Structure, electronic, spectroscopic and reactivity investigations of pharmacologically active compound 1–acetyl–3–indolecarboxaldehyde – An experimental and theoretical approach

Article abstract of DOI:10.1016/j.molstruc.2018.03.045

The experimental and theoretical studies on the structure and vibrations of 1–acetyl–3–indolecarboxaldehyde (AIC) have been carried out by utilising FT–IR, FT–Raman, FT–NMR and quantum chemical density functional theory (DFT) method. The FT–IR and FT–Raman spectra are recorded in the region 4000–400 cm^?1 and 4000–100 cm^?1, respectively. The geometry of AIC is optimised by B3LYP method with 6–31G** 6–311++G** and cc–pVTZ basis sets. The more stable minimum energy conformer has been found by analyzing the potential energy profile. The fundamental vibrational frequencies, infrared intensities, Raman intensities and bonding features of this compound are determined. The HOMO and LUMO energy difference show that, the charge transfer occurs within the molecule. The electrostatic potential and thermodynamic properties of the compound at the different temperatures have been calculated. ¹H and ¹³C NMR chemical shifts of the compound are determined by Gauge Invariant Atomic Orbital (GIAO) by using B3LYP/6–311++G** method. The electrostatic potential of AIC lie in the range +1.22e × 10^?2 to ?1.22e × 10^?2. The limits of total electron density of the complex is +4.906e × 10^?2 to ?4.906e × 10^?2.

