Probing mechanism of α-formylketene dithioacetal towards the facile formation of functionalized pyrimidines: A structural approach

Accepted Manuscript

Probing mechanism of α-formylketene dithioacetal towards the facile formation of

functionalised pyrimidines: A structural approach

Monu Joy, Adebayo A. Adeniyi, Annie Mathews, Bijo Mathew, S. Prasanth, Mohmoud

E.S. Soliman, Jalaja J. Malayan, E.R. Anabha

PII:

S0022-2860(16)30791-8

10.1016/j.molstruc.2016.07.107

MOLSTR 22810

DOI:

Reference:

To appear in: Journal of Molecular Structure

Received Date: 6 May 2016

Revised Date: 25 July 2016

Accepted Date: 27 July 2016

Please cite this article as: M. Joy, A.A. Adeniyi, A. Mathews, B. Mathew, S. Prasanth, M.E.S. Soliman,

J.J. Malayan, E.R. Anabha, Probing mechanism of α-formylketene dithioacetal towards the facile

formation of functionalised pyrimidines: A structural approach, Journal of Molecular Structure (2016),

doi: 10.1016/j.molstruc.2016.07.107.

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ACCEPTED MANUSCRIPT

Graphical Abstract

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S

C

S1

O1

C7

C6

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ACCEPTED MANUSCRIPT

Probing mechanism of α- Formylketene dithioacetal towards the facile

formation of functionalised pyrimidines: a structural approach

Monu Joy^a,d*, Adebayo A. Adeniyi^b, Annie Mathews^a, Bijo Mathew^c, S Prasanth^d, Mohmoud

E.S. Soliman^b, Jalaja J Malayan^a, E R Anabha^e

^aDepartment of Chemistry, Baselius College, Kottayam-686001, Kerala, India

^bSchool of Health Science, University of KwaZulu-Natal, Westville, Durban 4001, South

Africa

^cDivision of Drug Design and Medicinal Chemistry Research Lab, Department of

Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad -678557, Kerala, India

^dSchool of Pure & Applied Physics, MG University-686560, Kerala, India

^eDepartment of Chemistry, Sree Narayana College, Thrissur-680566, Kerala, India

Abstract

α-Formylketene dithioacetal is an active precursor for the synthesis of a variety of

organic compounds including pyrimidines and its functionalized materials. The present study

deals with the structural versatility of a solid representative compound from the family of α-

formylketene dithioacetal to the formation of functionalized pyrimidines derivatives through

experimental as well as theoretical methods. 2-(3,4-dimethoxybenzoyl)-3,3-

bis(methylsulfanyl)prop-2-enal, the representative compound was synthesized with a reported

protocol and characterized through spectral methods. The complete three dimensional solid

state structural studies were carried out utilizing single crystal X-ray crystallographic

technique along with theoretical methods like classical and accelerated molecular dynamics

simulation. Various quantum chemical parameters were also discussed to reveals the

complete molecular geometry and reactivity of designated compound.

Formyl ketene dithioacetal; Pyrimidine; Single Crystal XRD; Molecular Dynamics, Quantum

Chemical Calculations

^*Corresponding and first author: (Present address)

Monu Joy

School of Pure & Applied Physics

MG University-686560

Kerala, India

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1. Introduction

α- Formylketene dithioacetals are multifarious starting materials for the synthesis of

number of heterocyclic compounds such as pyridines and nicotinonitriles [1]. They can be

prepared by the reaction of ketones containing active methelene group with carbon disulfide

in the presence of a strong base like sodium ter-butoxide and subsequent alkylation to

generate ketene dithioacetals and then the formylation of the corresponding ketene

dithioacetal with 1.5 equivalents of Vilsmeier- Haack reagent [2]. The aldehydic moiety is

stabilized through conjugation of π electrons towards the aromatic region where as the

formylation will not performed over aliphatic ketene dithioacetals via Vilsmeir – Haack

approach [2, 3].

Scheme 1

It is a doubly activated unique building block because of the presence of both ketonic and

aldehyde functional groups in addition to the ketene dithioacetal moiety at the α-position. As

each of these three groups has varying reactivity towards condensing agents, their selectivity

can be utilized effectively for the synthesis of a wide variety of substituted and annulated

heterocycles [2, 4]. One of the vital class of compounds that can be synthesized from α-

formylketene dithioacetals is pyrimidine derivatives; they demonstrate a diverse array of

biological and pharmacological activities including anticonvulsant, antibacterial, antifungal,

antiviral and anticancer properties [5, 6]. Pyrimidine-5-carbaldehydes are valuable precursors

for the synthesis of drugs used for the treatment of Alzheimer disease [7]. Some annulated

pyrimidines are used in the treatment of cardiovascular diseases [8] and insomnia [9]. It is

important to learn the electronic structure and its reactivity of the α-formylketene dithioacetal

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towards the formation of pyrimidine derivatives and also it is possible to establish the

optimum criteria for the synthesis of further useful pyrimidine derivatives in future. So here

we

reveal

the

structural

adaptability

of

2-(3,4-dimethoxybenzoyl)-3,3-

bis(methylsulfanyl)prop-2-enal (Mol1) towards the one pot formation of pyrimidines through

experimental and theoretical electronic structure. From the light of above view, herein we

establish the complete X-ray crystallographic, classical and accelerated molecular dynamics

(AMD) and quantum chemical properties of Mol1, one of the crystalline α-formylketene

dithioacetals obtained through Vilsmeir–Haack reaction on 3,4-dimethoxybenzoylketene

dithioacetal following the procedure of Asokan et al [2] as an extension of our interest in

sulfur containing compounds [10]. To the best of our knowledge neither detailed theoretical

calculation nor detailed crystallographic parameters of this compound have been reported yet.

2. Experimental

2.1 Synthesis

Mol1 had been synthesized with a reported method [2]. 3,4-dimethoxy acetophenone

18mg (0.1M) was dissolved in CS₂(7mL, 0.1M) and it was added dropwise to an ice-cold

suspension of sodium t-butoxide (0.2M) in dry THF. The reaction mixture was allowed to stir

for 5-6 hours. After 6 hours 29mL of methyl iodide (0.2M) was added dropwise. The

temperature should be 0 to 5^°C. The reaction mixture was allowed to stand for 10 hours,

reaction was quenched by adding water and the product is extracted using ethyl acetate, dried

over anhydrous sodium sulphate (Scheme 1a). The α-oxoketene dithioacetal was purified by

column chromatography using 2:8 ethyl acetate-hexane mixture solution. The purified ketene

dithioacetal was treated with Vilsmeier-Haack reagent as follows. 14.2g of α-oxoketene

dithioacetal(0.05M) was treated with 1.5 equivalent of POCl₃in dry DMF at -5 to 0^°C, to

obtain the title compound with 80% yield (Scheme 1b). The compound was purified using

column chromatography with 3:7 ethyl acetate-hexane solution and was crystallized using the

same solution through slow evaporation. FT-IR spectrum was recorded using thermo Nicolet,

