Crystal structure analysis and quantum chemical study of two macrocyclic compounds

Article abstract of DOI:10.1016/j.molstruc.2019.127434

The synthesis of new organic macrocyclic nonlinear optical materials with good performance has taken the prime focus of research due to the unlimited design possibilities. Two macrocyclic structures, confirmed by 1H, 13C NMR and FT-IR, namely spiro pyrrolidine grafted methyl macrocycle C₂₈H₂₆N₂O₃ and 1,2,3 triazole bridged pyrrolidine grafted chloro macrocycle C₂₉H₂₇Cl₁N₄O₃0.5(H₂O) are analysed by single crystal X-ray diffraction method. The UV–Vis spectra of the two compounds show that these crystals are transparent in the entire visible region. The global reactivity descriptors such as ionization potential, electron affinity, electronegativity, chemical hardness, chemical potential, chemical softness, electrophilicity index and nonlinear optical parameters such as dipole moment (μ) and static second order hyperpolarizability (γ) are determined in gas phase at the molecular level by semiempirical quantum chemical method with the coordinates obtained from X-ray diffraction as the starting geometry. In addition, the bioactivity scores were calculated from the chemical skeleton.

Full text of DOI:10.1016/j.molstruc.2019.127434

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Crystal structure analysis and quantum chemical study of two macrocyclic
compounds
G. Maragatham, P. Prabhakaran, P. Rajakumar, S. Lakshmi
PII:
S0022-2860(19)31543-1
DOI:
https://doi.org/10.1016/j.molstruc.2019.127434
MOLSTR 127434
Reference:
To appear in: Journal of Molecular Structure
Received Date: 15 March 2019
Revised Date: 25 October 2019
Accepted Date: 16 November 2019
Please cite this article as: G. Maragatham, P. Prabhakaran, P. Rajakumar, S. Lakshmi, Crystal structure
analysis and quantum chemical study of two macrocyclic compounds, Journal of Molecular Structure
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Crystal structure analysis and
Quantum chemical study of two Macrocyclic compounds
G. Maragathama, P. Prabhakaranb, P. Rajakumarb S.Lakshmia *
a, a* Department of Physics, S.D.N.B. Vaishnav College for Women, Chromepet, Chennai 600 044, India.
b Department of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India.
a* Corresponding author e-mail address:lakssdnbvc@gmail.com.
CCDC references: 1877992 , 1868550
Abstract
The synthesis of new organic macrocyclic nonlinear optical materials with good
performance has taken the prime focus of research due to the unlimited design
possibilities. Two macrocyclic structures, confirmed by 1H, 13C NMR and FT-IR, namely
spiro pyrrolidine grafted methyl macrocycle C28H26N2O3 and 1,2,3 triazole bridged
pyrrolidine grafted chloro macrocycle C29H27Cl1N4O30.5(H2O) are analysed by single
crystal X-ray diffraction method. The UV-Vis spectra of the two compounds show that
these crystals are transparent in the entire visible region. The global reactivity descriptors
such as ionization potential, electron affinity, electronegativity, chemical hardness,
chemical potential, chemical softness, electrophilicity index and nonlinear optical
parameters such as dipole moment (ꢀ) and static second order hyperpolarizability (γ) are
determined in gas phase at the molecular level by semiempirical quantum chemical method
with the coordinates obtained from X-ray diffraction as the starting geometry. In addition,
the bioactivity scores were calculated from the chemical skeleton.
Graphical Abstract
Keywords
Macrocyclic Molecules
UV-Vis Characterization
1H and 13C NMR analysis
Crystal structure analysis
Hydrogen bonding
Quantum chemical calculation
NLO parameters
Bioactivity scores

1. Introduction
Spiro cyclic compounds are of recent interest because of their conformational features and
structural implications for biological systems. Spiro heterocycles like spiropyrrolidines possess
pharmacological, therapeutical, anticancer, antitubercular, antiviral, anti-HIV, antibacterial and
antifungal activities [1]. Some spiro compounds are used as pesticides [2] and laser dyes [3] They
are also used as electroluminescent devices [4]. Spiro pyrrolidine derivatives possess potential
antileukemic [5], anticonvulsant [6], antiviral [7] anti-inflammatory [8], antimicrobial and
antifungal activities [9].
Triazole derivatives find increasing attention in the field of drug discovery due to their anti-
inflammatory [10], antibacterial [11], antimicrobial [13] antitubercular, antioxidant [14],
anticancer [14], analgesic, anti-fungal and antiviral [15] and antitrypanosomastid activities [16]
and find application in diverse areas of medicine [17]. The ability of nonlinear optical (NLO)
materials to transmit, process and store information forms the basis of emerging optoelectronic
and photonic technologies [18]. Donor/acceptor substituted benzene derivatives are known to
produce high molecular nonlinearity [19]. Triazole derivatives can act as highly efficient
multiphoton absorption molecules for photoluminescence and can be used in NLO applications
[20]. Organic molecules capable of NLO applications typically consist of aromatic p-electron
systems asymmetrically endcapped with electron donating and accepting groups to impart the
electronic bias [21]. The inverted triazole architecture, which ensures high dipole moment
provides an appealing strategy in the design of new NLO materials [22]. 1,2,3-triazole based
compounds can act as NLO materials [23]. Triazole-containing Platinum(II) acetylides possessing
third order NLO property can be used in optical power limiting (OPL) application [24]. The
electronic and optoelectronic properties of the macrocycles largely depend on the π-systems
inserted into the macrocycles [25]. Porphyrinoids, a class of macrocyclic compounds with huge
structural diversity, consisting of five-membered rings connected either directly or by bridging
atoms exhibit high degree of π-conjugation [26], tunable electronic, optical and photophysical
properties and constitute a promising building block for molecular optoelectronic devices [27].
Macrocyclic functionalized triazolophanes possess both optical and biological activities [28]. The
NLO parameters of seventeen reported macrocyclic molecules were calculated by semiempirical
quantum chemical method with the coordinates available in CSD as the starting geometry. This
study shows that these compounds are having NLO properties.

