Theoretical and experimental investigation of NMR, IR and UV-visible spectra of hydroxyl-substituted-4-chloromethylcoumarin derivatives

Article abstract of DOI:10.24820/ark.5550190.p010.982

UV-Visible, FTIR and NMR experimental and theoretical spectral results have been compared for five substituted-4-chloromethylcoumarin derivatives (6-OH, 7-OH, 6,7-di-OH, 7,8-di-OH and 5,7-di-OH-substituted-4-chloromethylcoumarins). The theoretical investigation was conducted using density functional theory (DFT), namely the M06-2X functional form with 6-311+G(2df,2p) basis set. The ¹³C-NMR and ¹H-NMR chemical shifts, vibrational spectra and molecular orbitals of the excited states were calculated based on their optimized geometries. The calculated values were found to have close agreement with the experimental values. The theoretical data are useful and could be important in the proper selection of compounds as intermediates for different chemical applications and modifications.

Full text of DOI:10.24820/ark.5550190.p010.982

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Arkivoc 2019, vi, 0-0
Theoretical and experimental investigation of NMR, IR and UV-visible spectra of
hydroxyl-substituted-4-chloromethylcoumarin derivatives
a
a
b
b
Chutipapha Loarueng, Bundet Boekfa, Suwatchai Jarussophon, Pawinee Pongwan,
b
b
a
Narongpol Kaewchangwat, Khomson Suttisintong, and Nongpanga Jarussophon*
aDepartment of Chemistry, Faculty of Liberal Arts and Science, Kasetsart University, Kamphaeng Saen Campus,
Nakhon Pathom 73140, Thailand
b
National Nanotechnology Center, National Science and Technology Development Agency, 130 Thailand
Science Park, Paholyothin Road, Klong Luang, Pathumthani, 12120, Thailand
Email: faasngj@ku.ac.th
Received 05-22-2019
Accepted 08-25-2019
Published on line 09-22-2019
Abstract
UV-Visible, FTIR and NMR experimental and theoretical spectral results have been compared for five
substituted-4-chloromethylcoumarin derivatives (6-OH, 7-OH, 6,7-di-OH, 7,8-di-OH and 5,7-di-OH-substituted-
4
-chloromethylcoumarins). The theoretical investigation was conducted using density functional theory (DFT),
1
3
1
namely the M06-2X functional form with 6-311+G(2df,2p) basis set. The C-NMR and H-NMR chemical shifts,
vibrational spectra and molecular orbitals of the excited states were calculated based on their optimized
geometries. The calculated values were found to have close agreement with the experimental values. The
theoretical data are useful and could be important in the proper selection of compounds as intermediates for
different chemical applications and modifications.
Keywords: Coumarins, UV-Visible, FTIR, NMR, MO theory, HOMO-LUMO, density functional theory, DFT
DOI: https://doi.org/10.24820/ark.5550190.p010.982
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Introduction
Coumarin derivatives are classified as part of the benzopyrone family, aromatic compounds which comprise
bicyclic systems containing a benzene ring fused to an α-pyrone ring. Coumarin derivatives are present in many
naturally-occurring products, including tonka beans and sweet clover, and there has been a growing interest in
1
their synthesis. Coumarin derivatives have been used widely as additives in the drug, food and cosmetic
industries. From a medicinal perspective, their derivatives have exhibited various intriguing biological activities
including anti-HIV, antimicrobial, anticancer, anti-inflammatory, anticoagulant, anticonvulsant, and antioxidant
2
,3
properties. The biological and pharmacological activities, and effective bioactivity in therapeutic applications
of coumarin derivatives have been shown to be dependent upon the substitution patterns on the basic coumarin
structure.4 Therefore, the substitution patterns may be used to modify the ring system for maximum
pharmacological and therapeutic benefit.
,5
Recently, the coumarin chromophore core structure has been used as a photo-labile protective group for
6
,7
carboxylates. This could present a significant investigational opportunity for controlling the release of several
active ingredients in agrochemical applications.8-10 In addition, a long alkoxy hydrophobic side chain (C16) has
1
1
been introduced to promote better adhesion of amphiphilic compounds applied on plant leaves.
-Chloromethylcoumarin derivatives act as good starting materials that could be simply enhanced to
4
produce a large number of coumarin derivatives based on the desired physical properties needed. A number of
studies of the spectroscopic and calculated-data results of this compound are intriguing.