Avatar 370 FT-IR Spectrometer equipped with a deuterated triglycine sulfate detector with

spectral range 4000-400 cm^-1and resolution 4 cm^-1. FT-Raman spectrum was recorded from

Bruker RFS 27: Stand alone FT-Raman Spectrometer with a scanning range of 50-4000 cm^-1

13

and a resolution of 2 cm^-1with a laser source of Nd: YAG 1064 nm. FT-NMR (¹H and C)

spectrum was taken in CDCl₃solution at room temperature and all signals were referenced to

1

TMS on a Bruker AVANCE III-(400MHz for H and 100MHz for ¹³C) FT-NMR

Spectrometer. 2-(3,4-dimethoxybenzoyl)-3,3-bis(methylsulfanyl)prop-2-enal, pale yellow

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coloured crystals; mp 108-110^°C; yield: (86%); IR (FT) ν_max/ cm^-1600, 1275, 1578, 1634,

1

1662, 2822, 2938, 2999; RAMAN (FT) ν_max/ cm^-11507, 1588, 1656, 2931; H NMR

(400MHz, CDCl₃): δ = 2.56, 2.46 (2s, 6H, methyl sulfanyl); 3.94 (s, 6H, dimethoxy); 6.85-

13

7.55 (m, 3H aromatic); 10.17 (s, 1H, aldehydic) ppm. C NMR (100MHz, CDCl₃): δ = 17,

18 (methyl sulfanyl); 56 (methoxy); 129 (aliphatic sp²hybridised); 121, 124, 132, 141,149,

154 (aromatic); 186 (ketonic); 192 (aldehydic) ppm.

2.2 Data Collection & Refinement

Single crystals of the compound suitable for X-ray diffraction were grown by slow

evaporation from ethyl acetate-hexane solution. The yellow crystals were prismatic. The

dimensions of the crystal used for data collection were 0.20 x 0.30 x 0.35 mm³. The crystals

belonged to Monoclinic system having space group P21/n with unit cell dimensions, a =

8.6760Å,

b = 16.0399Å, c = 11.2260Å, α = 90˚, β = 102˚ and γ = 90˚. Data were

collected using Brucker AXS Kappa Apex II CCD detector diffractometer using graphite

monochromatic Mo-Kα radiation (λ=0.71073Å) at 293K. The data reduced using the

program SAINT [11] and empirical absorption corrections are done using the SADABS [12].

The structure was solved by intrinsic phasing method using SHELXT-2013 [13]. The top 21

peaks formed the complete structure. The structure was refined using full-matrix least squares

method based on F²using SHELXL-2013 [14]. Five cycles of isotropic refinement were

followed by anisotropic refinement for the non-hydrogen atoms. The position of all hydrogen

atoms were geometrically fixed and treated with riding atoms, with C-H distances of 0.93 or

0.96 Å. Anisotropic refinements of the non-hydrogen atoms along with isotropic refinement

of hydrogen atoms has been carried out using 4990 reflections. Materials for publications

were prepared using, ORTEP [15], Mercury [16] programs. Detailed crystallographic data for

the structural analyses have been deposited with the Cambridge Crystallographic Data

Centre, CCDC with deposition number 1422213. Copies of this information can be obtained

from The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ,

UK

(fax:

+44-1223-336033;

e-mail:

deposit@ccdc.cam.ac.uk

or

www:

http://www.ccdc.cam.ac.uk).

2.3 Classical and Accelerated Molecular Dynamics

The crystallographic geometry was exploited to optimize the molecule using Gaussian

09[17] with functional/basis set of HF/6-31G* and the force field as well as atomic charges

were computed and fitted through the supporting package RED[18]. Parameterization was

done using the restrained electrostatic potential (RESP) method as implemented in the

package RED to fit the atomic partial charges of the atoms. The solute was immersed in an

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orthorhombic solvent box mixture of 20% acetonitrile and 80% water as an explicit solvent

system [19] using the package pyMDMix version 0.2 (http://mdmix.sourceforge.net).

Molecular dynamics was done using Amber 12 [20] and GPU based PMEMD programme

[21]. Partial mesh ewald (PME) method was used for the long range electrostatic potentials

with vdW cut-off of 12Å. Two level of minimization was done, first with strong constrained

on the molecule for 1000 steps (500 steepest descent followed by 500 steps of conjugate

gradient) and the second without constraint for 1000 steps of conjugate gradient only. The

system was gradually heated up to temperature of 300K in canonical ensemble for 50ps using

Langevin thermostat with a collision frequency of 1ps^-1and a harmonic restrained of 5

kcal/mol Å on the solutes. The density of the system was equilibrated for another 50ps in

NPT ensemble and the final equilibration at 300K temperature, 1bar pressure and a coupling

constant of 500ps was carried out for 500ns which were finally followed by 10ns production

MD. In all the steps of simulations, frame were recorded at every 500 steps of simulation and

a time step of 2fs and all bond lengths involving hydrogen atoms were restrained with

SHAKE algorithm [22]. In order to sufficiently sample the possible conformational minimal

of the molecule, we applied the accelerated molecular dynamic simulation (AMD) methods

[23] for another 10 ns.

2.4 Quantum chemical details

The molecular geometry optimization, calculations of energy and various quantum

chemical reactivity descriptors were carried out for Mol1 in an acetonitrile solvent system

with the Gaussian 09W [17] software package using DFT/B3LYP functional combined with

the standard 6-311G(d,p) basis set. DFT employed the B3LYP keyword which invokes

Becke’s three parameter hybrid method [24, 25] using correlation function of Lee et al.

HOMO–LUMO analysis was carried out in gas phase with B3LYP/6-311G(d,p) to explain

the charge transfer within the molecule. Ionization Potential (IE), Electron Affinity (EA),

Global Electronegativity (χ), Chemical Hardness (η), Chemical Softness (S), Chemical

Potential (ꢀ), Global electrophilicity index, Dipole Moment (Debye) have been calculated

using the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular

orbital (LUMO). The NBO analysis was performed using the Gaussian 09W package at the

B3LYP/6-311++G(d,p) level in order to understand various second order interactions

between the filled orbital’s of one subsystem and vacant orbital’s of another subsystem,

which is a measure of the intra-molecular delocalization or hyper conjugation [26]. Mulliken

population analyses have been calculated. Molecular electrostatic potential (MEP) analysis

has been used to find the reactive sites of the compound. The electrostatic potential contour

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map with the negative regions (assigned to red) of MEP were related to electrophilic attacks

and positive regions (assigned to blue) were related to nucleophilic reactivity. Fukui

functions and molecular electrostatic potential (MEP) were evaluated and analysed with

mPWIPW91/6-311G(d,p) level of theory.

3. Result & discussion

3.1 Spectral description

The IR data shows a peak at 2999cm^-1representing aromatic C-H stretching vibration.

