PREDICTION OF REACTIVE SIDE OF MOLECULE FOR

EPOXYDATION, CATALYTIC REDUCTION AND 1,3 DIPOLAR

ADDITION BY LOCAL REACTIVITY DESCRIPTOR.

R.Margabandu, K.Subramani*.
Department of Chemistry, Islamiah College, Vaniyambadi, PIN- 635751, Tamil Nadu ,
India.
Email: rmargabandu@yahoo.com

Abstract

If any molecule has more than one reactive side for specific reagent in that case the
preferred reactive side is theoretically[1] determined by means of local reactivity
descriptor called local softness for electrophilic, nucleophilic and free radical attack. In
the computational chemistry selection of method and basis set are important, wheather
semi-empirical (or) ab initio (or) DFT ,for calculation.The above selections are very
important because this decides the time of calculation. In this work we used semi-
empirical ZINDO[2] Hamiltonian for calculation of local softness. This method is very
faster than others and this hamiltonia yields result which is in agrement with practical.

Key Words : Quantum mechanical, Local Softness, Reactive side

INTRODUCTION

To day challenge for the chemist is to prepare the compound having desired activity for
the different field like drug discovery, polymer industry, corrosion inhibition and so on. if
our molecule has more than reactive side, when we write scheme for desired compound,
for specific reagent then first preferred reactive side is determined by computational
method. In Computational method first geometry of molecule to be optimized by
molecular mechanics or quantum mechanical method after that value of quantum
mechanical descriptor like Energy of HOMO, Energy LUMO,Diploe moments,Charge
density on atoms, Bond order between the two bond, Ionisation potential and electron
affinity are calculated. The desired information for molecule can be derived from the
value of quantum mechanical descriptor.The type descriptor value required is depends
upon type of information to be derived. The Computational method has changed the trend
and this can be simply written like as follows.

Optimization of structure → quantum mechanical descriptor calculation → prediction of

reactivity

By the above method we can save the time, money and hazardous generation by avoiding
trial and error method for synthetic scheme. If predicted reactive side is not desirable then
we go for different substitution (electron withdrawing and donating) to get desirable
reactive side.
RESULT AND DISCUSSION

Global reactivity descriptors

The several global reactivity descriptors of molecules such as Hardness

(η),chemicalpotential(µ), Softness(S) and electronegativity (χ)[3,4] are defined as.

η = ½ (I − A) (1)

µ = −½ (I + A) (2)

χ=-µ (3)

S = 1/ η (4)

I = Ionization energy , A= Electron affinity

I= E + - E
A= E - E¯

The condensed Fukui functions are local reactivity descriptor.

In practice a more convenient way of calculating the condensed Fukui functions[5] f(r)
for an atom k in a molecule are expressed as:

fk+ = [q k (N+1) − q k (N)] for nucleophilic attack (5)

fk– = [q k (N) − q k (N-1)] for electrophilic attack (6)

fko = ½[q k (N+1) − q k (N-1)] for radical attack (7)

where q is the electronic population of atom k in the molecule under consideration.N,N-

k

1 and N+1 are the electron density of neutral molecule, cation and anion respectively on
atom k of the molecule

The local softness (sª )s to an atom site say k, can be written as,
k

s ªk = f ª k S (8)

ª =+/ ° / –
where a = +/– / ° refer to nucleophilic, electrophilic and radical attacks, respectively
In most of the case local softness has the values of positive and negative[6] so this mixed
sign value of local softness leads to confusion to decide preferred side of attack hence
local softness can be written as follows

Three different types of condensed atomic descriptors (sf )ªk can be [6]readily obtained
as,
i.e.

(sf) ¯k = ( f ¯k)2 S (9)

governing electrophilic attack,

(sf) +k = ( f +k)2 S (10)

governing nucleophilic attack,

(sf) °k = ( f ° k)2 S (11)

governing radical attack,

The region of molecule having maximum value of local softness has the preference for
electrophilic,nucleophilic and free radical attack. The most useful and important
application of local softness is interpretation and prediction of reaction mechanism, and
regio-selectivity.