The utilization of density functional theory (DFT) to calculate and optimize molecular structures of
compounds, energies of chemical reactions, absorption energy and the scale value of harmonic vibrational
1
2-15
frequencies has been widely used in comparisons with the outputs from experimental results.
DFT
calculations have been accepted by the quantum chemistry community based on the highly efficient predictions
resulting from these computational approaches. Additionally, calculations of UV-Visible, FTIR and NMR
spectroscopic properties were determined using DFT methodology. Good agreement was observed between
1
6
the experimental and theoretical data. Al-Bayati and co-workers studied a solvent-free synthesis of new
coumarins characterized by UV-Visible, FTIR and NMR spectroscopic methods with the theoretical estimation of
1
7
atomic charges, heat of formation, and stereochemistry. Irfan and co-workers studied the geometries of
1
8
ground and excited states, excitation energies and UV absorption spectra of a variety of coumarin derivatives.
Similar to the work of Preat et al., their investigation used a time-dependent density functional theory (TD-DFT)
1
9
approach. Regulska and co-workers studied alkali metal phenoxyacetates for theoretical- and experimental-
2
0
data comparisons involving spectroscopic properties. Costa and co-workers studied the combined
experimental and structural, vibrational, and electronic properties theoretical data of glucoalkaloid
2
1
strictosidine. In order to sufficiently compare the experimental results with high-level calculations, appropriate
computational-approach methods should be investigated until the structures are optimized based on calculated
spectroscopic properties.
In our study, five coumarin derivatives, 4-chloromethyl-6-hydroxyl-coumarin, 4-chloromethyl-7-hydroxyl-
coumarin, 4-chloromethyl-6,7-dihydroxyl-coumarin, 4-chloromethyl-7,8-dihydroxyl-coumarin and 4-
chloromethyl-5,7-dihydroxyl-coumarin were synthesized using several chemical reaction conditions. The UV-
Visible, FTIR and NMR spectroscopic properties were measured and calculated to compare the experimental
and theoretical methods. The DFT M06-2X/6-311+G(2df,2p) basis set was used in this study to calculate the
theoretical data.
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Results and Discussion
Calculated Data. The chemical structures of 4-chloromethyl-6-hydroxyl-coumarin (compound A), 4-
chloromethyl-7-hydroxyl-coumarin (compound B), 4-chloromethyl-6,7-dihydroxyl-coumarin (compound C), 4-
chloromethyl-7,8-dihydroxyl-coumarin (compound D) and 4-chloromethyl-5,7-dihydroxyl-coumarin (compound
E) are shown in Figure 1. The geometry-optimization data of compounds A, B, C, D and E were calculated using
the M06-2X/6-311 + G (2df, 2p) basis set.
Figure 1. Chemical structures of coumarin compounds (A, B, C, D and E).
Those data were compared with UV-Vis, FTIR and NMR spectra obtained from the experimental results.
Initially, the bond lengths were assigned for the five coumarin structures. We have observed the shortest bond
length of C−H bonds for all of five coumarin compounds has a value ranging from 0.96-1.09 Å. The C−C bond
length of the polycyclic aromatic rings were found to be in the range of approximately 1.35-1.50 Å; the values
were almost identical. Moreover, it was found that the longest bond length of all five coumarin compounds
observed belonged to the C−Cl bond. The C−Cl bonds of all compounds (A, B, C, D and E) were demonstrated to
have a distance of approximately 1.80 Å [see Table S1 in Supplementary Materials (SM)]. Comparing the
optimized energies of the mono-hydroxyl-substituted coumarin isomers A and B, isomer B had a slightly lower
-1
energy value than isomer A, with an energy difference of 1.94 Kcal mol . Among the di-hydroxyl-substituted
coumarins (isomers C, D and E), the lowest energy value was found in isomer C. The different energy values
-1
between isomers C and D, and isomers C and E, were 3.01 and 0.83 Kcal mol , respectively. Moreover, the
structures of compounds A and B showed lower energy values compared with the di-hydroxyl-substituted
coumarins (C – E) and represented the more stable of the optimized structures (see Table S2 in SM). The atomic
Mulliken charges were analyzed from our calculated results. The regions of the aromatic ring occupied by the
hydroxyl groups of each compound tended to have greater electron density than the regions of the lactone
groups (see Table S3 in SM). The electron-density distributions of all five coumarin derivatives were also
generated in detail (see Table S4 in SM). This inductive-effect phenomena could be explained in good agreement
with the theoretical assumptions.
