Mechanism and free energy profile of base-catalyzed Knoevenagel condensation reaction

Article abstract of DOI:10.1039/c6ra10393f

The Knoevenagel condensation reaction is a classical method for carbon-carbon bond formation. This reaction can be catalyzed by homogeneous or heterogeneous bases, and in the past ten years many different solid bases catalysts have been investigated. In this report, we have done a reliable theoretical analysis of the reaction mechanism and free energy profile of acetylacetone reaction with benzaldehyde catalyzed by methoxide ion in methanol solution. The analysis was extended for solventless conditions and solid base catalysis. We have found that the enolate addition to the benzaldehyde is a rapid step, contrary to general assumptions on the mechanism. The rate-determining step is the leaving of the hydroxide ion from the anionic intermediate, with a predicted overall free energy barrier of 28.8 kcal mol^-1. This finding explains the experimental observation that more polar medium favor the reaction, once the transition state is product-like and involves the formation of the highly solvated hydroxide ion. The present results provides useful insights on this reaction system.

Full text of DOI:10.1039/c6ra10393f

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: E. V. Dalessandro,
H. P. Collin, M. S. Valle and J. Pliego, RSC Adv., 2016, DOI: 10.1039/C6RA10393F.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 22
RSC Advances
View Article Online
DOI: 10.1039/C6RA10393F
Mechanism and Free Energy Profile of Base-Catalyzed Knoevenagel
Condensation Reaction
Ellen V. Dalessandro, Hugo P. Collin, Marcelo S. Valle
and Josefredo R. Pliego Jr.,*
Departamento de Ciências Naturais, Universidade Federal de São João delꢀRei
36301ꢀ160, São João delꢀRei, MG, Brazil.
* pliego@ufsj.edu.br
1

RSC Advances
Page 2 of 22
View Article Online
DOI: 10.1039/C6RA10393F
Abstract
The Knoevenagel condensation reaction is a classical method for carbonꢀcarbon
bond formation. This reaction can be catalyzed by homogeneous or heterogeneous
bases, and in the past ten years many different solid bases catalysts have been
investigated. In this report, we have done a reliable theoretical analysis of the reaction
mechanism and free energy profile of acetylacetone reaction with benzaldehyde
catalyzed by methoxide ion in methanol solution. The analysis was extended for
solventless conditions and solid base catalysis. We have found that the enolate addition
to the benzaldehyde is a rapid step, contrary to general assumptions on the mechanism.
The rateꢀdetermining step is the leaving of the hydroxide ion from the anionic
intermediate, with a predicted overall free energy barrier of 28.8 kcal molꢀ1. This finding
explains the experimental observation that more polar medium favor the reaction, once
the transition state is productꢀlike and involves the formation of the highly solvated
hydroxide ion. The present results provides useful insights on this reaction system.
2

Page 3 of 22
RSC Advances
View Article Online
DOI: 10.1039/C6RA10393F
Introduction
Reactions leading to carbonꢀcarbon bond formation play a very important role in
synthetic organic chemistry. Among the many possible processes, the Knoevenagel
reaction is a classical example. The reaction needs a catalyst to procced and the most
usual homogeneous catalyst is an amine.1ꢀ3 A recent report has indicated that a
combination of Nꢀmethylꢀpiperidine and a phenol compound is an effective catalyst.4 In
the past two decades, many solid superbase heterogeneous catalysts have been
developed,5 and some examples of heterogeneous catalysts of Knoevenagel reaction are
modified Mg–Al hydrotalcite,6 modified zeolites,7, 8 alkali modified metal oxide,9 amine
immobilized on silica gel10 and 1,4ꢀdiazabicyclo[2.2.2]octane immobilized on
polystyrene,11 aminoꢀbased metalꢀorganic frameworks,12, 13 bifunctional acid–base ionic
16ꢀ20
liquid,14 proton sponges in mesoporous sílica,15 and several other catalysts.13,
Recently, List and coꢀworkers have reported the first example of a catalytic asymmetric
version of the Knoevenagel reaction.21
The reaction mechanism can follow at least two main pathways: a) iminium ion
formation, in the case of primary and secondary amines, and b) formation of enolate via
deprotonation by a tertiary amine, homogeneous base or solid base. In the present work,
we have investigated the enolate mechanism and our results should provide important
insights on the base catalyzed process in both homogeneous and heterogeneous
conditions. A general view of the mechanism is presented in Scheme 1. The species
(B−) can be a homogeneous or heterogeneous base. In the second case, we consider that
the proton exchange step takes place through a rapid equilibrium at the surface, and the
remaining of the reaction occurs in solution.
In experimental studies, Zhan et al. have proposed a mechanism and kinetic
model with enolate addition to benzaldehyde as the rate determining step in conditions
of no solvent and temperature of 393 K for ethyl acetoacetate conversion.7 In the same
way, Ziolek and coꢀworkers have investigated alkali metalꢀmodified oxide supports for
catalyzing the same reaction in high temperature and no solvent. They have investigated
several catalysts and measured the reaction kinetics.9 Yet another mechanism, not
investigated in this work, is the possibility of a rate determining reaction step to take
place on the solid catalyst surface. Thus, Saravanamurugan et al. has investigated the
3

RSC Advances
Page 4 of 22
View Article Online
DOI: 10.1039/C6RA10393F
zeolite heterogeneous catalyzed Knoevenagel reaction and have proposed a mechanism
taking place on the catalyst surface.8
Scheme 1: Proposed mechanism of baseꢀcatalyzed Knoevenagel reaction. Y can be –
COR, ꢀCOOR, ꢀCN.
4

