1. A THEORETICAL STUDY ON ASSOCIATIVE
MECHANISM FOR THE METATHESIS REACTION
BETWEEN A BARBITURATE KNOEVENAGEL
DERIVATIVE AND AN IMINE
SANDRA DEVASYA
16PCHE5668
2. INTRODUCTION
Knoevenagel compounds are α,β conjugated enone- formed by nucleophilic
addition of an active hydrogen compound to a carbonyl group followed by
a dehydration reaction.
Imines are important class of organic compounds, formed by the reaction of
primary amine with aldehyde or ketones under appropriate conditions.
Eg; Aldimines
2
3. General representation of exchange reaction of Knoevenagel type
C=C bond and Imine C=N bond by means of organocatalysis.
L- proline is a chiral secondary amine, used as the organocatalyst.
DMSO was choosen as the solvent.
The dynamic exchange between Knoevenagel type C=C bonds and
Imine C=N bonds leads the formation of large variety of organic
compounds.
Wilhelms, N.; Kulchat, S.; Lehn, J.- M. Helv.Chim. Acta 2012, 95, 2635– 2651
3
4. Reaction of C=C/C=N exchange between Knoevenagel compound and Imine
at room temparature in presence of CDCl3 in the absence of added catalyst.
4
J. Am. Chem. Soc., 2018, 140 (16), pp 5560–5568
5. Proposed associative mechanism for the metathesis reaction between
a barbiturate Knoevenagel derivative and an Imine through formation of
an Azetidine intermediate.
J. Am. Chem. Soc., 2018, 140 (16), pp 5560–5568
5
7. Knoevenagel compounds with electron donating groups are the favorable
products.
The conjugation Enhances
Increases the polarity of C=C bond
Reaction is fastest in weakly polar aprotic solvents like chloroform and
dichloro methane.
7
Reactant imine bearing an electron donating group are the most suitable
starting materials
8. To study the most feasible reaction pathway
To study the effect of substituents and solvent
OBJECTIVES
8
9. All structures were optimized at the B3LYP/def2-SVP level of theory.
Single point calculations were carried out at M06/def2-TZVPP level of theory.
Bonding analysis by NBO was carried out at the M06/def2-
TZVPP//B3LYP/def2-SVP level of theory using Gaussian 09 program
package.
COMPUTATIONAL METHODOLOGY
9
11. 11
The study of associative mechanism for the metathesis reaction between a
barbiturate Knoevenagel derivative and imine were carried out at M06/Def2-
TZVPP//B3LYP/Def2-SVP level of theory using Gaussian 09 package
Here we analyze two different situations,
In the first case imine is substituted with electron donating methoxy group and
Knoevenagel compound is substituted with methyl group.
In the second case imine is substituted with an electron withdrawing chloride
group, and Knoevenagel compound is substituted with same methyl group.
Here we have carried out the calculation in presence of chloroform using
Polarizable Continuum Model (PCM), and also repeat the reaction in the absence
of solvent
12. 12
Overall reaction energy (kcal/mol) in terms of ΔH and ΔG (given in parenthesis) in
the absence of solvent calculated at M06/Def2-TZVPP//B3LYP/Def2-SVP level of
theory.
Overall reaction energy (kcal/mol) in terms of ΔH and ΔG (given in parenthesis) in the
presence of solvent chloroform calculated at M06/Def2-TZVPP//B3LYP/Def2-SVP
level of theory.
Here Knoevenagel compound is substituted with methyl group and imine is
substituted with an electron donating methoxy group
The use of solvent chloroform stabilize the reaction by reducing the overall reaction
energy.
13. Mechanism for Metathesis reaction in presence of chloroform solvent, calculated at the
M06/def2-TZVPP//B3LYP/def2-SVP level of theory. Reaction energy (kcal/mol) in terms of
ΔH and ΔG (given in parenthesis). Here the reactant imine (R1) is substituted with methoxy
group and Knoevenagel compound (R2) is substituted with methyl group. 13
16. 16
Overall reaction energy (kcal/mol) in terms of ΔH and ΔG (given in parenthesis) in the
presence of solvent chloroform calculated at M06/Def2-TZVPP//B3LYP/Def2-SVP
level of theory.