In view of the above importance, the crystal structures of spiropyrrolidine grafted methyl
macrocycle (MMC) and 1,2,3 triazole bridged pyrrolidine grafted chloro macrocycle (CMC) were
determined and analysed. The chemical schemes of MMC and CMC are given below,
3-methyl-1-(p-tolyl)1,2,3,9,10,16a-hexahydro-16H-
3a,8-methanodibenzo[e,j] pyrrolo
[2,3-g][1]oxa[4]azacycloundecine16,17-dione.
MMC
(4-chlorophenyl)((22R,23R,24R,
Z)-21-methyl-61H-4,9-dioxa-
6(4,1)-triazola-2(2,4)pyrrolidina1,3(1,2)-
dibenzenacyclono naphane-23-yl)methanone
CMC
The effect of halogen substitution in the macrocyclic molecule is studied by the calculation of the
hyperpolarizability of the halogen replaced CMC. Furthermore, bioactivity scores of MMC and
CMC towards GPCR ligand, ion channel modulator, nuclear receptor legend, kinase inhibitor,
protease inhibitor and enzyme inhibitor were obtained by using Molinspriation software accessed
online.

2. Experimental
2.1. Synthesis and Crystallization
MMC: A solution of triazole linked chalcone ketone (0.729 mmol) and sarcosine (1.8 mmol) was
refluxed in dry toluene (50 ml) under a N2 atmosphere for 8–12 h at 110°C using the Dean–Stark
apparatus. After the completion of reaction as indicated by TLC, toluene was evaporated under
reduced pressure. The crude product was washed with water and extracted with ethylacetate (4 ×
20 ml). The combined organic layers were dried (MgSO4) and filtered, concentrated in vacuum.
The crude product was purified by column chromatography (hexane–EtOAc, 1: 1) to give the
macrocycle in 78% yield. The small portion of the compound was recrystallized from chloroform.
CMC: Compound was prepared through intramolecular 1, 3 dipolar cycloaddition of chalcone
aldehydes (300 mg, 0.614mmol, and 1.0 equiv.) and sarcosine (136.7 mg, 1.53 mmol) and
refluxed in dry toluene under N2 atmosphere for 12 h at 120°C using Dean-Stark apparatus. After
completion of the reaction as indicated by TLC, toluene was evaporated under reduced pressure.
The crude product was washed with water and extracted with dichloromethane (4x20ml). The
combined organic layer was dried (NaSO4) and filtered, concentrated in vacuum. The crude
product was purified by column chromatography using hexane/ethyl acetate (1:1) as eluent. The
small portion of the compound was recrystallized from chloroform.
2.2. 1H and 13C NMR spectral analysis
The 1H and 13C NMR spectra of MMC and CMC were recorded using a Bruker Advance III 500 MHz FT-
NMR spectrometer with TMS as internal standard and CDCl3 as the solvent.
2.3. FT-IR spectral analysis
FT-IR spectra of MMC and CMC were recorded using KBr pellets on a Jasco FTIR-4100 Spectrometer in
the 400-4000 cm-1 range.
2.4. UV-Vis spectral analysis
UV-Vis transmittance spectrum of MMC and CMC were recorded in the range 250-800 nm using Perkin
Elmer UV-Vis spectrometer Lambda 950 instrument.