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Table 1. Experimental and theoretical maximum-absorption wavelength (λmax), oscillator strength (ƒ) and
excitation energies (E) of coumarin derivatives by TD-DFT method
Exp.
Calc.
Compound*
λ
max
λ
max
E (eV)
ƒ
Solvent used
(
nm)
(nm)
356
329
350
322
325
A
B
C
D
E
352
330
348
331
329
4.0681
4.3984
4.1293
4.4939
4.4505
0.1272
0.3016
0.2644
0.2327
0.3081
Methanol
Methanol
Methanol
Methanol
Methanol
*
*
Calculated values were multiplied with the scaling factor in comparison with compound A
For coumarin compounds refer to Figure 1
Ultraviolet-visible spectral assignments. As a molecule absorbs energy, an electron is promoted from an
occupied molecular orbital (usually a non-bonding n or bonding π orbital) to an unoccupied molecular orbital
∗
∗
(
an antibonding π or σ orbital) of greater potential energy. In the absorption spectra evaluation studies, each
of the five coumarins were compared using experimental and computational approaches. Preat and co-workers
also studied the UV absorption spectra of substituted coumarins in which the substitution positions, labeled as
5
-Me, 7,8 di-OH and 6,7-OH, showed as 308, 334 and 337 nm, respectively. This was investigated using a
1
9
theoretical method with B3LYP/6-311+G (2d, 2p) basis level. In our case, all five purified coumarin compounds
were obtained from the chemical synthesis of mono- and di-hydroxyphenols and ethyl 4-chloroacetoacetate.
The experimental λmax values of the compounds A, B, C, D and E (in methanol) were found at 352, 330, 348, 331
and 329 nm, respectively. The absorption spectra for all of the coumarin compounds were calculated based on
ground-state geometries. The simulated λmax values obtained by the theoretical approach via TD-DFT and M06-
2X functionality with 6-311 + G (2df, 2p) as the basis set, presented at 356, 329, 350, 322 and 325 nm,
respectively (Table 1). The λmax values of both experimental and calculated results indicated great agreement
between both data sets. Typically, for substituents with unshared electrons of an aromatic compound, the non-
bonding electrons increase the length of the π-system through resonance, and shift the primary and secondary
absorption bands to longer wavelengths. In fact, the presence of the hydroxyl-group substitution at the C-6
position of compounds A and C showed the higher absorption when compared to each of their similarly-
substituted compounds. This may be due to a lone-pair-electron delocalization effect of an auxochrome
(hydroxyl group) on the aromatic ring causing a bathochromic shift. The frontier molecular orbital energies of
compounds A, B, C, D and E are listed in Table 2; the plot surfaces of the molecular orbitals are shown in Table
S4, pp S9-13, in the Supplementary Material. The highest occupied MO (HOMO) energy levels of compounds A,
B, C, D and E were -0.32, -0.32, -0.31, -032 and -0.32 eV, respectively. The lowest unoccupied MO (LUMO) energy
levels were 0.05, 0.06, 0.05, 0.06 and 0.06 eV, respectively. This finding was supported by the fact that the higher
electron density of the OH group at C-6 found in compounds A and C showed a lower energy level of LUMO
(0.05 eV). Thus, it presented a higher absorbance and narrow-energy levels. Conversely, the absence of an OH
group at C-6 of the coumarin compounds B, D, and E resulted in a higher energy level of LUMO (0.06 eV). The
HOMO-LUMO energy gaps were calculated using HF/3-21g. In addition, our calculations confirmed the lowest
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excitation energy for compounds A and C, compared to their di-OH analogues, at 4.0681 and 4.1293 eV,
respectively. In addition, the oscillator strengths (ƒ) were also predicted as shown in Table 1.
Table 2. Calculated energy levels of HOMO, LUMO and energy gap (eV).
Compound A
-0.45
Compound B
-0.44
Compound C
-0.44
Compound D Compound E
H - 3
H - 2
H -1
H
-0.44
-0.42
-0.33
-0.32
0.06
0.13
0.15
0.21
-0.38
-0.44
-0.42
-0.35
-0.32
0.06
0.13
0.15
0.22
-0.38
-0.43
-0.36
-0.32
0.05
0.13
0.14
0.20
-0.37
-0.42
-0.36
-0.32
0.06
0.12
0.14
0.20
-0.38
-0.42
-0.36
-0.31
0.05
0.13
0.14
0.20
-0.36
L
L + 1
L + 2
L + 3
Gap
Vibrational-frequency and intensity assignments. The computed frequencies and intensities of all coumarin
derivatives were determined theoretically using M06-2X/6-311 + G (2df, 2p) functionality as shown in Table 3.