Carbonyl stretching vibrations are visible at 1662 & 1634cm^-1. Peak at 1578cm^-1corresponds

to aromatic C=C double bond stretching vibration. Peak at 1275cm¹reveals C-O vibration in

the methoxy group. C–S vibration is visible at 600cm^-1. C-H vibrations corresponds to

methoxy group is at 2822cm^-1where as simple methyl group vibrates at 2938cm^-1. The

RAMAN spectrum represents a peak at 2931cm^-1represents the aromatic C-H stretching

vibration. The peak at 1656cm^-1corresponds to carbonyl frequency. 1588cm^-1belongs to the

aromatic C=C vibration. Aromatic C-C vibration is lying at 1507cm^-1. An intense peak

obtained between 100 and 125cm^-1shows the lattice vibration reveals the crystalline nature of

the compound. The ¹H NMR data show peaks at 2.56 and 2.46 ppm which can be assigned to

six protons of methylsulfanyl group. The peaks lying between 6.85-7.55 ppm represent three

aromatic protons and the peak at 3.94 ppm represents the 6 protons of two methoxy groups

13

attached on the benzene ring. The aldehydic proton is at 10.17ppm. The C NMR having a

peak at 192ppm represents aldehydic carbon and 186ppm for ketonic carbon. Peak at 17 and

18ppm corresponds to two methyl sulfanyl carbons whereas methoxy carbons lying at 56

ppm. The characteristic peaks between 121-154 ppm represent 6 aromatic carbons. The peak

corresponds to aliphatic double bonded carbon is observed at 129 ppm.

3.2 Crystallographic studies

The crystal data and structure solution details of the compound are given in Table 1.

Table 1

Empirical formula

Formula weight

Temperature

C₁₄H₁₆O₄S₂

312.41

293(2) K

Wavelength

0.71073 Å

Crystal system

Space group

Monoclinic

P 21/n

Unit cell dimensions

a = 8.6760(3) Å

b = 16.0399(4) Å

c = 11.2260(4) Å

a= 90°.

b= 102.093°

g = 90°.

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3

Volume

1527.57Å

4

Z

3

Density (calculated)

Absorption coefficient

F(000)

1.358 Mg/m

-1

0.336 mm

544

3

Crystal size

20 x 30 x 35 mm

11708

Reflections collected

Independent reflections

Completeness to theta

Refinement method

Data / restraints / parameters

3766 [R(int) = 0.0223]

25.242°, 99.9 %

Full-matrix least-squares on F

3766 / 0 / 181

2

Goodness-of-fit on F

R1 = 0.0370, wR2 = 0.1056

0.966

Crystal data

Figure 1

Mechanism of formation of pyrimidines from α- Formylketene dithioacetals

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The ORTEP diagram of the Mol1 is shown in Fig: 2 and the details of the data

collection specification and the parameters of the refinement are given in Table 1. Because of

the substitutions, the phenyl ring appears little distorted and angles are slightly out of

hexagonal structure ∠C3-C1-C2 119.5°, ∠C2-C4-C6 120.0°, ∠C4-C6-C5 119.8°, ∠C1-C3-

C5 120.7°, ∠C1-C2-C4 119.9° and the bond lengths ranges from 1.379 Å to 1.410 Å .

Figure 2

ORTEP diagram of the Mol1 with 50% polarisability

Two methoxy groups attached to the phenylic moiety and the phenyl group itself are

coplanar in nature as observed from the structure. Ketonic carbonyl group is slightly out of

plane as compared to the phenylic residues ∠O9-C8-C1-C3 12.7°. The methoxy substitution

contributes the crystalline nature via its triangular binding by means of its electron releasing

capacity through conjugation. It is proved because similar aroyl substituted formyl ketene

derivatives are semi solids [2]. Short inter molecular attraction of methoxy group and methyl

sulfanyl hydrogen help the three dimensional architecture of the crystal through non covalent

interaction as shown in the Fig: 3. An intra molecular hydrogen bonding pattern is depicted

by C-H…O and C-H…S interactions (Table 2) are also responsible to the three dimensional

architecture of the molecule in the monoclinic system.

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Table 2. Hydrogen bonding interactions of for Mol1.

___________________________________________________________________________

D-H...A d(D-H) Å d(H...A) Å d(D...A) Å <(DHA) °

__________________________________________________________________________

C(19)-H(33)...S(12)^#1

C(15)-H(29)...O(17)^#2

C(14)-H(27)...O(20)^#3

C(14)-H(27)...O(7)^#3

C(5)-H(24)...O(9)^#1

0.96

0.93

3.02

2.63

2.58

2.59

2.45

3.938(2)

3.515(2)

3.347(2)

3.339(3)

3.3678(18)

161.4

153.8

137.0

134.6

168.9

d: distance; D: Donor; A: Acceptor; H: Hydrogen

Symmetry transformations used to generate equivalent atoms:

^#1x+1/2,-y+1/2,z+1/2; ^#2x-1,y,z; ^#3-x,-y,-z+2

Figure 3

Triangular interaction of methoxy oxygen with methyl sulfanyl hydrogen

The feasibility of formation of pyrimidines from formyl ketenedithioacetal using

amidines can be rationalized according to the mechanism proposed by Topfl et al [27]. The

quantitative study of the same could be reveals here through its crystal structure: The methyl

sulphanyl groups are oriented in such a way as to avoid the steric interaction between them in

accordance with the torsion angles ∠C14-S12-C11-S13 44.6°, ∠C15-S13-C11-S12 42.8°

leading to the ease of formation of an acyclic N,S-acetal on addition with an amidine, and one

of the two methyl sulfanyl groups are susceptible for leaving as methyl thiol because C10-

C11 bond is rotatable. The dimethoxy acetophenone moiety with its extensive conjugation

helps the polarization of ketonic carbonyl group rather than aldehydic carbonyl, favors the

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formation of cyclic intermediate via intramolecular 1,2-nucleophilic amination reaction.

Electron releasing effect of two methoxy groups on acetophenon facilitates the conjugation of

the precursor as evident by the partial double bond character C10…C11 1.35 Å, C2…C4 1.37

Å and C3…C5 1.38 Å and partial single bond character C10…C16 1.46 Å, C8…C10 1.50Å,

C1…C8 1.48 Å, C1…C2 1.40 Å and C4…C6 1.41 Å but the conjugation is not extended to

the methyl sulfanyl groups S12…C14 and S13…C15 are 1.79 Å. The aldehydic group

appears completely out of plane from the rest of the residues, is due to the interaction (Fig. 4)

of aldehydic oxygen with methyl sulfanyl hydrogen and aldehydic hydrogen may leads to

unreacted on the formation of pyrimidines make it as a synthon for highly useful functional

pyrimidine derivatives.