2.5. Structure determination by single-crystal X-ray diffraction
Colourless, block shaped single crystals of MMC and CMC both having dimensions of 0.35mm x
0.25mm x 0.20mm were selected and mounted on a Bruker Kappa APEX-II CCD diffractometer
in SAIF IIT Madras, with a fine-focus sealed tube graphite-monochromated MoKα radiation (α =
0.71073 Å) at 296 K. The data was processed with SAINT and corrected for absorption using
SADABS [29]. In MMC, a total of 18744 reflections were collected, of which 3894 were
independent and 2835 reflections with I > 2σ(I). In CMC a total of 52497 reflections were
collected, of which 4542 were independent and 3699 reflections with I > 2σ(I). The structure of
MMC was solved by direct method using the program SHELXS97 [30], and was refined by
SHELXL97 [31] and the structure of CMC was solved by direct method using the program
SHELXT-2014/5 [32] and was refined by SHELXL97. In MMC, all H atoms were localized in
difference-Fourier maps and were constrained geometrically with C—H = 0.93Å, 0.96Å and
0.97Å for aryl, methyl and methylene H atoms, respectively; Uiso(H)=1.2Ueq(C) for aryl and
methylene H atoms, Uiso(H)=1.5Ueq(C) for methyl H atom. In CMC, all H atoms were localized in
difference-Fourier maps and were constrained geometrically with C—H = 0.93Å, 0.96Å and
0.97Å for aryl, methyl and methylene H atoms, respectively and O—H = 0.86-087Å with
Uiso(H)=1.5Ueq(C). Uiso(H)=1.2Ueq(C) for aryl and methylene H atoms; Uiso(H)=1.5Ueq(C) for
methyl H atom. The final full matrix least squares refinement gave R=0.040, wR=0.100 and
S=1.04 for MMC and R=0.0458, wR=0.1432 and S=1.087 for CMC. The triazole moiety and
atoms attached to it are disordered over two positions with the occupancy ratio of 53:47. The
disorder was resolved by successive Fourier electron density maps and least squares refinements.
The chemically equivalent distances are restrained to be equal (SADI) or to the corresponding
target values (DFIX) within an allowed standard deviation of 0.02Å. Anisotropic displacement
parameters of disordered atoms were restrained to show similar behaviour with an effective
standard deviation of 0.04 Å2. The occupancy of water solvent in the asymmetric unit is
constrained to 50% due to disorder in it and also restrained to be approximately isotropic.
Summary crystal data and parameters for MMC and CMC are given in Table 1. The molecular
structure and their packings are obtained using ORTEP [33] and PLATON [34].
Empirical formula
Formula weight
Temperature (K)
Wavelength(Å)
Crystal system
C28 H26 N2 O3
438.51
296(2)
0.71073
Triclinic
P 1
C29 H28 Cl N4 O3. 0.5 (H2O)
524.00
296(2)
0.71073
Monoclinic
P 21/n
Space group
Unit cell dimensions
a = 8.3397(3) Å
a = 7.7269(4) Å

b = 9.8697(3) Å
c = 13.7285(5) Å
α = 79.770(2)o
β = 85.675(2)°
γ = 85.791(2)°
1106.79(7)
b = 14.2300(7) Å
c = 23.6105(11) Å
α = 90o
β= 90.431(2)°
γ = 90°
Volume (Å3)
2596.0(2)
Z
2
4
Density (calculated) (Mg/m3)
Absorption coefficient(mm-1)
F(000)
1.316
0.086
464
0.35 x 0.30 x 0.25
2.101 to 25.000°.
-9<=h<=9,
1.341
0.188
1100
0.300 x 0.250 x 0.200
2.958 to 24.998.
-9<=h<=9,
Crystal size (mm3)
Theta range for data collection
Index ranges
-11<=k<=11,
-16<=l<=16
-16<=k<=16,
-27<=l<=28
Reflections collected
18744
52497
Independent reflections
Completeness to theta = 25.000°
Refinement method
3894 [R(int) = 0.0363]
100.0 %
4542 [R(int) = 0.0294]
99.5 %
Full-matrix least-squares on F2
3894 / 0 / 299
1.036
Full-matrix least-squares on F2
4542 / 338 / 449
1.090
Data / restraints / parameters
Goodness-of-fit on F2
Final R indices [I>2sigma(I)]
R indices (all data)
R1 = 0.0399, wR2 = 0.0869
R1 = 0.0639, wR2 = 0.1001
0.164 and -0.165
R1 = 0.0423, wR2 = 0.1112
R1 = 0.0556, wR2 = 0.1263
0.299 and -0.304
Largest diff. peak and hole (e.Å-3)
Table 1. Summary of crystal data and parameters for MMC and CMC respectively.
3. Computational Study
The molecular Mulliken atomic charge, global reactivity descriptors, dipole moment and static second
order hyperpolarizability of MMC and CMC were calculated using the semi-empirical molecular orbital
package, MOPAC 2016 [35]. The geometry obtained from the single-crystal XRD study of MMC and the
optimised coordinates related to 53% occupancy of the structure of CMC without water molecule were
used as input to this program. To optimize the geometry, Eigen vector Following (EF) geometry optimizer
was used. The Time-Dependent Hartree Fock (TDHF) theory was used to compute the molecular
hyperpolarizabilities. The keyword “PRESICE” was used as the convergence criterion for PM7 [36]. The
prediction of bioactivity scores towards GPCR ligand, ion channel modulator, nuclear receptor legend,
kinase inhibitor, protease inhibitor, enzyme inhibitor were calculated through Molinspiration software [37]
accessed online by giving the chemical skeleton as input.
4. Results and discussion
The synthetic schemes of MMC (scheme 1) and CMC (scheme 2) are shown below [38],

O
O
Me
OH
(i)
OH
Me
1
3
(ii)
Me
Me
Me
N
N
O
(iii)
O
O
O
O
N
O
O
7
5
Scheme 1
Reagent and conditions: (i) 4-Methylbenzaldehyde (2), aq. NaOH, EtOH, rt, 6 h, 85%. (ii),N-
alkylbromoketone (4), K2CO3, DMF, rt, 12 h, 76%. (iii) Sarcosine (6) Toluene, N2 atm, Dean–
Stark water separator, 8 h, 78 %.

