and the actual prevalence of neurodegen-
erative diseases have led to an intensive search for compounds that
interact with some specific receptors. In particular, in our research
group we have paid special attention to compounds that can inhi-
bit monoamine oxidase B (MAO-B isoform) and acetylcholinester-
ase (AChE) enzymes. In the last years we are synthesizing and
studying an important family of compounds, the coumarin deriva-
tonka bean, vanilla grass and sweet woodruff [1–3]. Derivatives of
this benzopyrone are of pharmaceutical interest because they have
been showing different important biological activities [1–3]. Cou-
marins have been described as anticancer, anti-inflammatory, anti-
microbial, cardioprotective, vasorelaxant and antioxidant agents
[4–13]. Furthermore, several coumarins showing a significant
MAO inhibitory activity, in some cases accompanied by AChE
inhibitory activity, have been reported by our research group,
and some of them are suggested as potential drugs with applica-
tion on neurodegenerative diseases [14–20]. Due to the biological
importance of these derivatives, the synthesis and characterization
⇑
Corresponding author. Tel.: +34 881 814 936.
E-mail addresses: mariacmatos@gmail.com (M.J. Matos), eugenio.uriarte@usc.es
(E. Uriarte), lourdes.santana@usc.es (L. Santana), qosanti@yahoo.es (S. Vilar).
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.03.014

M.J. Matos et al. / Journal of Molecular Structure 1041 (2013) 144–150
145
Scheme 1. Synthesis of compounds 1 and 2. Reagents and conditions: Pyridine, dicloromethane, 0 °C to r.t., 4 h.
Table 1
Crystal data and structure refinement parameters for compounds 1 and 2.
Compound 1
Compound 2
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
C17H13NO3
279.28
100(2) K
0.71073 Å
Triclinic
C17H12O4
280.27
100(2) K
0.71073 Å
Triclinic
P-1
P-1
Unit cell dimensions
a = 7.9932(4) Å,
a
= 113.893(3)°
a = 6.7771(7) Å, a = 91.563(8)°
b = 9.2074(6) Å, b = 97.003(3)°
b = 7.0925(9) Å, b = 91.436(7)°
c = 10.3711(7) Å,
667.43(7) Å3
2
c
= 101.145(3)°
c = 13.9318(18) Å,
654.49(14) Å3
2
c = 101.984(7)°
Volume
Z
Density (calculated)
Absorption coefficient
F(0 0 0)
1.390 Mg/m3
0.096 mmꢁ1
292
1.422 Mg/m3
0.102 mmꢁ1
292
Crystal size
Theta range for data collection
Index ranges
0.38 ꢂ 0.30 ꢂ 0.25 mm3
0.47 ꢂ 0.37 ꢂ 0.14 mm3
2.20–26.37°
2.93–26.02°
ꢁ9 6 h 6 9, ꢁ11 6 k 6 10, 0 6 l 6 12
9965
2715 [R(int) = 0.0326]
99.6%
Semi-empirical from equivalents
0.9773 and 0.8884
Full-matrix least-squares on F2
2715/0/196
ꢁ8 6 h 6 8, ꢁ8 6 k 6 8, 0 6 l 6 17
14,492
2573 [R(int) = 0.0479]
99.8%
Semi-empirical from equivalents
1.0000 and 0.9573
Full-matrix least-squares on F2
2573/0/191
Reflections collected
Independent reflections
Completeness to theta = 26.37°
Absorption correction
Max. and min. transmission
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
Largest diff. peak and hole
1.078
1.084
R1 = 0.0445, wR2 = 0.1049
R1 = 0.0622, wR2 = 0.1132
0.218 and ꢁ0.271 e Åꢁ3
R1 = 0.0438, wR2 = 0.1045
R1 = 0.0610, wR2 = 0.1127
0.237 and ꢁ0.259 e Åꢁ3
of coumarins is a topic of interest. The interaction between a spe-
cific molecule, a drug candidate, and a receptor occurs through rec-
ognition between the different compounds involved. An important
step in the study of molecular interaction processes is the determi-
nation of the structure of the potential drugs. This means carrying
out an analysis of the spatial arrangement of the different atomic
groups and their chemical properties. In this way, the first step
must be to obtain information about the intramolecular features
responsible for the 3D structure of the molecule under study. The
X-ray structure is an important tool to better understand the inter-
action of the compound with the active site of the enzyme.