Figure 4

Interaction of aldehyde oxygen with methyl sulfanyl hydrogen and aldehydic hydrogen

3.3 Molecular Dynamics simulation

X-ray crystallographic structure represents one frozen view of the molecule; whereas

all possible conformations are available in solution along with solvent effects. Acetophenone

or DMF is the solvent used in the formation of pyrimidines from α-Formylketene

dithioacetals but former gives higher yield [28]. Inclusion of solvent effects along with a

dynamic nature of the molecule is only given by Molecular Dynamics simulation and the

AMD is the best method for conformational minimal search. Herein we performed both

classical and AMD simulations for searching any possible conformations that are available

over a time period of 10ns. Throughout the 10ns classical molecular dynamics simulation,

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there is no observed change in the root means square displacement (RMSD) of the Mol1 but

significant changes was observed during the AMD simulation. The kinetic (EKTOT),

potential (EPTOT) and total (ETOT) energies for the 10 ns classical MD of the compound are

shown in Fig: 5a while the corresponding ones obtained through the AMD simulation are

shown in Fig: 5b. These plots clearly show that both classical and accelerated molecular

dynamics have similar EKTOT, EPTOT and ETOT surface and stable energy equilibrium

was observed in the two methods.

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Figure 5a

The kinetic, potential and total energies of the ligand for the 10 ns of molecular dynamics

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Figure 5b

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The kinetic, potential, total energies and RMSD of the ligand for the 10 ns of accelerated molecular

dynamics

After the 10 ns of classical MD simulation, the structure of the compound interacting

with the solvent molecules of acetonitrile (ANT) and water (WAT) within the range of radius

less than 4 Å is shown in Fig: 6. Both acetonitrile and water molecule do not have any HB

interaction with the ligand but they both exhibit a vDw contact within the range of -0.2 to -

0.4 as shown in Table 3.

Figure 6

The vDw interaction of solvent molecules (water and acetonitrile) with the ligand after the 10 ns

simulation steps.

Table 3

Ligand atom

LIG 1 C13

LIG 1 H14

LIG 1 H8

Solvent atom

ANT 211 N1

WAT 236 O

vDw

Distance

3.563

-0.238

-0.272

-0.376

-0.381

2.897

2.876

LIG 1 C10

3.581

The Vdw contact interaction of the solvent molecules (ANT and WAT) with the Mol1

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The geometry of the ligand remains virtually the same after the 10ns of classical MD

simulation without any root means square displacement (RMSD) reveals the stability of the

conformation within the solvent system. In order to explore the conformational space for any

possible geometrical minimal, the AMD method was applied as described in the

methodology. After the 10 ns of AMD simulation, three additional conformations of the

compound were identified as local minimum as shown in Fig: 7. The conformational changes

in the ligand were determined in terms of the changes in the selected two dihedral angles O-

C6-C7-S1 (RC1) and O1-C6-C7-S (RC2) as shown in Fig: 7. The energy surface clearly

shown that three more minimal geometries of the ligand were obtained in the order of A > B

> C respectively in terms of the potential energy surface as shown in Table 4.

Figure 7

S

B

O1

S1

A

S

C7

S1

O1

C6

C7

C6

O

S

C

S1

O1

C7

C6

O

The conformational minimal’s of the ligand obtained through the AMD simulation

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Table 4.

Step (ps)

State

RC1 (Degree)

RC2 (Degree) PMF(kcal/mol)

RMSD from initial

geometry (Å)

0

Initial

91.481

97.932

-49.259

847

C

A

B

-58.799

41.947

1.574

0.000

0.232

2.107

0.837

1.264

1424

8751

65.604

137.116

107.987

The dihedral angles (RC1 and RC2), potential of mean force (PMF), and root mean square

displacement (RMSD) of the local minimum geometries obtained during the AMD simulation

From the dihedral angles it is evident that no parts of the molecule are orthogonal to

each other, hence the delocalization of electron density over the dimethoxy acetophenon

moiety stabilized towards the mechanism of formation of pyrimidines. Planarity of the

methoxy groups is lost and the conformational orientation of methyl sulfanyl groups and the

aldehydic moiety appears to be changed with respect to AMD based conformations and there

are no intermolecular interactions associated with these conformations.

3.4 Natural Bond Orbital Analysis

The Natural Bond Orbital (NBO) calculations were performed using Gaussian09 software

package with B3LYP/6-31G(d,p) method. It offers a valuable platform for exploring charge

transfer or conjugative interaction in molecular systems and is an efficient method for

studying molecular bonding characteristics and interaction among bonds. The larger the

stabilization energy value, the more intensive is the interaction between electron donors and

electron acceptors, i.e. the more donating tendency from electron donors to electron acceptors

and the greater the extent of conjugation of the whole system. The NBO analysis is already

proved to be an effective tool for chemical interpretation of hyperconjugative interaction and

electron density transfer from the filled lone pair electron. The second order Fock matrix was

carried out to evaluate donor (i)–acceptor (j) interaction in the NBO analysis [29]. For each

donor (i) and acceptor (j) the stabilization energy E(2) associated with the delocalization i to j

is as follows:

(ꢄ )^ꢅ

ꢁꢂ

ꢀ(2) = ∆ꢀ_ꢁꢂ= ꢃ

^ꢁ(ꢀ_ꢂ− ꢀ_ꢁ)

Where q_iis the donor orbital occupancy, E_iand E_jare the diagonal elements and F_ijis the off

diagonal NBO Fock matrix element. In NBO analysis large E(2) value shows the intensive

interaction between electron-donors and electron-acceptors and if it is large, greater the

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extent of conjugation of the whole system. The possible intensive interactions are given in

Table 5.

Table 5

Second order perturbation theory analysis of Fock matrix in NBO basis for NDDP

E(2)^a(KJ

Donar (i)

Type

ED (i) e

Acceptor (j)

Type

ED (j) e

mol^-1)

E(j)-E(i)^b(a.u.)

F(i,j)^c(a.u.)