O
O
O
O
O
H
(ii)
H
(i)
H
Br
OH
10
(iv)
O
12
8
(iii)
O
H
N3
O
Cl
O
14
11
CH3
(v)
O
N
Hc
Ha
N N
O
Hb
N
(vi)
OHC
O
O
O
O
Cl
N
N
15
16
N
Cl
Scheme 2
Reagent and conditions: (i) Dibromoethane (9), K2CO3, DMF, rt, 2 h (64%).;
(ii) propargyl bromide, K2CO3, DMF, rt, 12 h 92%. (iii) 4-Chloroacetophenone (13) NaOH, EtOH,
rt, 6 h (83%).; (iv) NaN3, DMF, rt, 8 h (94%).; (v) O-Alkylazidoaldehyde (11), CuSO4·5H2O,
Sodium ascorbate, THF: Water (1:1), rt, 10 h 92%.; (vi) Sarcosine (6), Toluene, N2 atm, Dean–
Stark water separator, 8 h (78%).
4.1. 1H, 13C NMR and FT-IR spectral analysis
1H, 13C NMR and FT-IR of MMC (Fig. 1a, 1b &1c) and CMC (Fig. 2a, 2b & 2c) were analysed for the
confirmation of their molecular structures. The observed characteristic peaks are assigned as
follows.
1H NMR (300 MHz, CDCl3) of MMC
δ 2.24 (s, 3H); 2.34 (s, 3H); 3.44 (t, J = 7.5 Hz, 1H); 3.75-3.86 (m,3H); 4.33 – 4.51 (m,3H); 4.78-4.89
1H); 6.68 (d, J = 8.1 Hz, 1H); 6.74– 6.82 (m, 2H); 6.98 -7.04 (m, 3H); 7.16 (t, J = 7.5 Hz, 1H); 7.19 (d, J =
7.8 Hz, 1H); 7.25- 7.28 (m,2H); 7.29(d, J = 7.2 Hz,1H); 7.39 (d, J = 7.8 Hz,1H);
Fig. 1a. 1H NMR spectrum of MMC.

13C NMR of MMC (75 MHz, CDCl3)
δ 20.97, 35.4, 42.7, 61.1, 65.1, 71.5, 110.4, 115.7, 122.2, 123.7, 127.8, 127.9, 12.7, 128.8, 129.1, 130.1,
132.3, 136.3, 137.4, 142.9, 157.9, 186.6, 198.7.
Fig. 1b. 13C NMR spectrum of MMC.
FT-IR of MMC
Macrocylic carbonyl (C=O) 1719cm-1 and oxindole carbonyl (C=O) 1662 cm-1.
Fig. 1c. FT-IR spectrum of MMC.
1H NMR (300 MHz, CDCl3) of CMC
δ 2.10 (s, 3H); 2.69 (t, J = 8.7 Hz, 1H); 3.33 (t, J = 7.8 1H); 3.74 – 3.78 (m, 1H); 4.02 (d, J = 8.7 Hz, 1H);
4.17 – 4.42 (m,1H); 4.26 - 4.35 (m,1H);4.71 – 4.98 (m, 2H ); 5.01(d, J = 14.1 Hz, 1H); 5.35, 5.48 ( ABqJ
= 11 Hz,2H); 6.31 (d, J = 8.1 Hz, 1H); 6.72 – 6.80 (m, 3H); 6.84 -6.91 (m, 2H); 7.01- 7.04(m,3H); 7.19-
7.27 (m, 3H); 8.25 ( s,1H ).
Fig. 2a. 1H NMR spectrum of CMC.
13C NMR (75 MHz, CDCl3) of CMC
δ 39.9, 44.4, 49.6, 51.4, 62.3, 63.3, 65.3, 66.4, 110.9, 112.6, 121.3, 121.8, 126.3, 126.6, 127.7, 128.2,
128.4, 128.9, 129.6, 132.6, 136.2, 137.9,144.2, 155.1, 157.4, 199.7.ppm.
Fig. 2b. 13C NMR spectrum of CMC.
FT-IR of CMC
Macrocylic carbonyl (C=O) 1683 cm-1.
Fig. 2c. FT-IR spectrum of CMC.
4.2. UV-Vis absorption spectral analysis
The UV-Vis spectra of MMC and CMC are shown in Fig. 3a & 3b. The absorption bands at 301 nm
(MMC) and 257 nm (CMC) may be due to the n-π* transistion and π-π* transition respectively. The band
gap energy values of MMC and CMC obtained from the cut-off wavelength (λc) using the relation Eg=
hc/λc are equal to 4.127 eV and 4.834 eV respectively. Absence of absorption between 400 nm and 800 nm
in the UV-Vis spectrum is the key requirement for materials possessing NLO property [39]. The lower cut-
off wavelength and band gap energy are indicative of NLO property.

