ASSOCIATIVE MECHANISM FOR THE METATHESIS REACTION BETWEEN A BARBITURATE KNOEVENAGEL DERIVATIVE AND AN AMINE

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
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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
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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.
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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
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6. Effect of Substituents
The C=C/C=N exchange reaction between Kn compounds Kn1-Kn5 and
Aldimines A1-A6 in CDCl3 at room temperatures.
entry starting
reactant
s
reaction time
(min)
aldimine ratio
(reactant:prod
uct)
1 Kn1 + A2 60 1:0.21
Kn2 + A1 15 0.22:1
2 Kn1 + A3 15 1:0.55
Kn3 + A1 7 0.55:1
3 Kn1 + A4 ≤3 1:0.90
Kn4 + A1 11 0.91:1
4 Kn1 + A5 ≤3 0.54:1
Kn5 + A1 22 1:0.56
5 Kn1 + A6 ≤3 0.09:1
Kn6 + A1 30 1:0.09 6

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.
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 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
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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
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10. RESULTS AND DISCUSSION
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 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

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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

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TS1
TS2
TS3 TS4

15. OPTIMIZED GEOMETRIES
R1 R2 BS1
INT1 INT2 INT3
P1 P2
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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.

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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.

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TS1 TS2
TS3 TS4

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 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.

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R1' R2՛ BS 1՛
INT1՛ INT2՛ INT3՛
P1՛ P2՛

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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)
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(R1)
(R2)
LUMO (-1.66) HOMO (-6.64) HOMO-3 (-6.91)
(R2՛)

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 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
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Global minima = -23.17 kcal/mol
-16.92 kcal/mol
Global maxima = 20.30 kcal/mol

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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.

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