BD

C

O

C

1 - C

2 - C

2 - H 22

3 - C

3 - H 23

4 - C

2

3

8

4

σ

π

σ

π

σ

π

σ

π

1.97054

1.64644

1.9784

BD*

C

1 - C

2 - C

2 - H 22

3 - H 23

4 - O 20

8 - O

1 - C

2 - H 22

3 - C

3

8

4

σ*

π*

σ*

π*

σ*

π*

σ*

π*

σ*

π*

0.02187

0.06229

0.02392

0.01423

0.01499

0.02592

0.01491

0.0219

0.06229

0.01423

0.01313

0.01499

0.01232

0.07164

0.39062

0.3524

3.78

1.86

3

1.26

1.15

1.26

1.17

1.18

1.06

1.26

1.25

1.15

1.17

1.28

1.18

1.17

1.08

0.28

0.27

0.26

1.24

1.25

1.26

1.24

1.06

1.25

0.67

1.28

1.18

1.2

1.24

1.1

0.3

0.29

1.09

1.11

1.05

0.9

1.27

1.16

1.19

1.25

1.18

1.08

1.09

1.11

1.07

1.28

1.18

1.26

1.18

0.98

0.99

1.46

1.48

1.46

1.37

1.3

0.062

0.042

0.055

0.038

0.044

0.064

0.044

0.061

0.047

0.045

0.05

0.034

0.046

0.044

0.011

0.067

0.062

0.073

0.049

0.047

0.045

0.046

0.025

0.021

0.028

0.022

0.058

0.053

0.037

0.059

0.048

0.065

0.067

0.032

0.059

0.032

0.061

0.02

0.054

0.034

0.053

0.038

0.063

0.062

0.031

0.029

0.058

0.056

0.046

0.053

0.044

0.049

0.047

0.038

0.036

0.043

0.026

0.053

0.045

0.057

0.049

0.033

0.074

0.062

0.014

0.057

0.032

0.06

1.53

2.05

4.82

1.89

3.67

2.33

2.16

2.41

1.21

2.28

2.14

0.54

20.52

17.83

23.35

2.47

2.24

2

2.14

0.63

0.51

0.79

3.27

2.96

1.45

3.5

2.64

16.76

18.55

1.17

3.93

1.18

4.4

0.54

2.91

3.15

1.24

2.82

1.51

4.65

4.45

1.14

0.97

3.92

3.07

2.24

2.8

9

2

8

5

3 - H 23

5 - H 24

8 - C 10

1 - C

2 - C

5 - C

8 - O

1 - C

2 - C

3 - C

8 - O

3

4

6

9

2

3

4

5

9

0.38483

0.16842

0.0219

1.9784

0.02187

0.02392

0.01313

0.01491

0.07164

0.03039

0.26554

0.0219

0.06229

0.01423

0.03362

0.02503

0.39062

0.38483

0.0219

0.02187

0.02392

0.03362

0.02592

0.02187

0.06229

0.01499

0.02569

0.01232

0.02503

0.0219

0.02187

0.01313

0.02569

0.02392

0.01423

0.02569

0.01232

0.0084

8 - C 10

C 10 - C 11

1.97893

1.70466

1.97441

1.97552

1.9798

C

O

1 - C

2 - H 22

2

8

4 - C

6 - O

1 - C

5 - C

1 - C

2 - C

4 - C

6

7

3

6

2

3

4

6

4 - O 20

1 - C

5

3

8

3 - H 23

5 - C

5 - H 24

6 - O

1 - C

3 - C

5 - C

2 - C

2 - H 22

5 - C

5 - H 24

7 - C 19

6

7

2

3

5

6

4

1.9798

6

1.96977

1.99122

1.97999

1.65568

1.97694

1.9918

6

2.07

2.99

2.81

1.2

1.1

1.6

O 20 - C 21

0.00791

0.0219

4 - O 20

5 - C

5 - H 24

6 - O

C

1 - C

2 - C

5 - C

2

4

6

0.02392

0.02569

0.00706

0.01313

0.01499

0.03362

0.02592

0.01232

0.39062

0.3524

0.38483

0.02187

0.01313

0.03362

0.02569

0.02503

0.02392

0.01313

0.02569

0.00684

0.03362

0.0219

C 21 - H 36

0.61

2.73

2.06

3.25

2.74

1.16

22.33

16.67

0.87

3.69

1.13

4.3

0.95

0.52

1.59

1.04

0.97

0.54

3.06

1.29

1.17

0.73

0.51

3.63

6

C

3 - C

3 - H 23

4 - C

4 - O 20

5 - H 24

1 - C

2 - C

5 - C

1 - C

3 - C

4 - C

5 - C

6 - O

2 - C

3 - C

5 - C

5

1.2

6

1.23

1.09

1.2

3

4

6

3

5

6

7

4

5

6

0.3

0.29

0.28

1.1

1.11

1.04

1.08

0.91

1.49

1.5

1.47

1.38

1.33

1.63

1.53

1.46

1.06

0.41

0.029

0.019

0.044

0.035

0.034

0.024

0.057

0.041

0.038

0.03

7

1.9918

1.99201

1.99437

1.97319

C 19 - H 32

7 - C 19

C

4 - C

1 - C

6

2

8

8 - O

9

0.06229

0.07164

0.26554

0.39062

8 - C 10

C 10 - C 11

1 - C

0.022

0.038

C

3

17

ACCEPTED MANUSCRIPT

BD

LP

C

8 - O

8 - C 10

9

π

σ

π

σ

π

σ

π

σ

π

σ

π

σ

π

σ

π

σ

π

1.97319

1.96748

1.98187

1.8445

1.9734

BD*

C 10 - C 11

C 10 - C 16

S 12 - C 14

σ*

π*

σ*

π*

σ*

π*

σ*

π*

σ*

π*

σ*

π*

σ*

π*

σ*

π*

σ*

π*

σ*

π*

σ*

π*

σ*

π*

σ*

π*

σ*

0.03039

0.0605

1.54

1.49

0.59

2.37

0.56

3.21

0.77

4.84

1.67

0.61

0.66

2.71

2.69

0.56

0.58

1.02

2.44

3.7

0.99

3.49

0.73

1.47

21.37

0.57

1.79

0.73

3.91

3.81

1.26

4.46

0.59

0.68

4.18

1.83

0.54

0.8

1.97

0.63

2.01

1.44

0.56

2.16

1.96

1.48

0.79

6.34

3.55

3.38

3.06

3.42

0.91

7.47

1.13

1.74

1.13

33.28

4.87

2.48

1.26

17.21

20.51

1.03

0.54

4.67

0.77

0.83

0.71

0.84

20.39

1.12

2.89

3.35

3.43

1.24

2.03

7.18

5.68

0.6

0.96

0.83

0.53

1.22

1.11

1.23

1.1

0.81

1.07

1.24

0.79

1.17

1.24

0.95

0.94

1.36

0.76

0.87

0.31

0.3

0.45

0.44

0.3

1.25

0.7

1.08

1.27

0.86

1.25

1.12

0.82

1.12

1.05

1.24

0.8

0.034

0.032

0.016

0.048

0.022

0.056

0.026

0.056

0.038

0.025

0.021

0.051

0.052

0.021

0.033

0.039

0.052

0.016

0.03

0.017

0.024

0.072

0.024

0.033

0.025

0.063

0.051

0.036

0.064

0.02

0.01247

0.02187

0.06229

0.03039

0.0605

0.04841

0.05791

0.06229

0.16842

0.07164

0.0605

C

1 - C

3

8

C 10 - C 11

C 10 - C 16

C 11 - S 13

C 16 - H 18

C 10 - C 11

C 10 - C 16

C 11 - S 12

C 11 - S 13

S 12 - C 14

S 13 - C 15

C 14 - H 26

C 15 - H 30

C 16 - O 17

C 16 - H 18

C 19 - H 32

O 20 - C 21

C 21 - H 36

O

S 12

S 13

O 17

O 20

C

1 - C

8 - O

8 - C 10

8

9

C 10 - C 16

C 11 - S 12

C 11 - S 13

C 16 - O 17

0.056

0.04841

0.00462

0.06229

0.01491

0.16842

0.26554

0.01247

0.01233

0.16429

0.01491

0.16842

0.07164

0.03039

0.056

C

1 - C

8 - O

8