Full text of DOI:10.1016/j.molstruc.2018.03.045

Accepted Manuscript
Structure, electronic, spectroscopic and reactivity investigations of
pharmacologically active compound 1–acetyl–3–indolecarboxaldehyde – an
experimental and theoretical approach
G. Durgadevi, V. Arjunan, S. Thirunarayanan, M.K. Marchewka, S. Mohan
PII:
S0022-2860(18)30334-X
10.1016/j.molstruc.2018.03.045
MOLSTR 24984
DOI:
Reference:
To appear in:
Journal of Molecular Structure
Received Date:
Revised Date:
Accepted Date:
27 December 2017
10 March 2018
13 March 2018
Please cite this article as: G. Durgadevi, V. Arjunan, S. Thirunarayanan, M.K. Marchewka, S.
Mohan, Structure, electronic, spectroscopic and reactivity investigations of pharmacologically active
compound 1–acetyl–3–indolecarboxaldehyde – an experimental and theoretical approach, Journal
of Molecular Structure (2018), doi: 10.1016/j.molstruc.2018.03.045
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ACCEPTED MANUSCRIPT
Structure, electronic, spectroscopic and reactivity investigations of pharmacologically
active compound 1–acetyl–3–indolecarboxaldehyde – an experimental and theoretical
approach
G. Durgadevi1, V. Arjunan2*, S. Thirunarayanan1, M.K. Marchewka3, S. Mohan4
1Research and Development Centre, Bharathiar University, Coimbatore 641 046. India.
2Department of Chemistry, Kanchi Mamunivar Centre for Post-Graduate Studies,
Puducherry–605 008. India.
3Institute of Low Temperature and Structure Research, Polish Academy of Sciences, 50–950
Wroclaw 2, Poland.
4School of Sciences and Humanities, Vel Tech University, Avadi, Chennai – 600 062. India.
Abstract
The experimental and theoretical studies on the structure and vibrations of 1–acetyl–
3–indolecarboxaldehyde (AIC) have been carried out by utilising FT–IR, FT–Raman, FT–
NMR and quantum chemical density functional theory (DFT) method. The FT–IR and FT–
Raman spectra are recorded in the region 4000–400 cm–1 and 4000–100 cm–1, respectively.
The geometry of AIC is optimised by B3LYP method with 6–31G**, 6–311++G** and cc–
pVTZ basis sets. The more stable minimum energy conformer has been found by analyzing
the potential energy profile. The fundamental vibrational frequencies, infrared intensities,
Raman intensities and bonding features of this compound are determined. The HOMO and
LUMO energy difference show that, the charge transfer occurs within the molecule. The
electrostatic potential and thermodynamic properties of the compound at the different
1
temperatures have been calculated. H and 13C NMR chemical shifts of the compound are
determined by Gauge Invariant Atomic Orbital (GIAO) by using B3LYP/6–311++G**
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method. The electrostatic potential of AIC lie in the range +1.22e × 10–2 to –1.22e × 10–2.
The limits of total electron density of the complex is +4.906e × 10–2 to –4.906e × 10–2.
Keywords: 1–acetyl–3–indolecarboxaldehyde; FT–IR; FT–Raman, FT–NMR; DFT.
Corresponding author. E–mail address: varjunftir@yahoo.com (V. Arjunan)
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1. Introduction
Indole and its derivatives have found numerous pharmaceutical applications such as
anticancer [1], antioxidant [2], antibacterial [3], antidepressant [4], anxiolytic [5] as well as
anti–HIV [6] properties. Many drugs are available in the markets which contain indole
moiety as their pharmacophore such as delavirdine, a nonnucleotide reverse–transcriptase
inhibitor, used for the treatment of HIV type I [7], yohimbine for the treatment of male
impotency [8], oxypertine for the treatment of schizophrenia [9], arbidol for the treatment of
influenza infection [10], sumatriptan for migraine treatment [11], ondansetron for the
suppression of nausea [12], alosetron for the treatment of irritable bowel syndrome [13] and
perindopril for the treatment of hypertension [14].
Basically, indole derivatives posses hypertensive, anthalmintic, antibacterial and anti–
parkinsonian activities [15]. They possess potent antiamoebic activity, DNA cleavage,
antifungal activity, analgesic and anti–inflammatory properties [16]. Indole–3–
carboxaldehyde used as antibacterial, antifungal, antiamoebic and cytotoxic agents. Barstis et
al. [17] analysed the fundamental vibrational frequencies of 4–, 5– and 6–fluoroindols.
Arjunan et al. [18] investigated the vibrations of 5–aminoindole. Carney et al. [19]
characterised the hydrogen–bonding topologies of indole–water, 1–methylindole–water, and
3–methylindole–water clusters. Suwayan et al. [20] studied the polarized infrared and Raman
spectra of 5–methoxyindole. Morzyk–Ociepa et al. [21] determined the crystal structure of
indole–2–carboxylic acid. Comparative spectroscopic studies on indole and its derivatives,
namely 3–formylindole,1–methyl–3–formylindole, 1–ethyl–3–formylindole, 3–acetylindole,
1–methyl–3–acetylindole, 1–ethyl–3–acetylindole and 1,3–diacetylindole were reported by
Billes et al. [22]. Nagaraja et al. analysed the antioxidant activities and synthesis of indole–3–
carboxaldehyde analogues bearing aryl amines moieties [23].
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The knowledge of the electronic structure and spectral properties are particularly
significant to assess the relationship between biological activity and molecular structure.
Hence, owing to the wide spread applications, synthetic and biological activity evaluation of
1–acetyl–3–indolecarboxaldehyde, detailed vibrational and electronic characteristics of the
molecule has scientific worth. In the present investigations, detailed vibrational analysis
using FT–IR and FT–Raman spectra along with quantum chemical DFT studies, molecular
electrostatic potential, thermodynamic properties and NMR chemical shifts of 1–acetyl–3–
indolecarboxaldehyde have been reported for the first time.
2. Experimental Procedure
2.1. Synthesis of 1–acetyl–3–indolecarboxaldehyde
The compound has been synthesised by using the reported procedure [22].
Phosphorus oxychloride (10 mL) was added drop by drop to ice–cooled dimethylformamide
(30 mL), followed by addition of indole (100 mmol). This mixture was stirred at 100 oC for 2
hrs and then poured onto 500 g of ice. The pH value of the mixture was set to 6 by addition of
saturated aqueous NaOAc solution and it was extracted with toluene (200 mL, four times).
The combined toluene solutions were dried over anhydrous Na2SO4, and then concentrated to
a volume of 50 mL by distillation under reduced pressure. Chromatography on silica gel
using toluene as eluent followed by recrystallization from ethanol yield indole–3–
carboxyaldehyde (I).
N–Acylation of indole–3–carboxaldehyde (I) with acetylchloride in the presence of
triethylamine gives 1–(acetyl)–3–indole carboxaldehyde (II). Acetyl chloride (2.5 mmol) in
10 ml of tetrahydrofuran (THF) was added dropwise into the well stirred solution of indole–
3–carboxaldehyde (2 mmol) and triethylamine (2.5 mmol) in 10 ml of THF. The reaction
mixture was stirred at room temperature for about 3 hr. After the completion of reaction, the
reaction mass was quenched in ice-cold water and the product was extracted in diethyl ether.
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The ether layer was washed with 5% NaHCO3 followed by distilled water. The solid product
1–(acetyl)–3–indole carboxaldehyde (II) was obtained by drying the ether layer over
anhydrous Na2SO4. The synthesised compound was characterised by elemental analysis and
spectroscopic techniques.
2.2. Materials and methods
The synthesised compound 1–(acetyl)–3–indole carboxaldehyde (AIC) has been used
to record the FT–IR and FT–Raman spectra. The FT–IR spectrum of the compound was
recorded on a Bruker IFS 66V spectrometer equipped with a Globar source, Ge/KBr beam
splitter and a TGS detector in the range of 4000–400 cm–1. The spectral resolution is 2 cm–1.
The FT–Raman spectrum of the compound was also recorded in the range 4000 to 100 cm–1
using the same instrument with FRA 106 Raman module equipped with Nd:YAG laser
source operating at 1.064 μm with 200 mW power. A liquid nitrogen cooled–Ge detector was
1
used. The frequencies of all sharp bands are accurate to 2 cm–1. The H (400 MHz; CDCl3)
and 13C (100 MHz; CDCl3) nuclear magnetic resonance (NMR) spectra were recorded at
room temperature on a Bruker HC400 instrument. The chemical shifts for protons are
reported in parts per million scales (δ scale) downfield from tetramethylsilane.
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2.3. Computational details
The structural characteristics and the normal vibrations of AIC are determined by the
B3LYP correlation functional calculations with Gaussian 09 [24] program package, invoking
gradient geometry optimisation [25,26]. The gradient corrected density functional theory
(DFT) with the three–parameter hybrid functional (B3) [27,28] for the exchange part and the
Lee–Yang–Parr (LYP) correlation function [29], with the standard 6–311++G** and cc–
pVTZ basis sets has been utilised for molecular structure optimisation, determination of
energy, vibrational frequencies and thermodynamic properties of the compound.
Isoelectronic molecular electrostatic potential has been calculated using cc–pVTZ
basis set. The molecular electrostatic potential (MEP) at a point r in the space around a
molecule (in atomic units) can be expressed as [30]:

ZA
RA  r
  (r')dr'
V (r) 



r' r
A
where, ZA is the charge on nucleus A, located at RA and ρ(r′) is the electronic density function
for the molecule. The first and second terms represent the contributions to the potential due to
nuclei and electrons, respectively. V(r) is the resultant electric potential at each point r, which
is the net electrostatic effect produced at the point r by both the electrons and nuclei of the
molecule. GaussView 5.0.8 visualisation program [31] has been utilised to produce the MEP
surface, the shapes of highest occupied molecular orbital (HOMO) and lowest unoccupied
molecular orbital (LUMO) orbital.
The 1H and 13C NMR isotropic shielding constants are calculated with GIAO method
[32,33] using the optimised parameters obtained from B3LYP/cc–pVTZ method. The effect
of CDCl3 solvent on the theoretical NMR parameters was included using the PCM model.
The isotropic shielding constant values are used to calculate the isotropic chemical shifts δ
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with respect to tetramethylsilane (TMS) using the relation δiso(X) = σTMS(X) – σiso(X), where
δiso – isotropic chemical shift and σiso – isotropic shielding constant.
The Raman scattering activities (Si) calculated by Gaussian 09W program are suitably
converted to relative Raman intensities (Ii) using the relationship [34]:
f (0 i )4 Si
Ii 
i[1 exp(hci / kT)]
where, v0 is the laser exciting frequency (cm−1) in this work the excitation wavenumber is
used as v0 = 9398.5 cm−1, which corresponds to the wavelength of 1.064 μm for Nd:YAG
laser, vi is the vibrational wavenumber of the ith normal mode, h–Plank constant, c–velocity
of light and k–Boltzmann constant, f is the suitably chosen normalisation factor (10–38) for all
the peak intensities and T–temperature in Kelvin (298.15 K).
The bonding–anti bonding interactions can be quantitatively described in terms of the
NBO approach that is expressed by means of second–order perturbation interaction energy
E(2) [35–38]. The stabilisation energy E(2) associated with i (donor) → j (acceptor)
delocalisation is estimated from the second–order perturbation approach [38]:
F2 (i, j)
E(2)  qi
 j i
where, qi is the donor orbital occupancy, εi and εj are diagonal elements (orbital energies) and
F(i,j) is the off–diagonal Fock matrix element.
2.4. Structure–activity descriptors
Both global and local reactivity descriptors are determined by using finite difference
approximation to reveal the reactivity of the molecule. The vertical ionization potential (I),
electron affinity (A) and the electron populations are determined by B3LYP/cc–pVTZ
method. The energy of the N–electron species is found by restricted B3LYP method while the
energies of the N–1 and N+1 electronic species are calculated by using open shell restricted
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B3LYP method with cc–pVTZ basis set. The reactivity of individual atom can be determined
by using Fukui functions [39,40] which is interpreted either as the change of electron density
ρ(r) at each point r when the total number of electrons is changed or as the sensitivity of
chemical potential (μ) of a system to an external perturbation at a particular point r.