The differences of the calculated vibrational frequencies of the coumarin compounds were compared with the
associated monitored experimental FTIR data. A scaling factor of the calculated FTIR spectrum at 0.9489 (M06-
2X 6-311++G(d,p)) was applied to these vibrational frequencies for the DFT. In addition to the bond strength
and atomic masses, the vibrational frequency of a bond is also significantly affected by the electronic and steric
factors of the surroundings. Considering the vibrational frequencies of OH-stretching, the exact position and
shape of this band depends largely on the degree of H-bonding. A medium-to-strong absorption band from 3700
-1
to 3400 cm is a strong indication that the sample is an alcohol or phenol. A sharp peak typically occurring in
gaseous or extremely dilute solutions represents unbound or free OH group(s) while alcohols and phenols in
condensed phases are typically strongly hydrogen bonded, causing broadened bands at lower frequencies. Our
calculated results predicted OH-stretching frequencies of all five hydroxyl-substituted coumarins at lower
-
1
-1
frequencies (2964-3030 cm ) than the actual experimental results (3111-3294 cm ). The frequency differences
-1
are approximately in the range of 150-250 cm . The strongest and sharpest band belonging to C=O stretching
absorption, however, could be calculated to be around 1767-1774 cm , which are higher frequencies than our
experimental results (1652-1695 cm ). Our predictions of OH-stretching and C=O stretching absorption bands
seem not to be accurate when the H-bonding (inter- and intramolecular) resonance effects are involved. The
precise predictions of frequencies could be coming from C−C stretching, C=C stretching and C−Cl stretching.
-1
-1
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-1
-1
Table 3. Experimental and theoretical harmonic frequencies (cm ) and intensities (Km mol ) assignments for coumarin derivatives.
Compound A
Exp. Calc. Int.
Compound B
Compound C
Exp. Calc. Int.
(cm ) (cm )
Compound D
Compound E
Exp.
(cm )
3294
Calc.
(cm )
3030
Int.
5
Exp.
(cm ) (cm )
Calc.
Int.
5
Exp.
(cm ) (cm )
3111 2964
Calc.
Int.
7
Assignment
-1
-1
-1
-1
-1
-1
-1
-1
-1
-1
(
cm )
(cm )
3027
3229
4
5
3272
094
2971
738
3022
3
5
3170
3017
O−H stretch
=C−H stretch
−C−H stretch
C=O stretch ester
C=O stretch
3
3090
2969
2976
2952
2942
2947
5
2953
2953
5
1
1738
1665
1579
1437
1768 794
1572 102
1429 213
1695
1606
1558
1774
1620
1556
753
106
145
1659
1621
1767 805 1665
1566 235 1610
1768 748 1652 1771 769
1617 153 1594 1618 295
C=C stretch
1582
1389
1227
1505 112 1585
1433 183 1512
1292 337 1311
1580
1493
91
75
1459 1439 120
1369
Aromatic ring
stretch
C−O stretch
1
449
1
232
175
1312
1137
818
1286
802
226
36
1290 202 1260 1231 151
1169
1
1038
861
818
28
865
861
33
851
790
28
827
824
51
C−Cl stretch
*
Int. = intensity
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NMR experimental and theoretical results. The structure of an organic compound may be analyzed and
identified by NMR spectroscopy that is capable of assigning the carbon skeleton and adjoined hydrogen atoms.
The atomic numbering of compounds A, B, C, D and E are assigned as shown in Figure 2. The experimentally
1
3
1
observed C NMR and H NMR chemical shifts of all five coumarin compounds, using DMSO-d as solvent and
6
TMS as internal reference, are presented in Table 4. The calculation of chemical shifts was carried out
theoretically using M06-2X/6-311+ G (2df, 2p) basis level.
Figure 2. The atomic numbering of 4-chloromethyl-6-hydroxyl-coumarin (compound A), 4-chloromethyl-7-
hydroxyl-coumarin (compound B), 4-chloromethyl-6,7-dihydroxyl-coumarin (compound C), 4-chloromethyl-7,8-
dihydroxyl-coumarin (compound D) and 4-chloromethyl-5,7-dihydroxyl-coumarin (compound E).