1.Reactive side for epoxydation

Epoxydation of olefinic double bond can be achieved by two reagent they are 1)
hydrogen peroxide in sodium hydroxide.2) m-chloroperoxybenzoic acid. Only olefinic
double bond having conjugation with carbonyl double can be converted to epoxide by
hydrogen peroxide in sodium hydroxide. Double bond does not have conjugation with
another double bond can be converted to epoxide by m-chloroperoxybenzoic acid.
Mechanism for epoxidation by hydrogen peroxide and m-chloroperoxybenzoic acid are
as follow. From the mechanism it is clear that epoxydation by m-chloroperoxybenzoic
acid proceeds through nucleophilic attack and epoxydation by hydrogen peroxide in
sodium hydroxide proceeds through electripkilic attack.
1. General Mechanism.
COOH

H
O

O O +
O

Cl
Cl

2.
 _
O O O
O
H2O2,NaOH H
O
O
O
_
OOH

Example 1

O 3
1
C
C
5
6
C
O C
H2O2,NaOH A
O

O
Epoxydation at 1,3 double bond

3 Epoxydation at 5,6 double bond

1
C O
C
5 H2O2,NaOH
6
C
O C
3
1
C
C
5
6
C
O C
O
B

Epoxydation by hydrogen peroxide in sodium hydroxide is proceeding through

nucleophilic attack so we can conclude that the region of molecule having higher value of
local softness for nucleophilic attack is the preferred region for epoxydation by the
hydrogen peroxide in sodium hydroxide. The 25(R)-1,4,6-spirostatrien-3-one (1) has two
reactive side for epoxydation by hydrogen peroxide in sodium hydroxide so possible
isomer are A and B.In practical we got the isomer A[7]. Our theoretical calculation also
predicts same isomer by the local softness calculation. Theoretical results are as follows.
The quantum mechanical descriptor are shown in the table 1 and local softness for
nucleophilic attack are shown in the table 2. It is clear that C3 has higher value for local
softness of nucleophilic attack and the possible isomer is(A) in agreement with practical
one.
Table : 1 Table 2

Descriptor Value(au)
Energy of HOMO -0.3158
Energy of LUMO -0.0235
Energy of E,Neurtral -216.257
Energy of E+, Cation -216.001
Atom
Energy of E-,Anion -216.313 No (sf)+
Ionization Potential 0.2556 1 0.006
Electron affinity 0.056 3 0.077
5 0.057
Hardness 0.0998
6 0.008
Softnes 10.02004

Example 2

5 8
6
C 7
C
OH C C
O
O A
m-CPBA

O
Epoxydation at 6,7 double bond
O

Epoxydation at 7,8 double bond

m-CPBA
5 8
6
C 7
C
HO C C

5 8
25(R)-4,6-spirostadiene-3?-ol 6
C 7
C
OH C C
O

2
Epoxydation by m-Chloroperoxybenzoic acid is proceeding through electrophilic attack
so we can conclude that the region of molecule having higher value of local softness for
electrophilic attack is the preferred region for epoxydation by the mChloroperoxybenzoic
acid. The 25(R)-4,6-spirostadiene-3β-ol[7] (2) has two reactive side for epoxydation by
m-chloroperoxybenzoic acid so possible isomer are A and B. In practical we got the
isomer a and our theoretical calculation also predicts same isomer by the local softness
calculation. Table 3 & 4 shows the quantum mechanical descriptor and local softness for
electrophilic attack of the 25(R)-4,6-spirostadiene-3β-ol(2) respectively. The local
softness is higher for the C6 hence possible product is A.