(r)
N

v(r)








f (r) 


v(r)

N
Yang and Parr [40] introduced local softness s(r) to predict the reactivity. The s(r)
describes the sensitivity of the chemical potential of the molecule to the local external
perturbation and is obtained by multiplying Fukui function f(r) with global softness S. The
local softness values are used in predicting the reactive sites towards electrophilic,
nucleophilic and free radical reactions and regioselectivity etc.


(r)

s(r)  




v(r)
s(r)  f (r)S
where, S is the global softness which is inversely related to global hardness (η).
The Fukui functions of the individual atoms of the neutral, cationic and anionic
species of AIC are calculated by B3LYP/cc–pVTZ method. The reactivity at the atomic level
is described by the condensed forms of the Fukui function for an atom k in a molecule which
is expressed as:
fk (r)  qk (N 1)  qk (N) for nucleophilic attack;
fk (r)  qk (N)  qk (N 1) for electrophilic attack and
1
fko (r) 

qk (N 1)  qk (N 1)
for free radical attack.

2
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In these equations, qk is the atomic charge (evaluated from the natural populations
analysis by NBO method) at the kth atom in the neutral (N), anionic (N+1) or cationic (N–1)
form of the molecule.
The local softness, relative electrophilicity ( sk
/
sk ) and relative nucleophilicity (
sk / sk ) indices, the dual local softness Δsk and the multiphilicity descriptors (Δωk) have also
been determined to predict the reactive sites of the molecule. The local reactivity descriptors
of the individual atoms of the molecule ska  fkaS
,
ka  fka and fka where, a = +, – and 0
represents local philicity quantities describing nucleophilic, electrophilic and free radical
attack, respectively.
3. Results and discussion
3.1 Structure properties
The optimisation of geometry of AIC has been performed within the Cs point group
symmetry and the most stable geometry is shown in Figure 1. The optimised bond lengths
and bond angles calculated at B3LYP method using 6–311G, 6–311++G** and cc–pVTZ
basis sets are presented in Table 1 and compared with the relevant experimental X–ray
diffraction data of ethyl 1–acetyl–1H–indole–3–carboxylate [41]. The data of B3LYP/cc–
pVTZ method are taken for comparison unless otherwise stated. In the benzene part, the bond
lengths C4–C5, C5–C6 and C6–C7 are shorter than C7–C8, C8–C9 and C4–C9 due to the
electron withdrawing power of the substituents in the hetero ring. The bond angles are 120o
and more except C5–C4–C9 and C6–C7–C8 like other indole derivatives [42]. The benzene
part of the molecule is slightly distorted around C7 (bond length C6–C7 = 1.389 Å; bond
angle C6–C7–C8 = 117o) like other indole derivatives. The bond length C6–C7 and the bond
angle C6–C7–C8 of ethyl 1–acetyl–1H–indole–3–carboxylate are 1.379 Å and 116.9o,
respectively. It is evident that these distortions are not due to the alkylation of the system, but
rather the characteristics of the indole moiety. The short bond distance of C2–C3 (1.365 Å)
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confirm the double bond and is comparable with the standard aromatic C=C bond (1.40 Å).
The carbonyl bond distance C15=O16 (1.207 Å) is shorter than C21=O22 (1.213 Å) due the
more electronegative N1 adjacent to C15. The C8–C9 bond is substantially longer in indole
(1.409 Å) than the similar bond in either pyrrole (1.382 Å) or benzene (1.396 Å). It should
also be noted that in AIC, the C9–C8 bond length (1.409 Å) is elongated, in comparison to
indole (1.382 Å) [42]. The presence of acetyl and aldehyde groups in the pyrrolic ring of AIC
affect the bond lengths and angles in the hetero ring. The N–C bonds of the pyrrolic ring of
indole are longer than indole. The C–N bond length (C2–N1 = 1.384 Å and C8–N1 = 1.416
Å) in the five membered ring are not equal. The average C–N bond length of indole is 1.37
Å. The bond length of C9–C4 (1.395 Å) in AIC is shorter than the corresponding bond in
indole molecule (1.425 Å). On the other hand, the bond length of C4–C5 (1.381 Å) in AIC
agreed well with the corresponding bond length of indole (1.382 Å). The orientation of the
acetyl and aldehydic carbonyl groups are coplanar with the hetero ring (C2–C3–C21–O22
and C2–N1–C15–O16 = 180o). The DFT results indicates that the conjugated six membered
and five–membered rings of indole moiety are coplanar (N1–C8–C9–C4 torsional angle is
180.0o and N1–C8–C9–C3 torsional angle is 0o). The theoretically determined bond
parameters show very good agreement with experimental data shown in Table 1.
3.2 Thermodynamic properties
The zero point vibrational energy, thermal energy, specific heat capacity, rotational
constants, entropy and dipole moment of AIC are determined by B3LYP method using
various basis sets at 298.15 K and 1 atm pressure are listed in Table 2. The heat capacity at
constant pressure (Cp), entropy (S) and enthalpy change (ΔH0→T) which describes the
thermodynamic stability at given conditions of pressure and temperature are determined in
the temperature range 25–500 K using B3LYP/6–311++G** method and presented in Table
3.
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The regression coefficient (R2) determined for these observed relations of the
thermodynamic functions with temperatures is equal to 0.999. The corresponding relations
between the thermodynamic properties and temperature are represented by the equations
S0 = 213.29 + 0.914 T – 3.839x10–5 T2
(R2 = 0.999)
(R2 = 0.999)
(R2 = 0.999)
m
C0p,m =23.674 + 0.624 T – 1.249x10–4 T2
ΔH0m = –0.1464 + 0.0295 T + 2.816 10–4 T2
The variations of thermodynamic parameters with temperature are shown Fig. 2. It
can be observed that these thermodynamic parameters increase with rise of temperature due
to the fact that the molecular vibrational intensities increase with temperature [43,44].
3.3 Electrostatic potential surface analysis
The molecular electrostatic potential, V(r) at any given point r(x, y, z) in the vicinity
of a molecule, is defined in terms of the interaction energy between the electrical charge
generated from the molecule electrons and nuclei and a positive test charge (a proton) located
at r. The total density isosurface, total electron density mapped with electrostatic potential
surface and the contour map of electrostatic potential of AIC are shown in Fig. 3. The
negative (red) regions of MEP were related to electrophilic and the positive (blue) regions
were related to nucleophilic reactivity. The presence of green region in the MEP surface
corresponds to a potential halfway between the two extremes red and dark blue colour. The
MEP surface of AIC shows the presence of more electron density around the carbonyl
oxygen characterised by red colour. The electrostatic potential of AIC lie in the range +1.22e
× 10–2 to –1.22e × 10–2. The limits of total electron density is +4.906e × 10–2 to –4.906e ×
10–2.
3.4 Frontier molecular orbital analysis
Essential facts on frontier molecular orbitals have been presented in earlier
investigations [45–47]. Determination of energy difference between highest occupied
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molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) which
determine the stability and charge transfer properties [48]. The computed HOMO, HOMO–1,
LUMO and LUMO+1 orbital energies and the energy gap are given in Table 2. The shapes of
frontier molecular orbitals are shown in Fig. 4. The positive and negative phases of the
molecular orbital are represented in red and green colour, respectively. From the plot one can