9

C 10 - C 11

S 12 - C 14

S 13 - C 15

C 16 - O 17

C

8 - O

8 - C 10

9

1.9734

C 10 - C 11

C 11 - S 12

C 10 - C 11

C 10 - C 16

S 12 - C 14

C 14 - H 26

1.98053

1.97876

1.98765

1.97881

1.98634

1.98666

1.99645

1.97373

1.98603

1.99074

1.99211

1.99047

1.96479

1.81946

1.97765

1.88563

1.9763

0.03039

0.0605

0.01247

0.00592

0.07164

0.03039

0.01233

0.00486

0.03039

0.056

0.26554

0.056

0.04841

0.056

0.025

0.06

C

8 - C 10

C 10 - C 11

S 13 - C 15

C 15 - H 30

C 10 - C 11

C 11 - S 12

C 10 - C 11

C 11 - S 12

C 11 - S 13

C 11 - S 12

C 11 - S 13

C 10 - C 11

C 10 - C 16

C 10 - C 11

0.043

0.019

0.027

0.043

0.02

1.11

1.19

0.78

0.6

0.77

0.76

0.7

0.69

1.64

1.51

0.38

0.94

0.9

0.033

0.03

0.019

0.035

0.033

0.044

0.031

0.046

0.052

0.05

0.057

0.05

0.028

0.081

0.03

0.04841

0.03039

0.0605

0.26554

0.07164

0.02503

0.03362

0.02592

0.03362

0.02569

0.0168

0.00684

0.01678

0.38483

0.0168

0.01678

0.06229

0.07164

0.06229

0.07164

0.26554

0.04841

0.0111

0.01285

0.16842

0.03039

0.26554

0.04841

0.0111

0.01285

0.03039

0.01513

0.03039

0.26554

0.056

0.00592

0.01513

0.01123

0.05791

0.0605

0.05791

0.16842

0.0605

0.05791

0.02392

0.03362

0.01833

0.01808

0.00706

0.3524

C

8 - C 10

6 - O

4 - C

7

6

1.33

0.89

1.07

1.11

0.99

1.02

0.99

0.34

0.76

1.15

1.09

0.73

0.66

0.26

0.63

0.79

1.09

0.26

0.84

0.25

0.42

0.71

0.72

1.21

1.08

0.85

0.26

0.44

0.72

0.69

1.16

1.12

0.28

0.72

0.69

1.12

1.07

0.99

1.02

0.34

0.75

4 - O 20

7

9

4 - C

5 - C

6

C 19 - H 31

C 19 - H 32

C 19 - H 33

0.038

0.03

0.1

C

5 - C

6

C 19 - H 31

C 19 - H 33

0.057

0.048

0.033

0.101

0.105

0.015

0.018

0.055

0.026

0.027

0.012

0.025

0.065

0.02

0.043

0.046

0.058

0.033

0.038

0.04

0.046

0.019

0.045

0.044

0.027

0.038

0.033

0.017

0.106

0.104

0.082

0.027

0.03

C

1 - C

8 - C 10

1 - C

8 - C 10

8

C 10 - C 11

C 11 - S 13

C 14 - H 25

C 14 - H 27

1.9763

1.78576

1.9793

C 8 - O 9

C 10 - C 11

C 11 - S 13

C 14 - H 25

C 14 - H 27

C 10 - C 11

C 15 - H 28

C 10 - C 11

C 11 - S 12

C 14 - H 26

C 15 - H 28

C 15 - H 29

C 16 - H 18

C 10 - C 16

C 16 - H 18

1.9793

1.86534

1.98322

1.89528

1.96457

1.8409

3.28

3.17

1.29

1.5

LP

1.2

C

8 - O

9

1.21

19.21

19.36

7.44

0.87

1.15

1.17

1.74

30.91

5.16

5.09

C 10 - C 16

C 16 - H 18

C

2 - C

4 - C

4

6

C 21 - H 34

C 21 - H 35

C 21 - H 36

C 2 - C 4

C 21 - H 34

C 21 - H 35

0.031

0.038

0.096

0.058

0.057

1.8409

0.01833

0.01808

18

ACCEPTED MANUSCRIPT

BD*

C

5 - C

8 - O

6

9

π*

0.38483

0.16842

0.26554

BD*

C

1 - C

3

π*

σ*

π*

σ*

0.39062

0.03039

0.0605

0.06229

0.01491

0.16842

0.01233

260.5

81.62

0.72

0.98

0.96

1.16

4.91

1.5

0.01

0.02

0.57

0.45

0.46

0.57

0.01

0.14

0.082

0.075

0.058

0.055

0.047

0.061

0.015

0.035

C 10 - C 11

C 10 - C 16

C

C 10 - C 11

1 - C

8 - O

8

9

S 13 - C 15

^aE(2) means energy of hyperconjugative interactions (stabilization energy in kcal/mol).

^bEnergy difference between donor and acceptor I and j NBO orbitals in a.u.

^cF(ij) is the Fock matrix elements between I and j NBO orbitals in a.u

The resonance stabilization of molecule can be rationalised through the interaction of

various orbitals. The aromatic system having extensive conjugation over π systems as evident

with the interaction of π^*(C5-C6) to π^*(C1-C3), having a strong stabilization energy of 260.5

kcal mol^-1. Conjugative interaction of π(C5-C6) to π^*(C1-C3) and π^*(C2-C4) leads to a

stabilization energies of 22.33 and 16.67 kcal mol^-1respectively. The interaction of π(C2-C4)

to π^*(C1-C3) and π^*(C5-C6) along with π(C1-C3) to π^*(C2-C4), π^*(C5-C6) also favours the

aromatic delocalization of electron density with stabilization energies 16.76, 18.55, 20.52 and

17.83 kcal mol^-1respectively. The electron releasing effect of methoxy group and its

contribution to the aromatic system can be rationalized through the interaction of π(O20) and

π^*(C2-C4) along with π(O7) and π^*(C5-C6) with a stabilization of 30.91 and 33.28 kcal mol^-1.

Among the two sulphur atoms, S12 is more stable because of the delocalization with π^*(C10-

O11) having stabilization energy of 20.39 kcal mol^-1where as S13 interact with the same

orbital with an energy of 7.18 kcal mol^-1, therefore the leaving methyl thiol could be contain

S13 on reacting with amidines. This interaction is also favours by contribution from π(O17)

to σ^*(C10-C16) lead to conjugation. π(C1-C3) to π^*(C8-O9) reveals the extension of

conjugation over the ketonic carbonyl group leading to the formation of cyclic intermediate

through 1,2-nucleophilic addition leads to the formation of pyrimidine with a stabilization

energy of 23.35 kcal mol^-1, this interaction favours the back donation of π^*(C8-O9) to π^*(C1-

C3) with strong stabilization of 81.62 kcal mol^-1. And the ketonic carbonyl acts as a electron

delocalization bridge as evident by the interaction of π(O9) with σ^*(C8-C10) and σ^*(C1-C8)

along with a stabilization energy 20.51 and 17.21 kcal mol^-1.