Page 5 of 22
RSC Advances
View Article Online
DOI: 10.1039/C6RA10393F
Some theoretical studies of the Knoevenagel reaction have been published.14, 22,
Although these studies provide insights on the mechanism, a reliable picture of the
23
process needs an accurate theoretical approach. Nevertheless, in some cases the authors
have used the B3LYP functional for calculating energy, which is not reliable for this
system,24 or have not investigated all the mechanisms. It is also important the inclusion
of the solvent effect, correction for adequate standard state, and computation of the
Gibbs free energy. As it was emphasized by Plata and Singleton,25 multistep ionic
reactions in polar solvents requires careful use of theoretical methods. Thus, it is
important an adequate choice of the electronic structure theory approach and reliable
treatment of the solvent effect. In this report, we have used high level of theory for
electronic energies and a sound approach for including solvent effects, mixing SMD
solvation model with empirical corrections. The aim of this work is to present a reliable
mechanism and free energy profile for a model Knoevenagel reaction. The system is the
Knoevenagel condensation of acetylacetone with benzaldehyde, catalyzed by methoxide
ion in methanol solution, presented in Scheme 2.
Scheme 2: Reaction system investigated in this work.
5

RSC Advances
Page 6 of 22
View Article Online
DOI: 10.1039/C6RA10393F
Theoretical methods
The reaction system presented in Scheme 2 was investigated by theoretical
calculations. We have included the solvent effect on the geometry optimizations and
frequencies, leading to more reliable description of this highly polar reaction. The
optimizations were done with the X3LYP functional26 and the 6ꢀ31G(d) basis set for
carbon and hydrogen, and 6ꢀ31+G(d) basis set for oxygen. We have named this basis set
as 6ꢀ31(+)G(d). The solvent effect in the optimizations was included through the CPCM
method27ꢀ32 for methanol solvent, and using 240 tesserae for atom to obtain more
reliable potential of mean force surface.33 Following this CPCM/X3LYP/6ꢀ31(+)G(d)
optimizations, we have done the corresponding harmonic frequency calculations. In
order to obtain accurate electronic energies, we have done single point energy
calculations with the X3LYP and M08ꢀHX34 functionals using the TZVPP basis set,35
augmented with sp diffuse functions on the oxygen atom. Additional calculations at
higher level of theory, the LPNOꢀCEPA/1 method36ꢀ38 in conjunction with the maꢀ
TZVPP basis set,39 were also performed.
A comment should be done on our choice of the electronic structure methods.
The X3LYP (and the closely related B3LYP) functional predicts reliable geometries and
harmonic frequencies. However, it may not be accurate for reaction energies. On the
other hand, the M08ꢀHX functional is much more reliable for reaction energies as
documented by Zhao and Truhlar.40 Thus, M08ꢀHX calculations should provide more
confident energies. We have also used a wave function based method, the LPNOꢀ
CEPA/1, recently developed for reliable calculations of medium size systems.41 The
performance of this method is between the CCSD and CCSD(T) approaches, and it will
be considered our best electronic energy values.
The CPCM optimizations include the electrostatic contribution to the solvation
free energy, the most important effect. However, for more reliable solvation
contribution, we have done single point energy calculations using the SMD method42
and the X3LYP/6ꢀ31(+)G(d) electronic density. Thus, the reaction and activation free
energy in solution were computed through the equations 1 and 2 below:
∆ꢀꢁꢂꢃ = ∆ꢄꢅꢃ + ∆ꢀꢆꢇꢈ + ∆∆ꢀꢁꢂꢃꢆ
(1)
6

Page 7 of 22
RSC Advances
View Article Online
DOI: 10.1039/C6RA10393F
∆ꢀꢁ‡ꢂꢃ = ∆ꢄꢅ‡ꢃ + ∆ꢀꢆ‡ꢇꢈ + ∆∆ꢀꢁ‡ꢂꢃꢆ
(2)
The first term in the right side is the electronic energy (LPNOꢀCEPA/1), the second
term is the vibrational, rotational and translational free energy contribution
(CPCM/X3LYP harmonic frequency calculation, corrected to 1 mol/L standard state)
and the last term is the solvation free energy contribution (SMD). All the X3LYP and
M08ꢀHX calculations were carried out with the GAMESS program,43, 44 and the LPNOꢀ
CEPA/1 method was done with the ORCA program system.45
Although the SMD model performs well for neutral solutes in methanol
solution,46 this model has a systematic deviation in the solvation free energy of ions.47
Thus, we have done empirical corrections in the relative free energy in order to obtain
more reliable free energy reaction profile. The first correction was done in the
calculation of pKa of some species, leading to the respective anions. The calculation is
based in the proton exchange reaction with the phenoxide ion:
HA + PhO−
→
A−
+
PhOH
ꢀGdep (HAꢀPhOH)
and the pKa is obtained from equation :
(
)
∆ꢀꢎꢅꢏ ꢌꢍ − ꢐℎꢑꢌ
(
)
(
)
ꢉꢊꢋ ꢌꢍ =
+ ꢉꢊꢋ ꢐℎꢑꢌ
(3)
(
)
ꢒꢓꢔꢕ 10
In the next step, it is done an empirical correction in the pKa, through the equation:47
(
)
(
)
ꢉꢊꢋ ꢌꢍ, ꢖꢗꢘꢘꢙꢖꢚꢙꢛ = 0.6025 ∙ ꢉꢊꢋ ꢌꢍ + 5.691
Based on this corrected pKa´s, we have obtained the free energy for deprotonation
reaction in methanol solution:
HA → A−
+
H+
ꢀGdep (HA)
The calculated values are presented in Table 1. These values, the relative free energy of
neutral species, and the free energy of activation for transition states closer to the
reference point were used to obtain the corrected free energy profile. The next equations
show how each calculation was done, taking acetylacetone, benzaldehyde and
methoxide ion as the reference point (zero free energy).
Enolate:
7