note that the region of HOMO and LUMO spread over the entire molecule. This indicates the
possibility of π → π* and n → π* transitions. The energy gap (ELUMO–EHOMO) of AIC is
found to be 4.4001 eV at B3LYP/6–311++G** method.
3.5 Donar-acceptor stabilisation energy analysis
The bonding–anti bonding interactions can be quantitatively described in terms of
second–order perturbation interaction energy E(2). The second–order interaction energies
(E(2)) above 4.0 kcal mol–1 between the donor–acceptor orbitals computed using B3LYP/6–
311++G** method are provided in Table 4. The interaction of electron–donating π–bonding
orbital (C2–C3) with the antibonding acceptor π*(C21–O22) orbital gives more stabilisation
of 22.14 kcal mol–1. The interaction of electron–donating π–bonding orbital (C4–C5) with the
anti bonding acceptor π*(C6–C7) and (C8–C9) orbitals has stabilisation energy of 20.48 and
20.4 kcal mol–1, respectively. The electron donation from the lone pair donor orbital n(N1) to
the antibonding acceptors π*(C15–O16) is seem to give a strong stabilisation, 42.91 kcal
mol–1 while the n  π*stabilisation energy of lone pair of electrons present in the nitrogen
atom (N1) to the antibonding orbital π*(C2–C3) is 32.59 kcal mol–1. These interactions
having more stabilisation energy favours electron delocalisation.
3.6. FT–IR and FT–Raman spectral analysis
The AIC molecule possesses CS point group symmetry and exhibits 63 normal modes
of vibrations comprising of 41 in–plane vibrations and 22 out of plane vibrations. The
distribution of 63 normal modes into the irreducible representation is given by ΓVib. = 41A′ +
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22A″. The vibrations of the A' species are in–plane modes and A" species are out of plane
modes. All the fundamental vibrations are active in both IR and Raman. Precise vibrational
spectral assignments are made to the peaks observed in FT–IR and FT–Raman spectra in
association with theoretically computed wavenumbers employing B3LYP methods and
literature. The wavenumbers, assignments and other characteristic features are presented in
Table 5. The scaling equations y = 1.0007x + 4.1389, y = 1.0051x – 17.1359 and y = 1.0018x
– 5.5221 are used to establish harmonisation with the experimental wave numbers the
calculated wave numbers obtained by using cc–pVTZ, 6–311++G** and 6–31G** basis sets.
The experimental and simulated infrared and Raman spectra from B3LYP method using pure
Laurentzian band shape with a bandwidth of FWHM of 4 cm–1 are presented in Figs. 5 and 6.
The simulated bands are in good agreement with experimental peaks. The complete and
precise assignment of the vibrational modes of AIC forms an invaluable basis for
understanding the vibrations of other indole derivatives that are of interest in biomolecular
systems. Correlation between experimental and theoretical frequencies are shown in Fig. 7.
3.6.1 C–H vibrations
The C–H stretching vibrations in the hetero aromatic moiety like indole are expected
in the region from 3200 to 3000 cm–1, which represents the characteristic region for the
hetero aromatic moiety [49,50]. The effect of formyl and acetyl groups on the C–H stretch is
more interesting. By investigating the five C–H vibrations of AIC, the higher one belong to
the pyrrole ring and the four lower wavenumbers belongs to benzene ring. The aromatic C–H
stretch bands overlap and are weak. The C–H stretching frequency of the formyl group is
expected in the lower region. Additionally, the formyl C–H stretch bands appear separately
but they are also very weak. The C–H in–plane and out of plane bending vibrations generally
lie in the range 1300–1000 cm–1 and 1000–800 cm–1 [50–52], respectively.
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Bands observed at 3128 cm–1 in FT–IR spectrum is attributed to the C–H stretching
vibrations of hetero ring. Bands observed at 3068, 3017 cm–1 in FT–IR and 3113, 3060, 3017
cm–1 in FT–Raman spectra have been designated to C–H stretching vibrations of benzene
ring. The in–plane and out of plane C–H bending vibration (aldehyde) are found respectively
at 1382 and 1010 cm–1 in IR spectrum. The aromatic in–plane C–H bending vibration of
indole has found near 1170 cm–1 in FT–IR and Raman spectra. This is well agreed with the
bands observed at 1128 cm–1 in FT–IR and 1132, 1015 cm–1 in Raman spectra due to the in–
plane C–H bending vibrations of benzene ring.
3.6.2 Methyl group vibrations
Methyl stretching modes are calculated in the range 3005–2900 cm–1. Asymmetric
and symmetric methyl deformation bands occur in IR with medium intensity at 1477, 1404
and 1368 cm–1, respectively [22]. The rocking vibration of CH3 is assigned to the band
observed in IR with its closer Raman counterpart at 938 cm–1. CH3 wagging mode is
calculated to occur at 1043 cm–1. As expected, the CH3 torsional mode is identified in Raman
spectrum at 198 cm–1.
3.6.3 C=O group vibrations
The effect of nitrogen on carbonyl group cause remarkable change in the υC=O
absorption region. The C=O stretching frequency of the acetyl group υC=O appear in the
higher region by 60 cm–1 than the formyl C=O group. Frequencies of the acetyl and formyl
C=O stretching vibrations are detected as very strong bands at 1733 and 1672 cm–1 in IR. The
Raman counter parts are 1721 and 1674 cm–1 [21,22]. Strong peaks observed at 770, 643 cm–
1
in IR and their counterparts of weak intensity peaks in Raman are identified as in–plane
bending vibrations of C=O. Out of plane bending vibrations of C=O are identified near 560
and 401 cm–1 in Raman spectrum.
3.6.4 C−C vibrations
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Normally, indoles absorb the IR radiation in the region 1630–1610 cm–1 due to the
ring C=C vibration [53,54]. Generally, the C=C stretching vibrations in aromatic compounds
are seen in the region of 1430–1650 cm–1 [54–56]. Ten C–C stretching modes are determined
in the range 1600–1100 cm–1 at B3LYP level. The C–C stretching modes of benzene ring are
found at 1604, 1342, 1088 and 1040 cm–1 in IR. Remaining peaks observed in the above said
region are assigned to the respective C–C stretching modes of the molecule. The assignments
for the in–plane and out of plane bending vibrations done in the lower frequency region are
presented in the Table 5.
3.6.5 C−N stretching
In indole compounds, the N–C stretching vibrations are identified with strong and
medium intensity at 1290–1280 cm–1 [57,58]. In the present study, these vibrations are
observed with strong intensity at 1321 1294 and 1207 cm–1 in IR spectrum. The
corresponding Raman counterparts are observed at 1320, 1246 and 1206 cm−1. In–plane and
out of plane bending vibration of CNC modes are attributed to the wavenumbers at 757
(theory) and 349 (experiment) cm−1, respectively.
1
3.7 H and 13C NMR spectral analysis
The GIAO [32,33] method is one of the most common approaches for calculating
1
isotropic nuclear magnetic shielding tensors. The 13C and H NMR chemical shifts are
determined by gauge independent atomic orbital (GIAO) method with B3LYP/cc–pVTZ
1
method. The H and 13C theoretical and experimental chemical shifts, isotropic shielding
constants and the peak assignments are presented in Table 6. The observed 1H and 13C NMR
spectra of the compound in CDCl3 solvent are given in the Figs. 8 and 9, respectively.
Aromatic carbons give signals with chemical shift values from 100 to 200 ppm.
1
The more effect on H chemical shift is to be expected at the methyl groups attached
with the unsaturated carbon atoms. Hence, the peaks identified at 2.094 (H18,20) and 2.74
15