1
13
Table 4. Experimental (TMS as internal reference) and theoretical H and C chemical shifts (ppm), with
theoretical calculations utilizing the Gauge-Independent Atomic Orbital (GIAO) method.
compound A
compound B
compound C
compound D
compound E
Atom a
H1
H2
H3
H4
H5
H6
H7
C2
δ
exp
δ
cal
δ
exp
δ
cal
δ
exp
δ
cal
δ
exp
δ
cal
δ
exp
δ
cal
7.30
7.09
9.85
7.15
4.98
4.98
6.66
8.04
7.91
4.37
7.73
4.63
4.27
6.92
6.74
10.66
6.83
7.66
4.94
4.94
6.41
8.59
4.64
7.20
8.59
4.73
4.22
6.75
6.79
10.39
9.46
7.13
4.91
4.91
6.41
7.69
5.96
4.35
7.76
4.62
4.26
6.77
10.18
9.38
6.81
7.14
4.90
4.90
6.38
5.35
4.37
7.22
7.95
4.70
4.30
6.77
6.27
10.42
6.21
10.89
5.02
6.81
4.55
6.54
4.89
5.32
3.96
6.56
5.02
6.23
159.9 172.2 161.5 171.9 160.5 172.8 160.1 171.7 161.5 171.7
115.6 138.6 113.2 133.0 109.4 134.2 110.1 134.4 108.8 132.3
153.8 170.9 155.4 171.6 150.7 171.4 151.4 172.6 156.5 173.6
109.6 124.1 126.6 146.6 108.9 123.2 115.5 132.9 160.1 174.4
C3
C4
C5
C6
150.3 171.2 109.4 125.7 142.9 154.6 111.0 123.3
99.2
111.0
C7
117.6 138.9 160.3 180.7 148.3 167.7 149.8 162.3 157.2 180.2
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Table 4. Continued
compound A
compound B
compound C
compound D
compound E
Atom a
C8
δ
exp
δ
cal
δ
exp
δ
cal
δ
exp
δ
cal
δ
exp
δ
cal
δ
exp
δ
cal
117.7 138.7 102.6 119.8 102.9 121.0 132.5 150.6
94.8
109.2
C9
146.6 167.6 151.1 177.5 150.6 170.7 143.7 161.5 152.1 179.0
C10
C11
120.3 134.3 111.1 126.1 111.2 125.1 112.3 128.7
41.4 47.6 41.4 47.7 41.6 48.6 41.5 47.5
99.8
45.00
114.3
51.2
a
For atomic numbering refer to Figure 2.
For the chemical shifts of the protons attached to the aromatic rings of the coumarin derivatives, the calculated
values tended to have slightly higher values (lower field) compared to the experimental values, i.e.,
approximately 0.4-0.7 ppm. In contrast, the chemical shifts of the protons at C-11 (chloromethyl group) from
1
the calculations were observed at higher fields compared to the observed values. The H chemical shifts of the
hydroxyl-hydrogens from the experiments appeared at lower fields (9-11 ppm.) while the computed chemical
shifts were in the range of 4-6 ppm. This may be due to the effects of intermolecular H-bonding of the coumarin
1
3
compounds in the media. In the case of the C chemical shifts, lower-field shifts were observed at C-2 and C-4
of all five coumarin compounds because of the electron-delocalization (resonance) effect of the electron-
withdrawing nature of the carbonyl group. In addition, the lower fields observed for the carbon attached to the
hydroxyl group at C5 - C9 were also observed in the range of 140-180 ppm depending on the hydroxyl-
1
3
substituted positions. The C chemical shifts of C-11 (CH −Cl), both from calculated and experimental results,
2
1
13
appear at around 40-50 ppm. The calculated H and C chemical shifts were predicted and in good agreement
with the experimental results.
Conclusions
In this study, the UV-Visible, FTIR and NMR spectra of five substituted chloromethylcoumarin derivatives were
compared using experimental and theoretical results. The calculated values of absorption, frequencies and
chemical shifts of hydrogen and carbon atoms of substituted-coumarin derivatives were found to be in close
agreement with the resulting experimental values. This work provides informative and useful spectroscopic-
data comparisons pertaining to intriguing synthetic chemical intermediates such as hydroxyl-substituted-4-
chloromethylcoumarin derivatives. This detailed data could be applied to the selection criteria of compounds
which could be used as intermediates for appropriate chemical modifications and applications. Further
investigations related to the chemical properties of these intermediates and other related derivatives, such as
amino-substituted-4-chloromethylcoumarins, are in progress.