Fig. 3a. UV-Vis spectrum of MMC.
Fig. 3b. UV-Vis spectrum of CMC.
4.3. Structural description
The molecular structures of MMC and CMC are shown in Fig. 4 & 5. MMC consists of two
phenyl rings A and B [A(C10-C15); B(C22-C25,C27,C28)], one spiro pyrrolidine ring C
(N2,C17,C18,C20,C21) and an indolinone ring D [(N1,C1,C18,C2-C7)], apart from one ketone
group (C16=O3), two methyl groups attached at C25 and N2, three carbon and one oxygen atom.
The dihedral angle between the atoms of the mean plane of the rings B and C is 88.18 (0)o. The
C26 atom of methyl group deviates by -0.0957 Å from the plane of the atoms containing ring B.
The shortest distance between two rings centroids A and B is 3.6970 (11) Å [symmetry code: 1-x,
-y, -z]. The packing of the molecules is shown in Fig. 6. Molecules are linked into chains parallel
to the b axis by one C-H...π interaction involving the C12 atom via atom H12 of ring A and the
centroid of ring B of symmetry-related molecules. The packing of the molecule features a C-H…π
interaction (Table 2).
Apart from three carbon and two oxygen atoms, CMC consists of two phenyl rings A and B
[A(C1,C25-C29); B(C7-C12)], a triazole ring (N1-N3,C4,C5), a pyrrolidine ring D(N4,C13-C16)
and one chlorophenyl ring [E(C19-C24)] with half water molecule in the asymmetric unit. This
compound crystallizes with disorder of the triazole moiety (N1’,N2’,N3’,C4’,C5’) and the atoms
(O1’,C2’,C3’,C6’,O2,C17’) attached to it (53:47) along with water molecule (50:50). The C16
carbon atom in pyrrolidine ring is attached to chlorophenyl unit through ketone group. The
dihedral angle between the atoms of the mean plane of the pyrrolidine ring with the chlorophenyl
ring is 77.97 (0)o. The dihedral angles between the mean plane of the atoms of the consecutive
rings A, B, C and D with the neighbouring rings (A/B, B/C, C/D and A/D) are 39.16(0)o,
79.61(0)o, 3.64(0)o and 80.91(0)o respectively. The torsion angle of C4-C6-O2-N2 (126.5(12)o
shows the amount of twisting produced by the triazole ring with the phenyl ring B. The packing of
the molecules is shown in Fig. 7. Molecules are linked into chains parallel to the c axis by one C-
H...π interaction involving the carbon atom C17 via H17 with the centroid of ring B of another
symmetry-related molecule (Table 3). In addition, a non-covalent C—Cl...Cg interaction
involving a lone-electron pair of the Cl atom with the antibonding orbitals of ring B is observed
[C1...Cg = 3.8606(11) Å; Cg is the centroid of ring B; symmetry code: (ii) 1/2+x, 3/2-y, ½+z]
having a ‘face-on’ geometry [40].

D-H...A
D-H H...A
2.79
D...A
D-H...A
171
Symmetry codes
1-x; -y; -z.
C12—H12... CgB 0.93
3.708(5)
Table 2. The Hydrogen-bond geometry of MMC (Å ,o); CgB is the centroid of the ring B.
D-H...A
D-H
0.93
H...A
2.71
D...A
D-H...A Symmetry codes
131 -1+x; y; z.
C17—H17... CgB
3.419(16)
Table 3. The Hydrogen-bond geometry of CMC (Å ,o); CgB is the centroid of the ring B.
Fig. 4. The molecular structure of MMC with the atom numbering scheme. Displacement ellipsoids are drawn
at the 50% probability level. Hydrogen atoms are excluded for clarity.
Fig. 5. The molecular structure of CMC with the atom numbering scheme. Displacement ellipsoids are drawn
at the 50% probability level. Hydrogen atoms are excluded for clarity. The disordered atoms are shown by
dotted lines.
Fig. 6. The packing of the molecules of MMC stacked along the c-axis.
Fig. 7. The packing of the molecules of CMC stacked along the c-axis.
Both MMC and CMC possess D-π-A-π-D system where the charge transfer takes place from the
donor at the end to the acceptor at the middle of the molecule. This will ensure the electronic
delocalization within the molecule and help to improve polarization and optical non-linearity.
Further, both the macrocyclic molecules are not planar. Due to the twisted conformation of MMC
and CMC there is a possibility for NLO response [41]. Stronger the π…π and C-H…π
interactions, more effective will be the contribution to the macroscopic NLO response [42]. The
intermolecular π-π and C-H…π interactions present in MMC and CMC extend the molecular
charge transfer and may contribute towards NLO properties. To gain further insight on the
molecular properties, theoretical study at molecular level is undertaken.
4.4.Theoretical calculation of Molecular parameters
4.4.1.Mulliken charge distribution
Dipole moment is a measure of the asymmetry in the charge distribution. The changes in atomic charges
affect dipole moment, molecular polarizability, electronic structure and a number of other properties [43].
The calculated Mulliken charge values of MMC and CMC are listed in Tables 4a and 4b. The donor atoms
possessing a negative charge are O1, O2, O3, N1 N2 (MMC) and N1, N2, N3, O1, O2, O3 (CMC). In
MMC, the carbon atom C26 has the highest negative charge, C12 with lower negative charge and C22 has
the lowest negative charge. The carbon atom C16 has the highest positive charge while C7, C10, C18
atoms possess less positive charge and C25 carbon atom possesses lowest positive charge. In CMC, the
carbon atom C17 with the highest negative charge, acts as the donor in intermolecular interaction. It is