RSC Advances
Page 8 of 22
View Article Online
DOI: 10.1039/C6RA10393F
∗
∗
(
)
(
)
(
)
(
)
ꢜ ꢙꢕꢗꢔꢝꢚꢙ = ꢜ ꢝꢖꢙꢚꢞꢔꢝꢖꢙꢚꢗꢕꢙ + ∆ꢀꢎꢅꢏ ꢝꢖꢙꢚꢞꢔꢝꢖꢙꢚꢗꢕꢙ − ∆ꢀꢎꢅꢏ ꢟꢙꢑꢌ
(4)
MS1a:
∗
∗
(
)
(
)
(
)
(
)
ꢜ ꢟꢠ1ꢝ = ꢜ ꢟꢠ1 + ∆ꢀꢎꢅꢏ ꢟꢠ1ꢝ − ∆ꢀꢎꢅꢏ ꢟꢙꢑꢌ
(5)
TS2:
‡
∗
∗
(
)
(
)
(
)
ꢜ ꢓꢠ2 = ꢜ ꢟꢠ1ꢝ + ∆ꢀꢁꢂꢃ ꢟꢠ1ꢝ → ꢓꢠ2, ꢠꢟꢡ
(6)
MS1b:
∗
∗
(
)
(
)
(
)
(
)
ꢜ ꢟꢠ1ꢢ = ꢜ ꢟꢠ1 + ∆ꢀꢎꢅꢏ ꢟꢠ1ꢢ − ∆ꢀꢎꢅꢏ ꢟꢙꢑꢌ
(7)
P1 + OH−
∗
∗
ꢣ
∗
∗
(
)
(
)
(
)
(
)
(
)
(
)
ꢜ ꢐ1 + ꢜ ꢑꢌ = ꢜ ꢐ1 + ꢜ ꢐ1 + ∆ꢀꢎꢅꢁꢏ ꢌꢤꢑ − ∆ꢀꢎꢅꢏ ꢟꢙꢑꢌ
(8)
TS4:
‡
∗
∗
∗
ꢣ
ꢣ
(
)
(
)
(
)
(
)
ꢜ ꢓꢠ4 = ꢜ ꢐ1 + ꢜ ꢑꢌ + ∆ꢀꢁꢂꢃ ꢐ1 + ꢑꢌ → ꢓꢠ4, ꢠꢟꢡ
(9)
These equations leads to more reliable stability of the ions, and better barriers of the
transition states, because we have used transition states with higher similarity with the
reference point of the reaction. In addition, we have found the SMD model has a
reasonable performance for ionꢀmolecule reactions in methanol solution.48
8

Page 9 of 22
RSC Advances
View Article Online
DOI: 10.1039/C6RA10393F
Experiments
We have done some experiments to provide more support to the view of this
reaction obtained from theoretical calculations.
Reaction using 10 mol% of NaOH: To a solution of acetylacetone (0.51 mL, 0.50 g,
5.0 mmol) and benzaldehyde (0.51 mL, 0.53 g, 5.0 mmol) in methanol (10.0 mL) was
added NaOH (0.02 g, 0.5 mmol) at room temperature. The reaction mixture was stirred
for 1 h and then warmed to reflux temperature during 24 h. The reaction was monitored
by TLC (Thin Layer Chromatography) and no reaction was observed.
Reaction using 100 mol% of NaOH : To a solution of acetylacetone (0.51 mL, 0.50 g,
5.0 mmol) and benzaldehyde (0.51 mL, 0.53 g, 5.0 mmol) in methanol (10.0 mL) was
added 0.5 mmol of NaOH at room temperature. After 24 h of reaction under reflux, the
reaction mixture was diluted with ethyl acetate (EtOAc) (10.0 mL) and saturated
aqueous NaCl (5.0 mL). The layers were separated, and the aqueous layer was extracted
with EtOAc (2 × 10.0 mL). The organic extracts were combined, dried over Na2SO4,
and evaporated to dryness under vacuum. The residue obtained was purified by
chromatography on silica gel (EtOAc/heptane 3:7 then EtOH) to furnish two major
fractions containing each one a mixture of compounds that could not be isolated. Polar
fraction (R
f
0.4ꢀ0,1; EtOAc/heptane 3:7) 1H NMR (500 MHz, CDCl3):
), 2.61 ( ), 2.15 ( , 1.5 Hz), 2.06 ( ) 2.02 ( ) 1.99 (
δ
7.2 (
s, l), 4.10
(dd, 14.3, 7.2 Hz) 3.3 (
s
s
d
s
s
s, l) 1,24 (m,
7.0, 2.3 Hz) ppm; 13C NMR (125 MHz, CDCl3): 197.3, 182.9, 129.4, 127.3, 126.4, 68.9,
1
60.5, 29.8, 21.1, 14.2. Apolar fraction (R
MHz, CDCl3): 7.39 (dd, 7.0, 1.4 Hz), 7.36 (
Hz) 7.32 ( ), 7.30 ( ), 7.28 ( , 2.1 Hz), 7.27 ( ), 7.24 (
), 6.91 ( ), 6.09 ( , 2.1 Hz), 4.03 ( , 7.2 Hz), 2.94 (dd, 4.0, 2.1 Hz), 2.6 (
1.17 ( , 14.2, 7.2 Hz). Spectra in the supporting information.
f
0.8ꢀ0.4; EtOAc/heptane 3:7); H NMR (500
δ
d
, 1.8 Hz), 7.35 (
), 7.22 (
d
, 1.7 Hz), 7.34 (
d, 1.5
s
s
d
s
s
s
), 7.19 ( , 4.2 Hz), 7.17
t
(
s
m
d
m
m
), 1.96 (s),
t
9