According to the latest findings related to the conformational
preferences of these molecules, it is interesting to investigate the
3-D structure of novel 3-substituted coumarins by using both exper-
imental and theoretical approaches. Computational approaches can
offer an alternative solution to determine the three-dimensional
molecular structure of the compounds under study. Depending on
the molecular complexity and the precision required for the study,
different types of calculations can be carried out. Molecular mechan-
ics methods [21] could be appropriate for the calculation of the 3-D
structure of large molecules while more accurate quantum mechan-
ical methods, such as ab initio calculations [22], would require long
periods of time making the complexity of the calculations a limiting
factor to be applicable in large systems. An intermediate level of
accuracy is provided by the so-called semiempirical quantum chem-
ical calculations that use some parameters from empirical data [23].
Among these methods, the rapid, inexpensive and user-friendly
AM1 and PM3 are probably two of the most popular methodologies
[24,25]. The analysisof semiempirical methodsresults is an interest-
ing tool for reproducing the experimental geometry of specific mol-
ecules for further studies directed to the molecular modeling and
design of active molecules.
In the current work described here, experimental and theoreti-
cal structural analysis of two synthesized 3-substituted coumarin
derivatives, presenting at that position an amide (compound 1)
or an ester (compound 2), were undertaken. Their structures were
characterized by experimental methods such as NMR spectrometry
and were finally determined by X-ray diffractometry and theoret-
ical calculations combining conformational analysis with AM1 and
PM3 methods. The comparison between the theoretical and the
crystal structure for both compounds showed a high level of simi-
larity. This fact manifested the capability of the theoretical meth-
ods to reproduce the experimental molecular geometry being an
alternative methodology to obtain three-dimensional information
when the crystal structure is not available.
2. Experimental section
2.1. Material and measurements
Melting points were determined using a Reichert Kofler ther-
mopan or in capillary tubes on a Büchi 510 apparatus and are

146
M.J. Matos et al. / Journal of Molecular Structure 1041 (2013) 144–150
Fig. 1. Molecular structures of compounds 1 and 2 with the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level.
uncorrected. 1H and 13C NMR spectra were recorded on a Bruker
AMX spectrometer at 300 and 75.47 MHz, respectively, using TMS
as internal standard (chemical shifts in d values, J in Hz) and
DMSO-d6 as solvent. Mass spectra were obtained using a Hewlett
Packard 5972-MSD spectrometer. Elemental analyses were per-
formed using a Perkin–Elmer 240B microanalyser and were with-
in 0.4% of calculated values in all cases. Silica gel (Merck 60,
230–00 mesh) was used for flash chromatography (FC). Analytical
thin layer chromatography (TLC) was performed on plates pre-
coated with silica gel (Merck 60 F254, 0.25 mm). The purity of
compounds was assessed by HPLC and was found to be higher
than 95%.

M.J. Matos et al. / Journal of Molecular Structure 1041 (2013) 144–150
147
Fig. 2. Superposition of the crystal structure (grey carbons) and the theoretical conformations (green carbons) obtained through AM1 (panels a and c) and PM3 (panels b and
d) for compounds 1 and 2. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
124.98 (C-8); 125.39 (C-4a); 128.71 (C-4); 129.45 (C-10); 129.93
Table 4
RMSD between the conformations obtained through theoretical methods and the X-
ray structures for compounds 1 and 2. RMSD values are shown for distances [Å], bond
angles [°], dihedral angles [°] and the heavy atoms coordinates (hydrogens were not
taken into account).
(C-6); 130.23 (C-5); 131.47 (C-7); 132.30 (C-30, C-50); 134.27 (C-
20, C-60); 135.71 (C-3); 137.65 (C-40); 145.51 (C-8a); 159.21 (C-2);
163.77 (OAC@O). EI MS m/z (%): 280 (M+, 8), 119 (100), 91 (29),
77 (8), 65 (12). Elem. Anal. Calc. for C17H12O4: C, 70.58; H, 4.10.