Experimental Section
General. Hydroquinone (1,4-dihydroxybenzene), resorcinol (1,3-dihydroxybenzene), 1,2,3-trihydroxybenzene,
1
,2,4-trihydroxybenzene, 1,3,5-trihydroxybenzene, ethyl 4-chloroacetoacetate, methane sulfonic acid and
DMSO-d were purchased from Sigma–Aldrich. Sulfuric acid and ethanol were purchased from Carlo Erba. Other
reagents were directly used as obtained commercially. Coumarin compounds A, B, C, D and E were synthesized
6
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in our laboratory; all of the desired products were obtained as purified solids. All synthesized compounds were
characterized and recorded by spectroscopic techniques. UV-Visible absorption spectra were recorded on an
Agilent Cary Series UV-VIS-NIR spectrophotometer. FTIR spectra of the coumarin compounds were recorded on
-1
a Thermo Scientific™ model Nicolet 6700 spectrometer in ATR mode within the region of 4000 – 400 cm . Only
1
13
significant absorptions are listed. H NMR and C NMR spectra of the coumarin compounds in deuterated
1
13
dimethyl sulfoxide (DMSO-d ) solution were recorded on a Bruker AVANCE HD 500 MHz ( H: 500 MHz, C: 125
6
MHz) using tetramethylsilane (TMS) as an internal reference. The chemical shifts (δ) and coupling constants (J)
are expressed in ppm and Hz, respectively. Melting points were uncorrected and determined on a Büchi Melting
Point B-545 apparatus. High-resolution mass spectroscopy was performed on a Bruker Daltonics spectrometer
model MicrOTOF (ESI+mode) and reported with ion mass/charge (m/z) ratios as values in atomic mass units.
4-Chloromethyl-6-hydroxyl-coumarin (compound A). To a round-bottom flask, hydroquinone (5.5 g, 50 mmoL)
and methane sulfonic acid (75 mL) were mixed and then ethyl-4-chloroacetoacetate (8.2 g, 6.3 mL, 50 mmoL)
was added dropwisely. The resulting solution was allowed to stir at room temperature for 12 h. Then iced water
(400 mL) was added and stirred for an additional 6 h. The suspension was filtered and washed with cold water
several times. The obtained solid was recrystallized in ethanol and dried under vacuum overnight to give
-1
compound A as a white solid (6.9 g, 65%). mp 222-223 °C; FTIR (ATR, νmax, cm ): 3229 (O−H), 2976, 2941 (-C−H)
1
1
665 (lactone C=O), 1579 (C=C), 1437 (aromatic ring), 1232, 1175 (C−O), 861 (C−Cl); H NMR (500 MHz, DMSO-
d
6
): δ
H
4.98 (2H, s, CH Cl), 6.66 (1H, s, =CHC=O), 7.09 (1H, dd, J 8.9, 2.7 Hz, C7−H aromatic), 7.15 (1H, d, J 2.7 Hz,
2
1
3
C5−H aromatic), 7.30 (1H, d, J 8.9 Hz, C8−H aromatic), 9.85 (1H, br s, C6-OH); C NMR (125 MHz, DMSO-d
6
): δ
C
HEPES/MeOH (20/80)
-1
-1
41.4, 109.6, 115.6, 117.6, 117.7, 120.3, 146.6, 150.3, 153.8, 159.9; UV-Vis λmax
(ε M cm ) 226
ClO [M+H] , 211.0162; found,
4
4
4
+
(1.33 x 10 ), 278 (0.62 x 10 ), 352 (0.25 x 10 ) nm; HMRS (ESI): m/z calcd. for C10
H
8
3
2
4
11.0153.