Here Knoevenagel compound is substituted with methyl group and imine is
substituted with a slightly electron withdrawing chloride group.
The reaction is slightly endothermic when the reactant imine is substituted with an
electron withdrawing chloride group.
The reaction is slightly exothermic when imine reactant is substituted with an
electron donating methoxy group.
That is, if we change the substituent attached to the imine reactant, it will affect the
overall reaction energy.
17. 17
Mechanism for Metathesis reaction in presence of chloroform solvent, calculated at
the M06/def2-TZVPP//B3LYP/def2-SVP level of theory. Reaction energy
(kcal/mol) in terms of ΔH and ΔG (given in parenthesis). Here the reactant imine
(R1՛) is substituted with chloride group and Knoevenagel compound (R2՛) is
substituted with methyl group.
19. 19
The reaction is slightly exothermic, that is it is favorable when we
use an electron donating group methoxy as the substituent for imine
reactant.
The energy barrier for the formation of INT1՛ is higher in the case of
chloride substituent compared to that of electron donating methoxy
group.
The energy barrier for the formation INT2՛ is also higher when we
chose the electron withdrawing chloride group.
In both cases the energy required for the formation of INT3 is
slightly higher.
Final step involve the formation of product also stabilized by using
the electron donating methoxy group.
21. 21
Atomic charges on important atoms of R1, R2 and R2՛ from NBO
analysis at M06/def2-TZVPP level of theory.
Molecule Atom Charge
R1 C1 -0.13
C2 0.00
C3 -0.28
R2 C1 -0.24
C2 0.14
C3 -0.14
N1 -0.42
R2’ C1 0.13
C2 -0.24
C3 -0.02
N1 -0.40
NBO analysis conform the first step of the reaction mechanism. The high
negative charge on the imine N atom undergoes nucleophilic attack on the
neutral charge on the C atom of C=C bond of Knoevenagel compound.
22. MOs of R1, R2 and R2՛
LUMO (-2.72) HOMO (-6.73) HOMO-1 (-7.15)
LUMO (-1.15) HOMO (-6.45) HOMO-3 (-7.05)
22
(R1)
(R2)
LUMO (-1.66) HOMO (-6.64) HOMO-3 (-6.91)
(R2՛)
23. 23
The LUMO of Knoevenagel compound R1 corresponds to the C=C π* orbital.
And the HOMO-3 of R2 and R2՛ indicate the lone pair of electrons on the imine N
atom.
R2 and R2՛ are expected to be more nucleophilic with a lone pair of electrons
on the N atom.
The energy difference of HOMO-3 of (R2 and R2՛) and LUMO of [R1] is very
small.
The lone pair of electrons on the imine N atom can easily undergoes
nucleophilic attack on C=C bond of Knoevenagel compound.
The important molecular orbital of reactant molecules confirm the first step of
the reaction mechanism.
24. ESP Plot of Reactants (R1, R2 and R2՛)
Global maxima=19.87 kcal/mol
Global minima= -33.16 kcal/mol
-2.45 kcal/mol
Global minima= -32.18 kcal/mol
Global maxima= 20.55 kcal/mol
-20.28 kcal/mol
Global minima= -28.48 kcal/mol
24
Global minima = -23.17 kcal/mol
-16.92 kcal/mol
Global maxima = 20.30 kcal/mol
25. 25
Conclusion & Future plans
Associative mechanism for the metathesis reaction between knoevenagel
compound and imine was verified computationally.
Substituents and solvents affect the reaction.
The energy barrier corresponding to the formation of INT3 from INT2 will be
slightly stabilized by the use of chloroform solvent, that is it has a stabilising
influence on high energy transition state (TS3).
Mechanism of the reaction also supports the formation of four- membered
azetidine intermediate.
The ESP analysis, Molecular orbital analysis and NBO analysis support the first
step of the reaction mechanism.
The electron donating methoxy group reducing the overall reaction energy.
Future plan - Study of concerted pathway.