clearly shown that the carbon atom C7 carries more positive charge and atoms C15 and C22, carry less
positive charge.
S.No Atom Charge
1
O2
-0.377582
-0.483721
-0.049898
-0.277249
0.517359
-0.592671
0.586612
-0.455678
0.305156
-0.492658
-0.160541
0.233369
-0.054321
0.226731
-0.151402
-0.194816
0.224104
-0.302071
0.243051
-0.190227
0.203620
0.031492
-0.362143
2
O1
3
C22
C15
C16
N1
4
5
6
7
C1
8
O3
9
C10
N2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
C21
H21
C14
H14
C2
C23
H23
C17
H17
C28
H28
C25
C11

24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
H11
C27
H27
C7
0.216730
-0.236614
0.198168
0.210816
-0.226286
0.203807
-0.168889
C24
H24
C20
H20A 0.196739
H20B 0.182576
C3
-0.089420
0.244990
0.167389
-0.286260
0.213524
-0.090883
0.196489
-0.295232
0.211582
-0.142951
H3
C18
C6
H6
C12
H12
C13
H13
C8
H8A 0.230610
H8B 0.203138
C4
H4
C9
-0.256145
0.209786
-0.167219
H9A 0.187663
H9B 0.188258

50
51
52
53
54
55
56
57
58
59
C19
-0.380730
H19A 0.200736
H19B 0.198533
H19C 0.184579
C5
-0.141627
0.197231
-0.597336
H5
C26
H26A 0.204807
H26B 0.199025
H26C 0.205901
Table 4a. Mulliken atomic charge of MMC.
S.No Atom Charge
1
N2
-0.051080
-0.266914
-0.104507
0.490300
-0.370894
-0.436054
-0.140832
0.234151
-0.311078
0.230913
0.236827
-0.148493
0.213598
-0.507231
2
N1
3
Cl1
C18
O2
4
5
6
O3
7
C13
H13
C16
H16
C7
8
9
10
11
12
13
14
C11
H11
N4

15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
C24
H24
C19
C25
O1
-0.126811
0.234564
-0.176424
-0.118119
-0.408737
0.029996
-0.115723
-0.259017
0.226834
-0.172014
C22
C12
C23
H23
C14
H14A 0.183261
H14B 0.189604
C26
H26
C9
-0.116451
0.248369
-0.138904
0.194839
0.044790
0.188229
-0.138486
0.236167
-0.318174
0.212215
-0.300963
0.214046
-0.221905
0.244764
H9
C15
H15
C20
H20
C8
H8
C29
H29
C21
H21

41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
C17
-0.369284
H17A 0.195282
H17B 0.158520
H17C 0.192722
C28
H28
C1
-0.156750
0.199905
0.205053
-0.256857
0.203903
-0.093096
C10
H10
C6
H6A 0.202399
H6B 0.209028
C27
H27
C5
-0.255767
0.210952
-0.099351
0.259600
-0.231906
-0.038727
-0.142613
H5
N3
C4
C2
H2A 0.214312
H2B 0.189358
C3
-0.157140
H3A 0.223846
H3B 0.231958
Table 4b. Mulliken atomic charge of CMC.

4.4.2. Global reactivity descriptors
The Highest occupied molecular orbital (HOMO) represents the ability of the molecule to donate
an electron and lowest unoccupied molecular orbital (LUMO) represents the ability to accept an
electron. HOMO and LUMO energies are very useful parameters for predicting the most reactive
position in π-electron systems. The HOMO is directly related to the ionization potential, while the
LUMO is directly related to electron affinity. The HOMO and LUMO energy values are used to
calculate global reactivity descriptors such as ionization potential (I = -HOMO eV), electron
affinity (A = -LUMO eV), electronegativity (χ =(1+A)/2 eV), chemical hardness (η = (1-A)/2 eV),
chemical potential (ꢀ = -(1+A)/2 eV), chemical softness (S = 1/(2η) eV-1) and electrophilicity
index (ω = ꢀ2/2η eV) [44]. The results are summarized in Table 5.
The HOMO and LUMO energies of MMC (-8.592eV, -0.393eV) and CMC (−8.744eV,-0.448eV),
show that charge transfer occurs within the molecule. HOMO-LUMO energy difference serves as
a measure of excitability and hence interaction of the molecule with other species [45]. MMC
possesses smaller energy gap than CMC. Both the compounds have lower (I) value and higher (A)
value. Global chemical hardness and softness (η, S) values are considered as a measure of
intramolecular charge transfer. It was observed that CMC has higher chemical softness and lower
chemical hardness than MMC. High chemical potential and electrophilicity index values are
associated with a good electrophilic character [46]. These values indicate that both MMC and
CMC have a tendency to accept electrons and hence electrophilic character.
Property
MMC CMC
-8.592 -8.744
-0.393 -0.448
8.199 8.296
HOMO (eV)
LOMO (eV)
│∆E│ = HOMO - LUMO gap (eV)
Ionization potentials, I = - HOMO (eV) 8.592 8.744
Electron affinity, A = - LUMO (eV)
Electronegativity, χ = (1+A)/2 (eV)
Chemical hardness, η = (1-A)/2 (eV)
0.393 0.448
0.697 0.724
0.304 0.276