-Chloromethyl-7-hydroxyl-coumarin (compound B). Resorcinol (5.29 g, 48 mmol) and ethyl-4-
SO (40 mL) and stirred at 0 °C for 2 h. Then
chloroacetoacetate (6.58 g, 5.4 ml, 40 mmol) were added to conc. H
2
4
ice and water (100 mL) were added, the suspension was filtered and washed with cold water. The obtained solid
was recrystallized in ethanol and dried under vacuum overnight to give compound B as a white solid (5.81 g,
2
3
-1
6
1
6
9%). mp 181-183 °C; FTIR (ATR, νmax, cm ): 3294 (OH), 2942 (-C−H) 1695 (lactone C=O), 1606 (C=C), 1558,
1
449 (aromatic ring), 1312 (C−O), 1137 (C−O), 818 (C−Cl); H NMR (500 MHz, DMSO-d
.41 (1H, s, =CHC=O), 6.74 (1H, d, J 2.0 Hz, C8−H aromatic), 6.83 (1H, dd, J 8.8, 2.0 Hz, C6−H aromatic), 7.66 (1H,
d, J 8.8 Hz, C5−H aromatic), 10.66 (1H, br s, C7-OH); C NMR (125 MHz, DMSO-d
13.2, 126.6, 151.1, 155.4, 160.3, 161.5; UV-Vis λmax
6
): δ
H
4.94 (2H, s, CH Cl),
2
1
3
6
): δ
C
41.4, 102.6, 109.4, 111.1,
HEPES/MeOH (20/80)
-1
-1
4
4
1
(ε M cm ) 217 (1.19 x 10 ), 330 (0.99 x 10 )
+
nm; HMRS (ESI): m/z calcd. for C10
H
8
ClO
3
[M+H] , 211.0162; found, 211.0164.
4-Chloromethyl-6,7-dihydroxyl-coumarin (compound C). 1,2,3-trihydroxybenzene (6.31 g, 50 mmoL) was
dissolved in conc. H SO (2 mL) and ethyl 4-chloroacetoacetate (8.23 g, 6.76 mL, 50 mmoL) was added to the
2
4
solution. The reaction mixture was stirred at 0 °C for 1 h. Then ice and water (100 mL) were added, the
suspension was filtered and washed with cold water. The obtained solid was recrystallized in ethanol and dried
-
under vacuum overnight to give compound C as a yellow solid (6.91 g, 61%). mp 265-266 °C; FTIR (ATR, νmax, cm
1
)
: 3272 (OH), 3094 (=C−H), 2971 (-C−H), 1738 (C=O), 1659 (lactone C=O), 1621 (C=C), 1582, 1389 (aromatic
1
ring), 1227 (C−O), 865 (C−Cl); H NMR (500 MHz, DMSO-d
6
): δ
H
4.91 (2H, s, CH Cl), 6.41 (1H, s, =CHC=O), 6.79
2
1
3
(
1H, s, C8−H aromatic), 7.13 (1H, s, C5−H aromatic), 9.46 (1H, br s, C6-OH), 10.39 (1H, br s, C7-OH); C NMR
HEPES/MeOH
(
125 MHz, DMSO-d
6
): δ
ε M cm ) 215 (1.63 x 10 ), 348 (1.11 x 10 ) nm; HMRS (ESI): m/z calcd. for C10
found, 227.0100.
C
41.6, 102.9, 108.9, 109.4, 111.2, 142.9, 148.3, 150.6, 150.7, 160.5; UV-Vis λmax
(
20/80)
-1
-1
4
4
+
(
H
8
ClO
4
[M+H] , 227.0111;
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Arkivoc 2019, vi, 0-0
Loarueng, C et al.
4-Chloromethyl-7,8-dihydroxyl-coumarin (compound D). 1,2,4-trihydroxybenzene (0.5 g, 3.96 mmoL) was
dissolved in conc. H SO (1 mL) and ethyl 4-chloroacetoacetate (0.65 g, 0.54 mL, 3.96 mmoL) was added to the
2
4
solution. The reaction mixture was stirred at 0 °C for 2 h. Then ice and water (50 mL) were added, the suspension
was filtered and washed with cold water. The obtained solid was recrystallized in ethanol and dried under
2
3
-
vacuum overnight to give compound D as a pale yellow solid (0.74 g, 82%). mp 198-200 °C; FTIR (ATR, νmax, cm
1
)
: 3170 (OH), 1738 (C=O), 1665 (lactone C=O), 1610 (C=C), 1585, 1512 (aromatic ring), 1311, 1038 (C−O), 851
4.90 (2H, s, CH Cl), 6.38 (1H, s, =CHC=O), 6.81 (1H, d, J 8.7 Hz, C6−H
aromatic), 7.14 (1H, d, J 8.7 Hz, C5−H aromatic), 9.38 (1H, br s, C7-OH), 10.18 (1H, br s, C8-OH); C NMR (125
1
(
C−Cl); H NMR (500 MHz, DMSO-d
6
): δ
H
2
1
3
HEPES/MeOH (20/80)
MHz, DMSO-d
6
): δ
C
41.5, 110.1, 111.0, 112.3, 115.5, 132.5, 143.7, 149.8, 151.4, 160.1; UV-Vis λmax
-1
-1
4
4
+
(ε M cm ) 217 (1.91 x 10 ), 331 (0.76 x 10 ) nm; HMRS (ESI): m/z calcd. for C10
H
8
ClO [M+H] , 227.0111; found,
4
227.0106.