RSC Advances
Page 10 of 22
View Article Online
DOI: 10.1039/C6RA10393F
Results and Discussion
Mechanism and Transition States
We have investigated the mechanistic possibilities presented in Scheme 1, and
included the direct reaction of acetylacetone to benzaldehyde. This transition state,
named TS2N, is presented in Figure 1. We can notice that this step needs an almost
complete transfer of proton from acetylacetone in the enol form to benzaldehydo before
to reach the transition state. The carbonꢀcarbon distance is very high, 2.51 Å. Although
the reaction free energy profile will be discussed in the next section, we can anticipate
that its free energy barrier is very high, 43.5 kcal molꢀ1 (Table 1). Thus, this pathway is
not viable and no reaction will take place by this mechanism.
In the anionic mechanism (Scheme 1), the nucleophilic attack of the enolate ion
to the benzaldehyde corresponds to TS2. The carbonꢀcarbon distance in this structure is
1.79 Å and the corresponding free energy barrier is only 15.6 kcal molꢀ1. Therefore, this
process is very favorable and leads to a rapid kinetics. The formed product, MS1a, has a
structure close to TS2, with a slightly shorter carbonꢀcarbon distance of 1.77 Å. In the
same way, it is slightly less stable, staying 15.1 kcal molꢀ1 above of the enolate plus
benzaldehyde reactants. The other transition state is TS4, and corresponds to leaving of
the hydroxide ion from MS1b (Figure 2) in step 4. The carbonꢀoxygen distance is high,
2.32 Å, suggesting a transition state very similar to the products.
10

Page 11 of 22
RSC Advances
View Article Online
DOI: 10.1039/C6RA10393F
TS2N
TS2
MS1a
TS4
Figure 1: Transition states and a key minimum for the acetylacetone (enolate) reaction
with benzaldehyde in methanol solvent.
11

RSC Advances
Page 12 of 22
View Article Online
DOI: 10.1039/C6RA10393F
Table 1: Relative thermodynamic properties calculated in this work.a
Values relative to benzaldehyde + acetylacetone + methoxide
X3LYPb
M08ꢀHXb
LPNOꢀCEPA/1c
ꢀGmol
ꢀ0.78
3.37
ꢀꢀGsolv
2.48
ꢀGsol
d
e
f
Enol isomer
MS1
ꢀ5.58
ꢀ2.64
1.70
5.18
ꢀ0.72
4.90
ꢀ13.14
0.57
ꢀ11.93
1.81
P1 + H2O
0.75
2.66
ꢀ6.50
16.94
ꢀ3.84
ꢀ16.28
Enolate +
benzaldehyde
ꢀ38.32
ꢀ37.78
ꢀ35.36
ꢀ33.22
TS2N
26.79
31.39
44.43
ꢀ0.95
43.48
Values relative to benzaldehyde + enolate
X3LYPb
4.31
M08ꢀHXb
LPNOꢀCEPA/1c
ꢀGmol
6.79
ꢀꢀGsolv
15.32
15.03
9.92
ꢀGsol
d
e
f
TS2
ꢀ6.71
ꢀ5.58
22.11
21.65
9.25
MS1a
MS1b
TS4
4.59
ꢀ6.73
ꢀ5.62
6.62
ꢀ4.21
30.02
48.25
ꢀ16.43
27.47
ꢀ14.15
ꢀ0.67
25.00
35.41
44.04
0.00
35.41
12.66
P1 + OH−
45.73
42.34
ꢀ31.38
Calculation of pKa and deprotonation free energy in methanol solution
pKa
pKa (corr)
21.46
ꢀGmol
33.66
41.82
0.43
ꢀꢀGsolv
ꢀ17.51
ꢀ25.45
ꢀ0.57
ꢀGsol
16.15
16.37
ꢀ0.14
16.33
0.32
ꢀGdep
29.27
29.40
19.46
29.38
19.73
CH3OH
26.17
26.33
14.23
26.30
14.56
H2O
21.55
acetylacetone
MS1(OH)
MS1(CH)
14.26
3.68
12.65
3.93
21.54
ꢀ3.61
14.47
Final relative free energy values in relation to benzaldehyde + acetylacetone + methoxide, with empirical
corrections
ꢀG
TS2N
43.5
5.2
MS1
Enolate
TS2
ꢀ9.8
5.8
MS1a
5.3
MS1b
ꢀ4.4
19.0
ꢀ3.7
ꢀ3.8
TS4
P1 + OH−
P1 + H2O
a – Units of kcal/mol. Standard state of 1 mol/L, 25 oC, for free energy values.
b – Using the TZVPP+diff basis set.
c – Using the maꢀTZVPP basis set.
d – We have defined ꢀGmol = ꢀEel + ꢀGvrt, and ꢀEel at LPNOꢀCEPA/1 level
e – Solvent effect.
f – Solution phase free energy
12