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(H19) ppm are assigned to the hydrogen atoms of methyl group. The methyl hydrogens (H18,
H19 and H20) are attributed to the upfield signals shows that these protons are under high
magnetic shielding. This is mainly due to the presence of hyperconjugative effect of the
methyl group. The hydrogen atoms H(10,11,12 and 13) of benzene ring shows peak in the
normal range of unsaturated hydrogen atoms and are assigned to the chemical shift values
8.264, 7.284, 7.416 and 8.390 ppm, respectively. The peak at 10.11 ppm is assigned to the
1
formyl hydrogen (H23) and noticed downfield in H NMR spectra is due to a influence of
C=O bond.
The peaks observed at 185.61 and 168.56 ppm in 13C NMR spectrum are attributed to
the acetyl and formyl group carbon atoms (C21 and C15), respectively. The partial ionic
character of the carbonyl group due to resonance, the influence of electronegative oxygen and
its deshielding effect renders a partially positive charge to the carbonyl carbon and thus
chemical shifts of C21 and C15 are lie in the very downfield. The carbon atoms associated
with benzene group are observed in the region 135.18 to 116.39 ppm of 13C NMR spectrum.
Methyl carbon atom C17 is observed in the upfield with chemical shift value 23.88 ppm. This
is mainly due to the hyperconjugative effect of methyl group [59,60]. The theoretical data
listed in Table 6 are in excellent agreement with the experimental values. Correlation
between experimental and theoretical 13C and 1H NMR Chemical shifts is shown in Fig. 10.
3.8. Analysis of structure–activity descriptors
The local and dual reactivity properties of AIC are determined by using the charges
derived from natural population analysis are summarised in Tables 7 and 8. The reactivity
order for the nucleophilic attack determined by fk, sk and ωk values is C9>C17>N1. Similarly
the order of reactivity for electrophilic attack is C8>C21>C17>C15. The order of reactivity
for free radical attack is C17>C8>C9. The carbon atom C17 is equally prone for nucleophilic,
electrophilic and free radical attack.
16