3.5 Mulliken Population Analyses

The calculation of atomic charges plays an important role in the application of

quantum mechanical calculations to molecular systems [30]. Our interest here is to describe

the electron distribution in Mol1 as broadly as possible. Mulliken charges were calculated by

determining the electron population of each atom for its activity assessment towards the

formation of pyrimidines derivatives. The Mulliken plot corresponding with B3LYP with 6-

311++G(d,p) method is shown in Fig. 8

19

ACCEPTED MANUSCRIPT

Figure 8

Mullikan population analysis based on the optimized structure reveals the partial

charge density of formyl ketenedithioacetal represented in Table IV. The atom C11 is highly

electronegative whereas C10 is electropositive reveals the extensive charge delocalization,

the decrease in bond length also support this. Substituted aromatic carbon atoms are

positively charged, where C1 shows less positive as 0.0579e due to the presence of electron

withdrawing effect of ketonic carbonyl moiety, as compared to C4 and C6 with 0.319e and

0.335e respectively, due to the attachment of electron releasing methoxy groups. C2, C3 and

C5 are the unsubtituted aromatic carbon atoms with negative population as -0.0565e, -

0.0139e and -0.0254e respectively shows the electronic delocalization within the ring and

extended to the whole molecule through conjugation. Both ketonic and aldehydic oxygen

atoms are highly electronegative as -0.5075 and -0.4766e respectively and the corresponding

bonded carbon atoms are positively populated, viz. C8 (0.3422e) and C16 (0.3719e) is also an

evidence for electronic delocalization leading to charge transfer between the aromatic system

and rest of the fractions through ketonic carbonyl group

The trigonal planar carbon (C11 -0.3068) with lack of non-bonded interaction

supports the mechanism by releasing methyl thiol leading to the formation of pyrimidines

where C14 and C15 are being in non-bonded interactions (from crystallographic data).

Ketonic carbonyl oxygen is highly polarized with a density of -0.5075e leads to make the

hydroxyl moiety in the intermediate structure followed by the removal of the same as water.

The aldehydic oxygen is also highly populated but this is unreacted over the reaction is due to

the extensive non-covalent interactions with various less populated atoms (Fig. 4). This

20

ACCEPTED MANUSCRIPT

interaction may brakes once pyrimidine is formed and the aldehyde facile to Konevenangel

condensation yielding functionalized pyridines.

3.6 Fukui function analysis

The Fukui function is among the most basic and commonly used reactivity

descriptors. The Fukui function is given as the change in the density function ρ(r) for the

molecule as a consequence of changing the number of electrons N in the molecule, under the

constraint of a constant external potential. The Fukui function is defined as:

∂ρ(r)

ꢄ(ꢆ) = ꢇ

ꢈ r

∂N

Where ρ(r) is the electronic density, N is the number of electrons and r is the external

potential exerted by the nuclease. Fukui functions are introduced, which are prescribed as

reactivity descriptors in order to identify the most reactive sites for electrophilic or

nucleophilic reactions within the molecule. The Fukui function indicates the susceptibility of

electronic density to deform at a given position upon accepting or donating electrons [31, 32].

Also, it is possible to define the corresponding condensed or atomic Fukui functions [33] on

the j^thatom site as,

ꢉ^ꢊ= ꢃ_ꢂ(ꢋ) − ꢃ_ꢂ(ꢋ − 1)

ꢂ

ꢉ^ꢌ= ꢃ_ꢂ(ꢋ + 1) − ꢃ_ꢂ(ꢋ)

ꢂ

1

ꢉ^ꢍ= ꢎꢃ_ꢂ(ꢋ + 1) − ꢃ_ꢂ(ꢋ − 1)ꢏ

ꢂ

2

For an electrophilic ꢉ^ꢊ(ꢆ), nucleophilic ꢉ^ꢌ(ꢆ) and free radical attack ꢉ^ꢍ(ꢆ) on the reference

ꢂ

molecule, respectively. In these equations, q_jis the atomic charge (electrostatic derived

charge) at the j^thatomic site in the neutral (N), anionic (N + 1) or cationic (N - 1) chemical

species.

The electrophilicity of the atoms is in the order of C8 > C15 > C14 > C1 > C11 >

C21> C19 > C5 > H22, whereas nucleophilic character is C3 > C4 > C1 > C6 > O20 > O7 >

O9 > H34 > H35 > H33 > H31 > S12 > S13 > H32 > H36 > H22 > O17 > C2 > H23 > H18 =

H30 > H25 > H26 > H27 > H28 > H29 > C8. Radical nature could be S12 > S13 > C3 > C10

> C16 > O17 > C4 > O9 > C6 > O20 > O7 > C1 > H30 > H34 > H26 > H31 > H29 > H35 >

H33 > H31 > H32 > H36 > H24 > H18 > H25 > H28 > H27 > H23 > C2 > H22. The

formation of pyrimidine can be explained on the basis of Fukui parameters (Table 6). The

initial amidine nucleophile can simply attack on C14 since it is a good electrophilic centre (

-

0.0278) whereas the two sulphur atoms are merely nucleophilic in nature as evidenced with

Table 1, followed by 1,2 cycloaddition also favours the electrophilic character of C11(-

21

ACCEPTED MANUSCRIPT

0.1332) and it is due to the delocalization of electron density over acetophenon moiety. The

aldehydic carbon (C25) exist as nucleophilic centre hence it is unreactive over the formation

of pyrimidine and susceptible for yielding highly functionalised pyrimidine derivatives

through Konevenangel condensation [28]. Mulliken population and Natural Bond Orbial

analysis support these phenomena. Both methoxy oxygen atoms are less nucleophilic in

nature as O10 is 0.0825 and O32 is 0.0911 because of the contribution of electron density

towards aromatic ring.

Table 6

Atoms

C1

f-

f+

f0

-0.0234 0.1010 0.0776

0.0008 0.0116 0.0123

-0.0144 0.0157 0.0014

0.0529 0.1480 0.2009

0.0007 0.0128 0.0136

0.0129 0.1317 0.1446

-0.0160 -0.0058 -0.0218

0.0067 0.0279 0.0346

0.0195 0.0966 0.1161

0.0057 0.0825 0.0882

-0.1332 0.0015 -0.1317

0.0721 0.0611 0.1332

0.2126 -0.0191 0.1936

-0.0278 -0.0040 -0.0318

0.1945 0.0345 0.2291

0.1878 0.0299 0.2177

-0.0368 -0.0147 -0.0514

0.0236 0.0086 0.0322

0.0428 0.0083 0.0511

0.0126 0.0064 0.0189

-0.0863 -0.0222 -0.1085

0.0229 0.0062 0.0292

0.0445 0.0060 0.0505

0.0500 0.0099 0.0599

0.1807 -0.0052 0.1755

0.0246 0.0099 0.0345

0.1482 0.0117 0.1599

-0.0181 -0.0258 -0.0439

0.0075 0.0357 0.0432

0.0081 0.0281 0.0362

0.0091 0.0358 0.0449

0.0043 0.0911 0.0954

-0.0230 -0.0184 -0.0414

0.0148 0.0385 0.0534

C2

H22

C3

H23

C4

C5

H24

C6

O7

C8

O9

C10

C11

S12

S13

C14

H25

H26

H27

C15

H28

H29

H30

C16

H18

O17

C19

H31

H32

H33

O20

C21

34H

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35H

36H

0.0109 0.0362 0.0471

0.0081 0.0280 0.0361

Fukui parameters

3.7 Molecular Electrostatic Potential

MEP provides a visual medium to understand the relative reactivity of the molecule through

its polarity, as shown in Fig: 9. MEP surface plot is a useful descriptive for the qualitative

interpretation of the sites for electrophilic and nucleophilic attacks as well as hydrogen

bonding interactions [34, 35]. The equation used to find the electrostatic potential is [36],