Chemical potential, ꢀ = -(1+A)/2 (eV) -0.697 -0.724
Chemical softness, S = 1/(2η) (eV)-1
Electrophilicity index, ω = ꢀ2/2η (eV)
1.645 1.812
0.800 0.950
Table 5. Global reactivity descriptors of the compounds MMC and CMC.
4.4.3. Static second order hyperpolarizability
The NLO response at molecular level is due molecular asymmetry and hence hyperpolarization of the π
electrons. Due to the overlap of p orbital, delocalization of electronic charge distribution leads to a high
mobility of the electron density. When laser light is incident on a molecule, the electric field interacts with
the charge distribution of the molecule and results in an induced polarization (P) or induced dipole moment
(ꢀ). In the presence of laser beam, this induced polarization will be non-linear in nature [47].The nonlinear
polarization at the molecular level and is given by [48].
P = ∑αijE + k ∑βijkE2 + ∑γijklE3
where αij = polarizability, βijk = first order hyperpolarizability, γijkl = second order hyperpolarizability (third
order effects) and i, j, k, l corresponds to the molecular coordinates. The materials show third order non-
linearity if the second order hyperpolarizability (γ) value is non-zero [49]. The theoretical value of dipole
moment and static second order hyperpolarizability of MMC and CMC are given in Table 6. These
theoretical values may provide an insight while designing the macrocyclic NLO materials.
Dipole moment ( ꢀ ) Debye
Components MMC
CMC
0.2471
-0.1191
ꢀx
ꢀy
ꢀz
Μ
-1.1997
0.3211
-1.1194
-2.0857
4.2177 Debye
5.3724 Debye
Second order hyperpolarizability( γ ) x10-35esu
Components MMC
CMC
67140.30854
60119.74273
23992.44138
22962.10432
γxxxx
γyyyy
γzzzz
36967.91720
16863.64161

11257.47270
7248.28589
19473.91447
13528.58923
6279.50268
γxxyy
γxxzz
γyyzz
γ
9964.15875
1.7921x10-35esu
1.8700 x10-35esu
Table 6. The dipole moment (ꢀ) and static second order hyperpolarizability (γ) and their components for
MMC and CMC
4.5. NLO parameters of reported macrocyclic compounds
The values of the static second order hyperpolarizability (γ) of a sample of seventeen reported
macrocyclic molecules which contain only C, O, N and H were calculated by semiempirical quantum
chemical method using MOPAC 2016 with the X-ray coordinates available in the CSD [50] as the
starting geometry (Table 7).
S.No
CSD
Refcode
CCDC
Number
Static second
hyperpolarizability
(γ)x10-35esu
4.1484
1.
HOYPUI
1015636
1226529
721796
915412
914819
258197
1310722
1059565
169025
229946
1222561
716306
2. OXTCNT10
3. FUQWUK
2.9973
1.8994
4.
5.
VICCIV
VICDUI
1.4409
1.2920
6. NOQTES01
1.0630
7.
8.
9.
ZEJRIP
SUMLUJ
UDAKOZ
1.0282
1.0138
0.9737
10. ARELAK
11. NOQTES
12. LOQBID
0.8957
0.8893
0.8862

13. BEMRUI
14. PAPVAE
15. DICDOI
16. KUSXEB
17. EICRGM
835501
261295
0.8524
0.7320
0.3502
0.3380
0.3375
1140232
1201555
1149153
Table 7. Calculated static second order hyperpolarizability of some macrocyclic compounds found in the
literature
The plot of static second order hyperpolarizability of the compounds found in the literature is shown in
Fig. 8. These compounds were found to have values ranging from 0.3375x10-30esu to 4.1484x10-30esu.
The static second order hyperpolarizability values obtained show that all the above macrocyclic
compounds possess nonlinear optical response. This analysis points out that macrocyclic compounds
may be suitable for use in the optical devices.
Fig. 8. Static second order hyperpolarizability γx10−35esu of the compounds found in the literature.
4.6. The effect of Halogen substitution on the Non-Linear Optical (NLO) properties of
macrocyclic molecules
In this context, an attempt is made to understand the effect of substitution of halogens at the para
position of the phenyl ring of chloro macrocycle by replacing the chlorine atom of CMC by other
halogen atoms such as flourine (CMC-F), bromine (CMC-Br) and iodine (CMC-I). The optimised
molecular structures of CMC-F, CMC-Br and CMC-I are shown in Fig. 9-11. The values of the