Page 13 of 22
RSC Advances
View Article Online
DOI: 10.1039/C6RA10393F
Other point which deserves attention is the comparison between the X3LYP
functional and the reliable LPNOꢀCEPA/1 method. For example, the energy of the MS1
structure in relation to the reactants is ꢀ11.9 kcal molꢀ1 at LPNOꢀCEPA/1 level, whereas
the X3LYP method predicts ꢀ0.7 kcal molꢀ1, an error of 11 kcal molꢀ1. On the other
hand, the M08ꢀHX functional performs much better, with an energy of ꢀ13.1 kcal molꢀ1
and a deviation of only 1.2 kcal molꢀ1. In the case of critical TS4 structure, the X3LYP
functional deviates 5 kcal molꢀ1 from the LPNOꢀCEPA/1 method. Considering the
similarity between X3LYP and B3LYP functionals, both of them should not be used for
predicting reaction energies for this class of reactions, although these methods are
reliable for calculating geometries.
Theoretical calculation of the pKa of some species in methanol
We have done a reliable calculation of the pKa of key species in methanol. The
results are presented in Table 1. Methanol and water have calculated pKa of 21.5 and
21.6, respectively, in good agreement with the experimental value of 18.6 for
methanol.49 For comparison, the uncorrected calculated pKa of methanol is 26.2. For
acetylacetone, we have predicted a pKa of 14.3. For the intermediate MS1 structure, the
pKa´s values are 21.5 for deprotonation of the OH group and 14.5 for deprotonation of
the CH group.
Free Energy Profile
A general view of the reaction is presented in Figure 2. The reaction steps of the
ionic mechanism are numbered in line with Scheme 1. In the uncatalyzed mechanism,
there is an isomerization from keto to enol form before the reaction. The barrier for this
nucleophilic attack is very high, 43.5 kcal molꢀ1, and the formed product intermediate,
MS1, is 5.2 kcal molꢀ1above of the reactants. Thus, for this system, the ketoꢀalcohol
intermediate should not be observed as a reaction product. Once the barrier by this
pathway is very unfavorable, we have not investigated the uncatalyzed elimination step.
The base catalyzed mechanism begin by deprotonation of the acetylacetone, a
process favorable by 9.8 kcal molꢀ1. This easy deprotonation is due the predicted pKa of
13

RSC Advances
Page 14 of 22
View Article Online
DOI: 10.1039/C6RA10393F
acetylacetone in methanol, 14.3. For methanol, the predicted pKa is 21.5. Based on this
free energy, all of the methoxide base will react. We should emphasize that the
methoxide base is present in catalytic quantity.
The second step is the nucleophilic attack of the enolate to the benzaldehyde.
The small barrier of 15.6 kcal molꢀ1 indicates that this step is very rapid and it is not rate
determining. Then, the mechanistic view of this reaction needs be revised. The MS1a
intermediate is very similar to TS2 and is slightly more stable. In the next step, there is
isomerization to MS1b, involving proton exchange with the solvent. Because these
reactions are usually rapid, we consider this step as a rapid equilibrium. The MS1b
structure is only 5.4 kcal molꢀ1 above of the enolate plus benzaldehyde reactants, and is
more stable than MS1a due to high charge dispersion. We should observe that at
microscopic level, the MS1a should take a proton of the solvent to generate MS1. In the
next step, it lose a proton to the medium to become MS1b. However, considering these
steps are rapid and MS1 is less stable than MS1b, we have not taken in account these
additional equilibria.
The critical step is the elimination of the hydroxide ion via TS4. The structure is
19 kcal molꢀ1 above of the neutral reactants and 28.8 kcal molꢀ1 above of the enolate
plus benzaldehyde. Therefore, this is the rateꢀdetermining step and the overall barrier
for this process is 28.8 kcal molꢀ1, resulting in a very slow kinetics at room temperature.
The hydroxide ion eliminated can exchange proton with methanol, leading to the final
product and reforming the methoxide catalyst. The product is 3.8 kcal molꢀ1 below of
the neutral reactants, indicating that this process is thermodynamically favorable.
Therefore, the catalytic process is thermodynamically viable. On the other side, the final
product plus methoxide is 6 kcal molꢀ1 above of the methoxide ion plus benzaldehyde. It
means that the use of stoichiometric quantity of methoxide ion makes the reaction
thermodynamically inviable. Consequently, increasing the quantity of catalyst, decrease
the maximum yield. Thus, using 10 mol% of the catalyst means that the maximum yield
will be 90%. This fact is due the high basicity of the methoxide ion. Hence, using less
basic catalyst, with pKa close to the acetylacetone reactant, is thermodynamically
advantageous.
14

Page 15 of 22
RSC Advances
View Article Online
DOI: 10.1039/C6RA10393F
Figure 2: Free energy profile of the acetylacetone reaction with benzaldehyde in
o
methanol solution at 25 C, catalyzed by methoxide ion. The free energy values were
obtained using the corrections discussed in the methodology section.
The free energy profile in Figure 2 allow us to write a kinetic law for the
catalyzed mechanism. The reaction rate expression is:
ꢛꢥꢐℎꢦꢌꢑꢧ
ꢥ
ꢧ
= −ꢨꢩꢊꢤꢊꢪꢦꢫꢋꢁꢅ ꢐℎꢦꢌꢑ
(10)
ꢛꢚ
Where the Cbase is the amount of base catalyst added, which will generate the enolate.
This value is constant and the resulting rate expression is first order in benzaldehyde.
The Kn and kn constants are equilibrium and rate constants of the respective steps
(Scheme 1 and Figure 2). The observed free energy barrier is 28.8 kcal molꢀ1 and the
resulting pseudo firstꢀorder rate constant, considering that Cbase = 0.10 mol/L, is:
ꢨꢂꢫꢁ = ꢨꢩꢊꢤꢊꢪꢦꢫꢋꢁꢅ = 4.8 x 10ꢣꢬꢭsꢣꢬ
(11)
15