Table : 3
Descriptor Value(au) Table ; 4
Energy
Atom of HOMO(sf)- -0.2964
No
Energy of LUMO 0.0283
Energy5of E,Neurtral
0.116 -219.91
Energy6of E+,0.144
Cation -219.638
7 0.037
Energy of E-,Anion -219.918
8 Potential
Ionization 0.128 0.2722
Electron affinity 0.0083
Hardness 0.13195
Softnes 7.57863 Example 3

N R1
O

Et2O,RT, 16hr O O

A
Nu_ attack on C1

1
C 2
C _ + R1
O N
O
+ Nu_ attack on C2
O O

R1 N
O
Et2O,RT, 16hr

O O

B
3

1, R1=C6H5
2, R1=4-ClC6H4
3, R1=4-MeOC6H5
4,R1=CH=CHC6H5
5,R1=CH(CH3)2
The 5-Methoxy-2(5H)- Furanone (3) undergoes[8] 1,3 dipolar addition and there is
possibility of getting two isomer A & B since 5-Methoxy-2(5H)- Furanone is not a
symmetrical one. In practical we got only Isomer A with five different (R1) and our
theoretical result also predicts the same. Table 5 & 6 shows the quantum mechanical
descriptor value and local softness for nucleophilic attack respectively.From the table 6 it
is clear that C1 of the molecule (3) is the preferred side for attack of nucleophilic
portion of 1,3 dipolar hence theoretical prediction in agreement with practical.

Table : 5 Table : 6
Descriptor Value(au)
Energy of HOMO -0.3822
Energy of LUMO -0.0215
Energy of E,Neurtral -68.7579
Energy of E+, Cation -68.4198
Energy of E-,Anion -68.7963
Ionization Potential 0.3381
Electron affinity 0.0384
Hardness 0.14985
Softnes 6.67334
Atom
No (sf)+
1 0.193
2 0.151

Example 4
H

N Ph
O

O
Pd/C O O
9
Ph A
N Reduction of 9,5
O 5 bond

O 4 Pd/C
O O 1
rReduction of 4,1 N Ph
bond O

O
O OH

The nitrile oxide adduct[8] of 5-Methoxy-2(5H)- Furanone (Molcuele 4) undergoes the

catalytic reduction and there is possibility of getting two isomer A & B since it contains
two susceptible double bond. In practical we got the isomer A. Table7 & 8 Shows the
quantum mechanical descriptor value and local softness for radical attack
respectively.The local softness for C5 is higher than C4 even if we consider hetero atom
N9 is higher than O1 so possible isomer is A. This is in agreement with practical result.
Table 7

Table8
Descriptor Value(au) Atom
No (sf)0
Energy of HOMO -0.3245
4 0.00106
Energy of LUMO -0.0283
5 0.1306
Energy of E,Neurtral -132.543
Energy of E+, Cation -132.244
1 0.00125
Energy of E-,Anion -132.599
9 0.285
Ionization Potential 0.2998
Electron affinity 0.0561
Hardness 0.12185
Softnes 8.206812

EXPERIMENTAL SECTION

All the molecule were initially geometry optimized in molecular mechanics using UFF
force field with convergence limit of 10 x 10-1 kcal/mol/Ang then the coordinate
generated in UFF has been taken for geometry optimization(neutral molecule) at
AM1( semi-empirical) in RHF method with convergence limit of 10 x 10-10 kcal/mol. The
optimized geometry at AM1[11] level has been taken for single point energy calculation
in ZINDO method at neutral,cation and anion[18]. The result of ZINDO method is used
for local softness calculation[9,10].The geometry optimization were carried out in
Arguslab software[12-17]. The geometry optimized molecule are shown below.

1
 2

CONCLUTIONS

The ZINDO( semi-empirical) method is sufficient to calculate reactive side of molecule

for electrophilic, nucleophilic and radical attack for small and big molecule by means of
local softness. The ZINDO Hamiltonian calculates faster than other Hamiltonian hence It
is not necessary to choose other time consuming Hamiltonian or ab initio or DFT for
reactive side prediction.

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