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The multiphilicity descriptors (Δωk) which can concurrently characterises both
nucleophilic and electrophilic nature of a chemical species. If (Δωk) > 0, then the site k is
favored for a nucleophilic attack, whereas if (Δωk) < 0, then the site k may be favored for an
electrophilic attack. For the compound AIC, from the dual local softness Δfk, Δsk and the
multiphilicity descriptors (Δωk) one can understand that the atoms C4, C7, N1, C6, C9, and
C17 are favorable for nucleophilic attack. The other atoms are more prone to electrophilic
attack.
4. Conclusions
(i)
The structural parameters and thermodynamic properties of the optimised geometry
have been determined. The deviation in bond lengths and bond angles are more
pronounced in AIC because the deviations are influenced not only by the ring strain
and also the steric hindrance of formyl and acetyl groups.
(ii)
The range of total electron density of the molecule is from +4.906e × 10–2 to –4.906e
× 10–2 while the extreme limits of the electrostatic potential is +1.22e × 10–2 to –1.22e
× 10–2.
(iii) The energies of important MOs of the compound are also evaluated from DFT
method. The LUMO–HOMO energy gap of the title compound determined by
B3LYP/cc–pVTZ method is 4.4001 eV.
(iv)
(v)
(v)
The vibrational frequencies of the compound have been precisely assigned, analysed
and the theoretical results are compared with the experimental wavenumbers.
The alkyl substitution shifts the aldehyde carbonyl stretching band frequencies to
somewhat higher values.
1H and 13C NMR chemical shifts are determined and are compared with the
experimental values. The methyl hydrogens (H18, H19 and H20) are attributed to the
17