Total electrostatic potential energy = Σ Electrostatic Potential energy

Potential Energy = ꢐ ^ꢑꢒꢑꢅ(k is the coulomb’s constant)

ꢓ

The colours in the map correspond to the different potential values. Potential increases in the

order of red < orange < yellow < green < blue, where blue indicates the strongest attraction;

red indicates strongest repulsion; and green indicates neutral electrostatic potential region

[37, 38]. From the figure it is evident that, the regions exhibiting the negative electrostatic

potential are localized near the electronegative oxygen atoms while the regions presenting the

positive potential are localized in the vicinity of the hydrogen atoms.

Aromatic pi electron density and its extension to ketonic carbonyl group can be seen

from the figure where more negative potential is combines with ketonic carbonyl oxygen, so

that corresponding carbon atom is more susceptible for nucleophilic attack reveals the

formation of acyclic N,S-acetal. Aldehydic oxygen is also electron rich but it is inactive

towards the formation of pyrimidine due to intermolecular interactions already explained in

crystallographic part. Methoxy groups are electron releasing towards aromatic ring and hence

it is less populated supports the mechanism of formation pyrimidines.

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Figure 9

Electrostatic potential of the Mol1

3.8 Frontier Orbital Analysis

Highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital

(LUMO) are very important parameters for quantum chemistry. We can determine the way

the molecule interacts with other species; hence, they are called the frontier orbitals. HOMO,

which can be thought the outermost orbital containing electrons, tends to act as electron

donor. On the other hand, LUMO can be thought the innermost orbital containing free places

to accept electrons [39]

The highest occupied molecular orbital (HOMO) energies and lowest unoccupied

molecular orbital (LUMO) energies have been calculated along with various other quantum

mechanical descriptors viz. ionization energy (IE), chemical hardness (η), electronegativity

(χ), total energy and dipole moment (Table V). Based on DFT-B3LYP model the total energy

of the molecule calculated is -1640.333 a.u. IE can be expressed as the negative of HOMO

orbital energy where as the negative of LUMO orbital energy corresponds to EA [33]. The

chemical hardness (η) corresponds to the gap between HOMO-LUMO orbital energy. The

larger the gap, harder is the molecule. HOMO-LUMO orbital energy gap (3.727eV) of the

molecule reveals the thermodynamic stability of the system. The ionization potential obtained

from theoretical calculation is also favours the stability of the molecule. The HOMO- LUMO

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energy gap explicates the charge transfer interaction is taking place within the molecule. The

calculated dipole moment value shows that the molecule is highly polar in nature. These

calculated parameters are suitable for future applications of the Mol1.

Table 7

Quantum chemical reactivity descriptors

E_HOMO(eV) = -5.659

E_LUMO(eV) = -1.932

E_HOMO-LUMO(eV) = 3.727

Total Energy (a.u.) = -1640.333

Ionization Potential (IE) = 5.659 eV

Electron Affinity (EA) = 1.932 eV

Global Electronegativity (χ) = 3.795 eV

Chemical Hardness (η) = 1.863 eV

Chemical Softness (S) = 0.536

Chemical Potential (ꢀ) eV = -3.795

Global electrophilicity index (ω) = 3.865

Dipole Moment (Debye) = 4.955

3.9 Transition State (TS) Analysis

The Synchronous Transit-Guided Quasi-Newton (STQN) Method, developed by H. B.

Schlegel et al [40], utilizes a linear synchronous transit or quadratic synchronous transit path

way to get more proximate to the quadratic region around the transition state and then utilizes

a quasi-Newton or eigenvector-following algorithm to consummate the optimization. As for

minimizations, it performs optimizations by default utilizing redundant internal coordinates.

This method will converge efficiently to the authentic transition structure utilizing an

empirical estimate of the hessian and congruous starting structures.

Scheme 2

TS analysis performed between these two intermediates (from Figure 1)

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Herein we performed QST3 [41] approach to simulate the transition state geometry

between Scheme 2 with DFT-B3LYP/6-31+G(d,p) method. The imaginary frequency

observed at -940.72 cm^-1show better correlation with the saddle point obtained with total

energy of -1407.076 Hartree. HOMO-LUMO gap corresponding to the TS is 0.13517 Hartree

reveal the easiness of internal rearrangement towards the formation of pyrimidines through

this mechanism. The double bond between C₁and C₂(Scheme 2) is also support this

mechanism via its rigidity toward rotation, hence the number of accessible geometry is

limited for the acyclic N,S-acetal.

Figure 10

TS geometry of acyclic N,S-acetal with a hydrogen bonding interaction between O3 and H11,

all other hydrogen atoms are omitted for clarity.

A strong hydrogen bonding interaction is observed between O3 and H11 (Figure 10)

which is a characteristic feature of this TS towards its stability; and the over clouding

electron density on ketonic carbonyl, inferred with MEP analysis of Mol1 is also supports

this interaction. The aldehydic carbonyl moiety and the amidine groups make a torsion angle

of -167.06° (C11-C10-C12-N2), hence it is confirmed as those groups are lying opposite to

each other reveals the difficulties upon reacting towards the formation of cyclic intermediate

via intramolecular 1,2-nucleophilic amination as described in the crystallographic part.

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4. Conclusion

The present study dealt with ease of formation of pyrimidine derivatives from α-

formylketene dithioacetal through electronic structure methods. Purposefully we synthesized

the designated compound (Mol1) by a traditional method of synthesis from Asokan et al and

characterized through spectral methods. Single crystal x-ray crystallographic study reveals

the complete experimental structure as well as its intermolecular interactions; and show how

it helps towards the formation functionalized pyrimidines. Classical and accelerated

molecular dynamics simulation gave an insight into the possible conformational changes of

the structure in acetonitrile environment and it discloses the various geometrical possibilities

and interactions with the designated solvent system. Various quantum chemical reactivity

parameters viz. NBO, Mulliken population, Fukui parameters, MEP, Frontier orbital analysis

and TS analysis were carried out and it support the feasibility of formation of pyrimidines via

ketonic carbonyl group rather than aldehydic carbonyl moiety.

Acknowledgements

Authors are thankful to SAIF CUSAT for data collection and IIRBS for NMR

facilities. One of the authors Monu Joy gratefully acknowledged Kerala State Council for

Science Technology and Environment (KSCSTE) for the financial support (No.

157/SPS/2013/CSTE).

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Article Doi

Probing mechanism of α-formylketene dithioacetal towards the facile formation of functionalized pyrimidines: A structural approach

DOI: 10.1016/j.molstruc.2016.07.107

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