Found: C, 70.60; H, 4.13.
Compound 1
Compound 2
RMSD
Distance
Angles
Dihedral angles
Heavy atoms coordinates
AM1
0.014
1.79
9.02
0.254
PM3
0.015
2.56
15.41
0.369
AM1
PM3
0.015
2.010
3.584
0.178
0.011
2.521
4.507
0.246
2.3. X-ray data collection and reduction
Pale yellow prismatic crystals of compounds 1 (C17H13NO3)
and 2 (C17H12O4) were mounted on a glass fiber for data collec-
tion. Cell constants and orientation matrix were obtained by
least-squares refinement of the diffraction data for 9965 and
14,492 reflections in the range of 2.20–26.37° and 2.93–26.02°,
respectively, measured on a Bruker APEX2 [26]. Data were col-
Table 5
Hydrogen bonds for compound 1 [Å and °].
DAHꢃ ꢃ ꢃA
N(12)–H(12)ꢃ ꢃ ꢃO(11)#1
d(DAH)
d(Hꢃ ꢃ ꢃA)
2.498(18)
d(Dꢃ ꢃ ꢃA)
3.2711(17)
<(DHA)
154.4(15)
lected by the
x scan technique at 100 K using radiation
0.835(17)
(k = 0.71073 Å), and were corrected for Lorentz and polarization ef-
fects. The crystal data and structure refinement were detailed in
Table 1 (compounds 1 and 2, respectively). A semiempirical
absorption correction was also performed.
Symmetry transformations used to generate equivalent atoms: #1 ꢁx + 1, ꢁy,
ꢁz + 1.
2.2. Synthesis of compounds 1 and 2
2.4. Structure solution and refinement
Compounds 1 and 2 (Scheme 1) were prepared according to the
protocol described by us [16]. Detailed protocol is described in
Supplementary data.
The structures were solved by direct methods [27], which re-
vealed the positions of all non-hydrogen atoms, and were refined
on F2 by a full-matrix least-squares procedure using anisotropic
displacement parameters. The program used to refine the struc-
tures was SHELXL97 [28]. All hydrogen atoms were located from
difference Fourier maps and were refined isotropically. Atomic
scattering factors were taken from International Tables for X-ray
Crystallography [29]. Molecular graphics were generated with Pla-
ton [30]. Finally, the software used to prepare material for publica-
tion was WinGX publication routines [31]. A summary of the
crystals data, experimental details, and refinements results is given
in Table 1.
4-Methyl-N-(coumarin-3-yl)benzamide (1). Pale yellow crys-
tals. Mp 187–188 °C. 1H NMR: 2.49 (s, 3H, CH3); 7.33 (s, 1H, H-
4); 7.38 (d, 2H, J = 7.6 Hz, H-6, H-8); 7.50 (d, 2H, J = 8.5 Hz, H-30,
H-50); 7.76 (d, 1H, J = 7.6 Hz, H-7); 7.83–7.88 (m, 3H, H-20, H-5,
H-60); 8.62 (s, 1H, NH). 13C NMR: 21.32 (CH3); 116.35 (C-8);
119.75 (C-4a); 124.57 (C-8a); 125.49 (C-4); 126.62 (C-5); 126.81
(C-6); 127.94 (C-20,C-60); 128.45 (C-7); 129.64 (C-30, C-50); 130.59
(C-10); 130.98 (C-3); 130.92 (C-40); 143.04 (C-2); 1450.53
(NHAC@O). DEPT: 21.32 (CH3); 116.35 (C-8); 125.49 (C-4);
126.62 (C-5); 126.81 (C-6); 127.94 (C-20, C-60); 128.45 (C-7);
129.64 (C-30, C-50). EI MS m/z (%): 280 (9), 279 (M+, 50), 239
(20), 134 (23), 112 (20), 98 (42) Elem. Anal. Calc. for
C17H13NO3: C, 73.11; H, 4.69. Found: C, 73.09; H, 4.65.