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upfield signals shows that these protons are under high magnetic shielding. This is
mainly due to the presence of hyperconjugative effect of the methyl group.
(vi)
(vi)
The n(N1) → *(C15–O16) stabilisation energy of lone pair of electrons present in
the nitrogen atom N1 and the C15–O16 antibonding orbital is 42.91 kcal mol–1 This
.
is the most stabilized than all other interactions.
The  → π* interactions, (C2–C3)  *(C21–O22) has more stabilisation energy
and is equal to 22.14 kcal mol–1.
(vii) The reactivity order for the nucleophilic attack determined by fk, sk and ωk values is
C9>C17>N1. The order of reactivity for electrophilic attack is C8>C21>C17>C15.
The order reactivity free radical attack is C17>C8>C9. The carbon atom C17 is
equally prone for nucleophilic, electrophilic and free radical attack.
(viii) From the dual local softness Δfk, Δsk and the multiphilicity descriptors (Δωk) one can
understand that the atoms C4, C7, N1, C6, C9, and C17 are favorable for nucleophilic
attack. The other atoms are more prone to electrophilic attack.
Thus, the present investigation provides complete and precise structural, electronic,
vibrational and reactivity aspects of 1–acetyl–3–indolecarboxaldehyde.
18

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Fig. 1. Optimised molecular geometry of 1-acetyl-3-indolecarboxaldehyde.
Fig. 2. Variation of thermodynamic parameters of 1-acetyl-3-indolecarboxaldehyde with
temperature

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Fig. 3. (A) Total electron density isosurface, (B) Total electron density mapped with electrostatic
potential surface and (C) Contour of electrostatic potential surface of 1-acetyl-3-
indolecarboxaldehyde.

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Fig. 4. Frontier molecular orbitals of 1-acetyl-3-indolecarboxaldehyde.

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Fig. 5. (A) Experimental FT-IR and simulated infrared spectra of 1-acetyl-3-
indolecarboxaldehyde by (B) B3LYP/6–31G**, (C) B3LYP/6–311++G**and
(D) B3LYP/cc-pVTZ methods.

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Fig. 6. (A) Experimental FT-Raman and simulated Raman spectra of 1-acetyl-3-
indolecarboxaldehyde by (B) B3LYP/6–31G**, (C) B3LYP /6–311++G**and
(D) B3LYP/cc-pVTZ methods.

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Fig. 7. Correlation between experimental and theoretical frequencies (A) 6–31G**, (B) 6–
311++G** and (C) cc-pVTZ basis sets.

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Fig. 8. (A) Experimental and (B) theoretical 1H NMR spectra of1-acetyl-3-
indolecarboxaldehyde.