4-Chloromethyl-5,7-dihydroxyl-coumarin (compound E). To round-bottom flask, 1,3,5-trihydroxybenzene (6.3
g, 50 mmoL) and methane sulfonic acid (75 mL) were mixed and then ethyl 4-chloroacetoacetate (8.2 g, 6.3 mL,
0 mmoL) was added dropwisely. The resulting solution was allowed to stir at room temperature for 6 h. Then
5
iced water (400 mL) was added and stirred for additional 6 h. The suspension was filtered and washed with cold
water several times. The obtained solid was recrystallized in ethanol and dried under vacuum overnight to give
2
3
-1
compound E as a white solid (11.6 g, 99%). mp 245-246 °C; FTIR (ATR, νmax, cm ): 3111 (OH), 3090 (=C−H),
2
1
969 (-C−H), 1652 (lactone C=O), 1594 (C=C), 1459, 1369 (aromatic ring), 1260, 1169 (C−O), 827 (C−Cl); H NMR
(
500 MHz, DMSO-d
6
): δ
H
5.02 (2H, s, CH Cl), 6.23 (1H, s, =CHC=O), 6.21 (1H, d, J 2.3 Hz, C6−H aromatic), 6.27
2
1
3
(1H, d, J 2.3 Hz, C8−H aromatic), 10.42 (1H, br s, C7-OH), 10.89 (1H, s, C5-OH); C NMR (125 MHz, DMSO-d
6
): δ
(ε M cm ) 217 (1.55
[M+H] , 227.0111; found, 227.0101.
C
HEPES/MeOH (20/80)
-1
-1
4
5.0, 94.8, 99.2, 99.8, 108.8, 152.1, 156.5, 157.2, 160.1, 161.5; UV-Vis λmax
4
4
+
x 10 ), 329 (1.05 x 10 ) nm; HMRS (ESI): m/z calcd. for C10
H
8
ClO
4
Computational Details. Initially, the 4-chloromethyl-6-hydroxyl-coumarin, 4-chloromethyl-7-hydroxyl-
coumarin, 4-chloromethyl-6,7-dihydroxyl-coumarin, 4-chloromethyl-7,8-dihydroxyl-coumarin and 4-
chloromethyl-5,7-dihydroxyl-coumarin were generated and optimized with a Gaussian 09 program. All
optimized structures were carefully checked to be the most stable structure at the optimized local structure.
Density functional theory (DFT) using the M06-2X functional approach was applied for this calculation. This
2
3
method was successfully applied to study the coumarin synthesis in the previous report. The basis set used
was 6-311+G(2df,2p). The time-dependent density functional theory (TD-DFT) and molecular orbital theory
1
3
1
were used to predict the adsorption-spectroscopy wavelengths. The C-NMR and H-NMR chemical shifts,
harmonic vibrational-frequency spectra, and molecular orbitals of the excited states were calculated based on
their optimized geometries using the Gauge-Independent Atomic Orbital (GIAO) method.
Acknowledgements
This work has been supported in part by grants from Graduate School Kasetsart University and Department of
Chemistry, Faculty of Liberal Arts and Science, Kasetsart University (Kamphaengsaen Campus).
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Arkivoc 2019, vi, 0-0
Loarueng, C et al.
Supplementary Material
Calculated geometrical parameters for bond-length distances, M06-2X/6-311+G(2df,2p), calculated charge and
calculated energy levels of HOMO, LUMO and energy gap (eV) (Tables S1, S2, S3, and S4) and experimental UV-
1
13
Visible, FTIR, H-NMR and C-NMR spectra, and high-resolution mass spectra (Figures S1, S2, S3 and S4) of five
-chloromethylcoumarin compounds (A, B, C, D and E) can be found in the supplementary material file.
4
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