2.5. Theoretical calculations
(Coumarin-3-yl)-4-methylbenzoate (2). Pale yellow crystals.
Mp 168–169 °C. 1H NMR: 2.43 (s, 3H, CH3); 7.44 (d, 2H,
J = 7.5 Hz, H-6, H-8); 7.51 (d, 2H, J = 8.1 Hz, H-30, H-50); 7.64 (d,
1H, J = 7.4 Hz, H-7); 7.75 (d, 1H, J = 7.6 Hz, H-5); 8.0 (d, 2H,
J = 8.2 Hz, H-20, H-60); 8.20 (s, 1H, H-4). 13C NMR: 21.30 (CH3);
A stochastic conformational search was carried out with the
help of MOE software [32]. Partial charges were calculated using
MMFF94 force field. The RMS gradient was 0.005 with an interac-
tion limit of 500. The conformations with the lowest energy were
representative of the calculation and were optimized with MOPA-

148
M.J. Matos et al. / Journal of Molecular Structure 1041 (2013) 144–150
a
c
ORIG
Fig. 3. Packing diagram of both structures viewed along the b axis.
C in the Schrödinger package [33,34] using AM1 and PM3 semiem-
pirical methods. The calculations were carried out in gas phase.
sponding benzoyl chloride (Scheme 1). Examination of the infor-
mation obtained from the NMR spectra enabled us to assign the
chemical shifts of the different protons and carbons for both com-
pounds. Also, the molecular structures of both compounds were re-
solved by X-ray diffractometry and are shown in Fig. 1, together
with the atomic numbering scheme used.
As it can be observed in Fig. 1, both molecules adopted some
similar aspects in the conformation of the crystal. Both coumarin
nucleuses and aromatic rings attached to the amidic or the ester
3. Results and discussion
Compound 1 was prepared in 71% yield, by amidation reaction
of the 3-aminocoumarin with the corresponding benzoyl chloride
(Scheme 1) [16]. Compound 2 was prepared in 69% yield, by an
esterification reaction of the 3-hydroxycoumarin with the corre-

M.J. Matos et al. / Journal of Molecular Structure 1041 (2013) 144–150
149
bridges in both molecules are planar, as expected. The main differ-
ence between the molecular structures of compounds 1 and 2 is
that in the first case the substitution at position 3 of the coumarin
scaffold is almost aligned with the substituent, and in the second
case it is almost perpendicular to it. The torsion angles between
the mean planes of compound 1 C4–C3–N12–C13 (ꢁ5.7°), C3–
N12–C13–C15 (ꢁ179.68°) and N12–C13–C15–C20 (ꢁ171.17°) are
typical of the torsion permitted by the rotation of the amidic group
at position 3. The torsion angles between the mean planes of com-
pound 2 C4–C3–O12–C13 (ꢁ72.52°), C3–O12–C13–C15 (171.82°)
and O12–C13–C15–C16 (ꢁ4.95°) are typical of the torsion permit-
ted by the rotation of the ester group at position 3. The greatest
conformational freedom of the molecules resides, therefore, in
the amidic bridge of compound 1 and in the ester bridge of com-
pound 2, composed by C3–N12–C13–C15 and C3–O12–C13–C15,
respectively.
similar reproduction of the bond lengths whereas AM1 calculation
afforded more coincident results with the crystal for angles and
dihedral angles (see Table 4). However, the results described in this
article do not justify the selection of one of the methods. Similar
results comparing the X-ray and theoretical conformations in
piperazine and coumarin derivatives were previously reported by
our research group [24,25].
Another important structural feature, which distinguishes the
studied molecules, is the capacity of formation of N(12)–
H(12)ꢃ ꢃ ꢃO(11) intermolecular hydrogen bonds of compound 1, de-
tailed in Table 5. The presence of these hydrogen bonds and the
conformation of the substituent at position 3 of the coumarin nu-
cleus, distinguish the packing diagram of both molecules. Packing
diagram of the structures allows the interpretation of the spatial
orientation of the molecules and are shown in Fig. 3.