RSC Advances
Page 16 of 22
View Article Online
DOI: 10.1039/C6RA10393F
Even considering the ebullition point of methanol, 64.7 oC, and taking the same free
energy, we can estimate:
ꢨꢂꢫꢁ = 1.6 x 10ꢣꢮsꢣꢬ
(12)
leading to a lifetime (1/kobs) of 70 days. The reaction should proceed efficiently only on
the temperature of 400 K, with an estimated lifetime of 2 hours. Although these are
rough estimates, our results indicate that this reaction system needs vigorous conditions
to proceed.
Experimental observations
The experiments in methanol solvent using 10 mol% of NaOH catalyst point out
that no reaction product was observed. This is in agreement with our predicted kinetics,
because based on equation (10), we should observe less than 1% of product. In the case
of reaction using 100 mol% of NaOH, the NMR analysis of aqueous and organic
fractions showed that benzaldehyde was fully consumed, since only a trace chemical
shift at 9.94 ppm was detected. The presence of only one chemical shift at 199.7 ppm
proves that no product was obtained, since it has two chemical shifts on that region. At
143.5 and 68.9 ppm we can note the presence of chemical shifts from the benzyl
alcohol. In addition, there are chemical shifts from the carboxylic acid at 175.3 and
135.9. Other chemical shifts from the protonated and unprotonated acetylacetone can be
seen at 182.9, 60.5, 40.7 and 33.7 ppm. Thus, using 100 mol% of NaOH base in
methanol under reflux, no Knoevenagel condensation product was obtained. Rather, we
have observed the Cannizzaro reaction. This is in line of our prediction that the
Knoevenagel product is thermodynamically unfavorable when using 100 mol% of
NaOH.
Comparison with experimental data for similar system
Rodriguez et al. have reported the kinetics of the reaction of ethyl acetoacetate
(and ethyl cyanoacetate) with benzaldehyde catalyzed by 1,8ꢀbisdimethylamino
16

Page 17 of 22
RSC Advances
View Article Online
DOI: 10.1039/C6RA10393F
naphthalene (DMAN, a proton sponge) in different solvents.50 They have observed an
important solvent effect: the reaction rate increases with the polarity. Thus, the reaction
of ethyl acetoacetate in DMSO was observed, while in acetonitrile not. The DMSO and
acetonitrile have similar solvation of cations. However, for small anions like the
fluoride ion, the solvation in DMSO is 8 kcal molꢀ1 more negative.51 This is in line with
our model, where the formation of a small and highly solvated OH− ion in TS4 should
be sensible to the solvent. Other important observation is the much higher reactivity of
ethyl cyanoacetate in DMSO. Thus, while they have observed 18% conversion of ethyl
o
acetoacetate during 120 min in DMSO and 80 C, the ethyl cyanoacetate has presented
50% conversion in a time of 50 min in room temperature and DMSO solvent. We can
make a rough estimate of the catalyzed free energy barrier for ethyl acetoacetate
reaction, considering that the reaction is first order in the reactants and in the catalyst,
finding a value of 26 kcal molꢀ1. This is in reasonable agreement with our value, even
considering the differences in the reactants and solvents.
Comparison with literature data for OH− addition to activated alkene
The reaction kinetics of hydroxide ion addition to activated alkenes has been
reviewed.52 In the case of benzylideneacetylacetone (P1 in this paper, see Figure 2),
Bernasconi et al. have reported an overall second order rate constant (kꢀ4 in this work,
ꢊꢬꢯꢰ ∙ ꢨꢤꢰꢤꢯ in their report) of 0.05 L molꢀ1 sꢀ1 for reverse of step 4, leading to G‡ =
ꢀ
19.2 kcal molꢀ1 in aqueous solution.53 Our calculation is in methanol. However, the
reaction rate in both solvents must be close, considering these solvents has similar
solvation of ions. Classical measurements of the rate constant of anionꢀmolecule
reactions in water and methanol support this view.54 Thus, considering our free energy
profile (Figure2), the reverse of step 4 has a free energy barrier of 22.7 kcal molꢀ1, in
good agreement with the experimental results. Other important observation from
Bernasconi et al. results is that the reverse reaction is thermodynamically favorable,
once they have observed the formation of benzaldehyde and acetylacetone products.
This finding provides more support on the quality of our predicted free energy profile.
Although the good agreement of our results with the Bernasconi et al. kinetics
data, as well as the higher thermodynamic stability of the enolate plus benzaldehyde in
relation to P1, they have suggested the reverse of step 4 is not rate determining. Rather,
17