global reactivity descriptors of all the four moleculesare provided in Table 8. The variation of
HOMO-LUMO energy gap is shown in Fig. 12. This value is found to be the highest for iodine
and the lowest for fluorine. It is observed that the chemical softness increases in the order (CMC-
I>CMC-Br>CMC>CMC-F), chemical hardness increases in the order (CMC-F>CMC>CMC-
Br>CMC-I) and electrophilicity index (ω) increases in the order (CMC-I>CMC-Br>CMC>CMC-
F) (Fig. 13 & 14). These values are associated with good electrophilic character. The static second
order hyperpolarizability (γ) values of all the four halogenated macrocyclic molecules CMC-F,
CMC, CMC-Br and CMC-I are shown in Table 9. They follow the order CMC-I>CMC-
Br>CMC>CMC-F (Fig.15) with the iodine substituted macrocycle possessing the highest value of
γ.
Fig.9. Optimised molecular structure of CMC-F

Fig.10. Optimised molecular structure of CMC-Br
Fig.11. Optimised molecular structure of CMC-I
Property
CMC-F
-8.732
-0.319
8.413
CMC-Br
-8.741
-0.457
8.284
CMC-I
-8.740
-0.465
8.275
8.740
0.465
HOMO (eV)
LOMO (eV)
│∆E│ = HOMO - LUMO gap (eV)
Ionization potentials, I = - HOMO eV) 8.732
Electron affinity, A = - LUMO (eV) 0.319
8.741
0.457

Electronegativity, χ = (1+A)/2 (eV)
Chemical hardness, η = (1-A)/2 (eV)
0.660
0.341
0.729
0.272
-0.729
1.838
0.977
0.733
0.268
-0.733
1.866
1.003
Chemical potential, ꢀ = -(1+A)/2 (eV) -0.660
Chemical softness, S = 1/(2η) (eV)-1
1.592
Electrophilicity index, ω = ꢀ2/2η (eV) 0.693
Table 8. Calculated global reactivity descriptors for optimised halogen substituted CMC
Fig. 12. HOMO-LUMO energy gap (eV) of CMC-F, CMC, CMC-Br and CMC-I

Fig. 13. Global chemical softness S (eV)-1of CMC-F, CMC, CMC-Br and CMC-I
Fig. 14. Electrophilicity index ω (eV) of CMC-F, CMC, CMC-Br and CMC-I
Compounds static first second hyperpolarizability(γ)x10-35esu
CMC-F
CMC
1.6678
1.8700

CMC-Br
CMC-I
1.9242
2.2694
Table 9. Calculated static second order hyperpolarizability (γ) x10-35esu of CMC-F, CMC, CMC-Br and CMC-
I.
Fig.15. Static second order hyperpolarizabilities (γ) x 10−35esu of CMC-F, CMC, CMC-Br and CMC-I
4.7. Bioactivity scores
The bioactivity scores for MMC and CMC towards GPCR ligand, ion channel modulator, nuclear receptor
legend, kinase inhibitor, protease inhibitor and enzyme inhibitor are arrived through Molinspiration
software (Table 10). The organic molecules with bioactivity scores >0, are interpreted as active, (-5.0-0.0)
as moderately active, and <-5.0 as inactive. For MMC, all scores are less than zero while for CMC, the
GPCR and EI happen to be very slightly greater than zero. Hence it can be concluded that both the
macrocyclic derivatives are moderately active.
Structures
GPCR
ICM
MMC
-0.19
-0.48
-0.54
-0.56
CMC
0.14
-0.13
-0.18
-0.36
KI
NRL

-0.38
-0.39
-0.18
0.07
PI
EI
Table 10. Bioactivity scores of the compounds MMC and CMC
5. Conclusion
Good quality single crystals of two macrocyclic compounds were grown by slow evaporation
1
technique. The structures are confirmed by H NMR, 13C NMR and FT-IR analysis. X-ray
diffraction reveals the three dimensional structures of the compounds. The UV-Visible spectra
showed good transparency in the visible region. The theoretical study of the molecular parameters
provides an insight on the non linear response of the macrocyclic molecules. The study of the
effect of halogen substitution starting from chloro macrocycle shows that the second order
hyperpolarizability at molecular level varies with the substituent (I>Br>Cl>F). The calculated
bioactivity scores show that both the compounds may be moderately active.
Acknowledgement
The authors thank the single-crystal XRD facility, SAIF IIT Madras, Chennai, for the data collection.
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HIGHLIGHTS
Crystal structure analysis of new chloro and methyl macrocyclic compounds by XRD
Characterisation by 1H, 13C NMR, FTIR and UV- Vis spectra
Calculation of global reactivity descriptors and static second order
hyperpolarizability using Mopac 2016.
The effect of halogen substitution on the third order Non Linear Optical (NLO)
Parameters.
Bioactivity scores using Molinspiration software.