In addition, many interesting intramolecular contacts are pres-
ent in both compounds. In particular, looking to Fig. 1 compound 1
shows interesting C4Hꢃ ꢃ ꢃO14, C20Hꢃ ꢃ ꢃO14 contacts while com-
pound 2 shows a C16Hꢃ ꢃ ꢃO12 contact. Moreover in compound 1
a short contact between two hydrogens (that bonded to C16, more
negatively charged and that bonded to N12 more positively
charged) is present. Some references about these contacts, referred
as non-conventional H-bond (Hꢃ ꢃ ꢃH and CHꢃ ꢃ ꢃO/N contacts), have
been already suggested and described [35,36].
Compound 1 is structurally similar to the compound described
by Jotani et al. [37]. The phenyl ring of that molecule (N-(2-oxo-
2H-chromen-3-yl)benzamide) forms a dihedral angle of 7.69° with
the fused ring system. In compound 1, as in that molecule, a dihe-
dral angel of 5.84° is formed between the phenyl ring and the fused
ring system. The observed conformation is also stabilized by the
described intramolecular NAHꢃ ꢃ ꢃO and CAHꢃ ꢃ ꢃO interactions. Dong
et al. also described amidic compounds structurally related with
these derivatives [38]. As described in that manuscript, the com-
plexity of the molecules (voluminous substituents – a benzyl group
at position 3 and a phenylamine at position 4) changed the related
position of the coumarin nucleus and the benzylamide at position
3.
4. Conclusion
In summary, we have determined and analyzed the entire struc-
tural parameters in the crystalline state of two coumarin deriva-
tives (with amide or ester functions at position 3), and proved
that the results are well reproduced by conformational analysis
and semiempirical AM1 and PM3 methods. Theoretical approaches
can be an alternative methodology to determine the 3D conforma-
tion for this type of derivatives when the crystal structure is not
available. We can also conclude that it is possible to modulate
the relative position of the coumarin scaffold and the aromatic ring
at position 3 by modifying the chemical substituent between both
moieties.
Acknowledgements
Partial financial support from Ministerio de Sanidad y Consumo
(PS09/00501) and Xunta de Galicia (PGIDIT09CSA030203PR) are
gratefully acknowledged. M.J.M. thanks Fundação para a Ciência
e Tecnologia (SFRH/BD/61262/2009) Grant. S.V. thanks the Angeles
Alvariño program from Xunta de Galicia (Spain).
Tables 2 and 3 (presented in Supplementary data) list the bond
lengths, bond angles and dihedral angles obtained for both com-
pounds 1 and 2, respectively, according to the X-ray analysis. The
results for the theoretical calculations (conformational analysis
with the refinement of the minimum energy structures through
AM1 and PM3 methods), for both compounds, are also included
in the tables.
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.molstruc.2013.03.014.
The final structures obtained through semiempirical methods
are highly coincident with the data extracted through X-ray. For
the compound 1, two possible conformational states are obtained
differing in the orientation of the 4-methylphenyl system regard-
ing the plane of the coumarin ring. The dihedral angle value for
O(14)–C(13)–C(15)–C(20) calculated through AM1 method can be
36.2 or ꢁ37.1 Å for the conformers. A conformational equilibrium
resulting in two different conformations was also obtained for
the compound 2 through the theoretical calculations. Both possible
conformational states differ in the orientation of the carbonyl
group regarding to the plane of the coumarin ring. The dihedral an-
gle value in C(3)–O(12)–C(13)–O(14) could be ꢁ7.7 or 7.2 Å for the
conformers (AM1 method). Fig. 2 shows the superposition of the
crystal structure and the conformations obtained through AM1
and PM3 for both compounds (conformers with a O(14)–C(13)–
C(15)–C(20) dihedral angle value of 36.2 for the compound 1 and
C(3)–O(12)–C(13)–O(14) dihedral value of ꢁ7.7 for the compound
2, using AM1 method). The comparison between the theoretical
and the crystal structure showed a high level of similarity. The
RMSD (root mean square deviation) values between the heavy
atoms coordinates are shown in Table 4. AM1 and PM3 yielded
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