RSC Advances
Page 18 of 22
View Article Online
DOI: 10.1039/C6RA10393F
they have proposed that decomposition of MS1b to the acetylacetone and benzaldehyde
reactants is slower. It is important to emphasize that the kinetics analysis has some
assumptions, which can lead to mistake. Our analysis point out that the reverse of step 4
is the rateꢀdetermining one and the decomposition of MS1b is very rapid, with ꢀ
G‡ =
10.2 kcal molꢀ1. Therefore, we think their analysis should be revisited on the light of our
results.
Base catalyzed heterogeneous catalysis
The free energy profile calculated in this work can be adapted for the reaction
involving the solid base. In this case, the first step in Scheme 1 involves a proton
exchange with base sites on the solid surface. Thus, the equilibrium equation can be
written as:
ꢱꢰꢥꢙꢕꢗꢔꢝꢚꢙꢧ
ꢊꢬ =
(13)
(
)
1 − ꢱꢰ ꢥꢝꢖꢙꢚꢞꢔꢝꢖꢙꢚꢗꢕꢙꢧ
Where ꢱꢰ is the fraction of protonated base sites. Usually, the experiments make use of
1 mol% to 10 mol% of sites in relation to reactants. Furthermore, the reactions are
conducted in high temperature and solventless. Considering that on these conditions
there is only a small fraction of deprotonation, because the medium has low polarity, the
rate law becomes:
(
)
ꢛꢥꢐℎꢦꢌꢑꢧ
ꢛꢚ
ꢊꢬ 1 − ꢱꢰ
ꢥ
ꢧ
= −ꢨꢩꢊꢤꢊꢪ ꢲ
ꢳ ꢐℎꢦꢌꢑ ꢥꢝꢖꢙꢚꢞꢔꢝꢖꢙꢚꢗꢕꢙꢧ
(14)
ꢱꢰ
The term in parenthesis is related to the strength of the base and it should be smaller
than 1. Stronger base leads to higher value of this term. From a kinetics viewpont, this
term add a “free energy barrier” to the overall barrier of 28.8 kcal molꢀ1, considering the
reaction of the enolate to benzaldehyde. We should consider that in experimental
18

Page 19 of 22
RSC Advances
View Article Online
DOI: 10.1039/C6RA10393F
conditions, there is not methanol solvent. Nevertheless, the table 1 point out the solvent
effect from enolate plus benzaldehyde to TS4 has ꢀꢀGsolv = 0. Considering that we have
done a correction for this step, the solvent effect should be some kcal molꢀ1 negative, in
line with the idea that more polar media favor the reaction. Thus, we should observe an
increase of the reaction rate with more polar solvent, although the effect amount few
kcal molꢀ1.
In order to apply the model proposed in this work, lets analyze some
experimental data of Ziolek and coꢀworkers.9 Those authors have measured the
Knoevenagel reaction of benzaldehyde with ethylacetoacetate, using potassiumꢀdopped
silica as catalyst. They have observed the formation of 75% of the condensation product
in a time of 300 min at 413 K without solvent. Thus, considering a concentration of 5
mol/L for each reactant, we can estimate an observed free energy barrier of 33 kcal molꢀ
1. This result is in line with our free energy barrier, even considering that our reaction is
simulated in methanol solvent. Therefore, we believe that the present analysis provides
the real free energy profile for this important and classical reaction system for both
homogeneous and heterogeneous base catalysis.
Conclusion
The mechanism and free energy profile of the Knoevenagel condensation
reaction between benzaldehyde and acetylacetone catalyzed by methoxide ion in
methanol solution have been investigated by theoretical methods. It was found that the
nucleophilic addition of the enolate to benzaldehyde is rapid and leads to the unstable
intermediate MS1a, similar to the transition state. This species can rearrange to MS1b
carbanion and the rateꢀdetermining step is the hydroxide ion elimination from this
intermediate, with an overall free energy barrier of 28.8 kcal molꢀ1. The analysis was
extended to solid base catalysis and solventless conditions, suggesting the important
role of base strength to generate enolate on this low polarity conditions. Based on these
findings, any improvement of the catalytic efficiency should pay attention on the
hydroxide ion elimination step.
19

RSC Advances
Page 20 of 22
View Article Online
DOI: 10.1039/C6RA10393F
Acknowledgments
The authors thank the agencies CNPq, FAPEMIG, and CAPES for support. This
work is a collaboration research project of members of the Rede Mineira de Química
(RQꢀMG) supported by FAPEMIG (Project: CEX ꢀ REDꢀ00010ꢀ14).
Supporting Information
The coordinates of the optimized structures and the NMR spectra are available.
References
1 A. Erkkilä, I. Majander and P. M. Pihko, Chem. Rev., 2007, 107, 5416.
2 Y. Wang, Z.-c. Shang, T.-x. Wu, J.-c. Fan and X. Chen, J. Mol. Catal. A-Chem., 2006, 253, 212.
3 B. List, Angew. chem. Int. Ed., 2010, 49, 1730.
4 S. K. Panja, N. Dwivedi and S. Saha, RSC Advances, 2015,
5 L. Chen, J. Zhao, S.-F. Yin and C.-T. Au, RSC Advances, 2013,
5
, 65526.
, 3799.
3
6 M. Lakshmi Kantam, B. M. Choudary, C. Venkat Reddy, K. Koteswara Rao and F. Figueras,
Chem. Commun., 1998, 1033.
7 X. Zhang, E. S. Man Lai, R. Martin-Aranda and K. L. Yeung, Appl. Catal. A - Gen., 2004, 261
,
109.
8 S. Saravanamurugan, M. Palanichamy, M. Hartmann and V. Murugesan, Appl. Catal. A -
Gen., 2006, 298, 8.
9 V. Calvino-Casilda, R. M. Martín-Aranda, A. J. López-Peinado, I. Sobczak and M. Ziolek, Catal.
Today, 2009, 142, 278.
10 K. Isobe, T. Hoshi, T. Suzuki and H. Hagiwara, Mol. Divers., 2005,
11 D.-Z. Xu, S. Shi and Y. Wang, RSC Advances, 2013, , 23075.
9, 317.
3
12 J. Gascon, U. Aktay, M. D. Hernandez-Alonso, G. P. M. van Klink and F. Kapteijn, J. Catal.
2009, 261, 75.
,
13 A. Burgoyne and R. Meijboom, Catal. Lett., 2013, 143, 563.
14 M. Boronat, M. J. Climent, A. Corma, S. Iborra, R. Montón and M. J. Sabater, Chem. Eur. J.
2010, 16, 1221.
,
15 E. Gianotti, U. Diaz, S. Coluccia and A. Corma, Phys. Chem. Chem. Phys., 2011, 13, 11702.
20

Page 21 of 22
RSC Advances
View Article Online
DOI: 10.1039/C6RA10393F
16 K. Sugino, N. Oya, N. Yoshie and M. Ogura, J. Am. Chem. Soc., 2011, 133, 20030.
17 G. Li, J. Xiao and W. Zhang, Green Chem., 2012, 14, 2234.
18 X. Dong, Y. Hui, S. Xie, P. Zhang, G. Zhou and Z. Xie, RSC Advances, 2013,
19 G. B. B. Varadwaj, S. Rana and K. M. Parida, Dalton Trans., 2013, 42, 5122.
20 L. Zhang, H. Wang, Z. Qin, J. Wang and W. Fan, RSC Advances, 2015, , 22838.
3, 3222.
5
21 A. Lee, A. Michrowska, S. Sulzer-Mosse and B. List, Angew. chem. Int. Ed., 2011, 50, 1707.
22 G. Frapper, C. Bachmann, Y. Gu, R. Coval De Sousa and F. Jerome, Phys. Chem. Chem.
Phys., 2011, 13, 628.
23 E. Bermúdez, O. N. Ventura and P. Saenz Méndez, J. Phys. Chem. A, 2010, 114, 13086.
24 R. Singh, T. Tsuneda and K. Hirao, Theor. Chem. Acc., 2011, 130, 153.
25 R. E. Plata and D. A. Singleton, J. Am. Chem. Soc., 2015, 137, 3811.
26 X. Xu, Q. Zhang, R. P. Muller and W. A. Goddard III, J. Chem. Phys., 2005, 122, 014105.
27 H. Li and J. H. Jensen, J. Comput. Chem., 2004, 25, 1449.
28 M. Cossi, N. Rega, G. Scalmani and V. Barone, J. Comput. Chem., 2003, 24, 669.
29 V. Barone and M. Cossi, J. Phys. Chem., 1998, 102, 1195.
30 J. Tomasi, B. Mennucci and R. Cammi, Chem. Rev., 2005, 105, 2999.
31 E. Cances, C. Le Bris, B. Mennucci and J. Tomasi, Math Mod Meth Appl S, 1999,
32 J. Tomasi and M. Persico, Chem. Rev., 1994, 94, 2027.
9, 35.
33 C. M. Silva, I. C. Dias and J. R. Pliego, Org. Biomol. Chem., 2015, 13, 6217.
34 Y. Zhao and D. G. Truhlar, J. Chem.Theory Comput., 2008,
35 F. Weigend and R. Ahlrichs, Phys. Chem. Chem. Phys., 2005,
36 T. Schwabe, J. Comp. Chem., 2012, 33, 2067.
4
, 1849.
, 3297.
7
37 F. Neese, A. Hansen, F. Wennmohs and S. Grimme, Acc. Chem. Res., 2009, 42, 641.
38 F. Wennmohs and F. Neese, Chem. Phys., 2008, 343, 217.
39 J. J. Zheng, X. F. Xu and D. G. Truhlar, Theor. Chem. Acc., 2011, 128, 295.
40 Y. Zhao and D. G. Truhlar, J. Chem.Theory Comput., 2011, 7, 669.
41 F. Neese, F. Wennmohs and A. Hansen, J. Chem. Phys., 2009, 130, 114108.
42 A. V. Marenich, C. J. Cramer and D. G. Truhlar, J. Phys. Chem. B, 2009, 113, 6378.
43 M. S. Gordon and M. W. Schmidt, in Theory and Applications of Computational Chemistry
eds. C. E. Dykstra, G. Frenking, K. S. Kim and G. E. Scuseria, Elsevier, Amsterdam2005,
pp. 1167.
,
44 M. W. Schmidt, K. K. Baldridge, J. A. Boatz, S. T. Elbert, M. S. Gordon, J. H. Jensen, S.
Koseki, N. Matsunaga, K. A. Nguyen, S. Su, T. L. Windus, M. Dupuis and J. A.
Montgomery Jr, J. Comput. Chem., 1993, 14, 1347.
45 F. Neese, WIREs Comput Mol Sci, 2012, 2, 73.
46 C. C. Zanith and J. R. Pliego, Jr., J. Comput. Aided Mol. Des., 2015, 29, 217.
47 E. L. M. Miguel, P. L. Silva and J. R. Pliego, J. Phys. Chem. B, 2014, 118, 5730.
48 E. L. M. Miguel, C. I. L. Santos, C. M. Silva and J. R. Pliego Jr, J. Brazil. Chem. Soc., 2016, DOI:
10.5935/0103-5053.20160095
.
49 C. Reichardt, Solvents and Solvent Effects in Organic Chemistry, Wiley-VHC, Weinheim,
Germany, 2011.
50 I. Rodriguez, G. Sastre, A. Corma and S. Iborra, J. Catal., 1999, 183, 14.
51 N. F. Carvalho and J. R. Pliego, Phys. Chem. Chem. Phys., 2015, 17, 26745.
52 C. F. Bernasconi, Tetrahedron, 1989, 45, 4017.
53 C. F. Bernasconi, M. W. Stronach and A. Kanavarioti, J. Org. Chem., 1994, 59, 3806.
54 A. J. Parker, Chem. Rev., 1969, 69, 1.
21

RSC Advances
Page 22 of 22
View Article Online
DOI: 10.1039/C6RA10393F
A reliable theoretical calculation of the free energy profile of a base-
catalyzed Knoevenagel reaction shows that hydroxide ion elimination step
is rate determining