Aldol Condensation Versus Superbase-Catalyzed Addition of Ketones to Acetylenes: A Quantum-Chemical and Experimental Study

Article abstract of DOI:10.1021/acs.joc.1c00388

The mechanism of aldol condensation of ketones in KOH/DMSO superbasic media has been investigated using the B2PLYP(D2)/6-311+G**//B3LYP/6-31+G? quantum-chemical approach. It is found that the interaction of three ketone molecules resulting in the formation of the cyclohex-2-enone structure [isophorone or 3,5-dicyclohexyl-5-methylspiro(5.5)undec-2-en-1-one] is thermodynamically more favorable than the interaction of two, three, or four molecules of ketone, resulting in the formation of linear products of the condensation. The formation of the condensation products with the isophorone skeleton can significantly hinder the cascade reactions of ketones with acetylenes [to afford 6,8-dioxabicyclo(3.2.1)octanes or acylcyclopentenols] promoted by superbases. In particular, the kinetically more preferable reactions of autovinylation of 2-methyl-3-butyn-2-ol and autocondensation of acetone are the reasons why interaction of acetone with acetylene does not lead to the products of the cascade assemblies. The predominant formation of the products of these side reactions is confirmed experimentally.

Full text of DOI:10.1021/acs.joc.1c00388

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Article
Aldol Condensation Versus Superbase-Catalyzed Addition of
Ketones to Acetylenes: A Quantum-Chemical and Experimental
Study
Vladimir B. Orel, Nadezhda M. Vitkovskaya,* Alexander S. Bobkov, Nadezhda V. Semenova,
Elena Yu. Schmidt, and Boris A. Trofimov
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ABSTRACT: The mechanism of aldol condensation of ketones in KOH/
DMSO superbasic media has been investigated using the B2PLYP(D2)/6-
311+G**//B3LYP/6-31+G* quantum-chemical approach. It is found that
the interaction of three ketone molecules resulting in the formation of the
cyclohex-2-enone structure [isophorone or 3,5-dicyclohexyl-5-
methylspiro(5.5)undec-2-en-1-one] is thermodynamically more favorable
than the interaction of two, three, or four molecules of ketone, resulting in
the formation of linear products of the condensation. The formation of the
condensation products with the isophorone skeleton can significantly hinder
the cascade reactions of ketones with acetylenes [to afford 6,8-
dioxabicyclo(3.2.1)octanes or acylcyclopentenols] promoted by superbases.
In particular, the kinetically more preferable reactions of autovinylation of 2-methyl-3-butyn-2-ol and autocondensation of acetone
are the reasons why interaction of acetone with acetylene does not lead to the products of the cascade assemblies. The predominant
formation of the products of these side reactions is confirmed experimentally.
Scheme 1. Mechanism of Aldol Condensation
(Autocondensation) of Acetone
INTRODUCTION
■
The aldol condensation in organic synthesis is one of the
fundamental reactions for the formation of a new carbon−
carbon bond.1−4 Catalyzed by both acids and bases, it involves
autocondensation or mixed condensation of aldehydes and
ketones yielding β-hydroxyaldehydes (β-aldols) or β-hydrox-
yketones (β-ketoles). Subsequent dehydration of β-aldols or β-
ketols delivers α,β-unsaturated aldehydes or α,β-unsaturated
ketones.3 In practice, aldol condensation is often catalyzed by
bases such as NaOH, KOH, Ca(OH)2, and Ba(OH)2.2,3 The
mechanism of the base-catalyzed aldol condensation includes
(i) the equilibrium formation of the enolate ion, (ii) the
addition of the enolate ion to the carbonyl group of the
aldehyde or ketone, and (iii) dehydration of the resulting aldol
or ketol (Scheme 1).2,3 Thus, it is the reaction of one carbonyl
compound, acting in an anionic form as a nucleophile, with
another carbonyl compound, acting in a neutral form as an
electrophile.
In media with high basicity, the proportion of enolate ions
increases, leading, accordingly, to enhancing the nucleophilic
properties of ketones. In particular, in a superbasic medium,
ketones are able to bond through the alpha carbon atom to the
triple CC bond of acetylenes (C-vinylation reaction).5
Superbasic media include systems with the Hammett acidity
function (H0) above 18.5, in which cations are most often
represented by cations of alkali metals (M = Li, Na, K, Rb, and
Cs) or tetraalkylammonium, while anions are hydroxide,
alkoxide, amide, hydrosulfide, alkylsulfidions, and carban-
ions.6−9 Typical Lewis bases such as sulfoxides, sulfones,
amines, amides, liquid ammonia, polyesters, phosphines, and
Received: February 19, 2021
Published: May 20, 2021
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phosphine oxides act as solvents in such media. The
extraordinary basicity of the systems containing these Lewis
bases and strong Brønsted bases (e.g., KOH or KOBut) is
associated with the synergism of Brønsted and Lewis bases
resulting from complexation between these two types of bases
by coordination of alkali metal cations with lone electron pairs
or other electron rich centers of the Lewis bases.7 It is assumed
that the specific solvation of the cation alone, which results in
the increased activity of the base anion, is the reason for
superbasicity.8 In addition, there is also a class of neutral
organic superbases based on guanidines, amidines, phospha-
zenes, and so forth, which is a subject of active development at
the time being. This class affords realization of many reactions,
including aldol condensation, under milder conditions and
with higher selectivity.10
Scheme 2. Examples of Cascade Reactions of Ketones with
Acetylenes in the Presence of KOH(OBut)/DMSO Leading
(from Top to Bottom) to 6,8-Dioxabicyclo[3.2.1]octanes
(Derivatives of Frontalin), Acylcyclopentenols, and
Acylterphenyls11
Interestingly, in non-deprotonated (neutral) ketone mole-
cules, superbases increase the electrophilic properties of the
carbonyl carbon atom, again due to complexation of the
superbase with the alkali metal cation. In particular, in
superbasic media, it is possible to significantly moderate the
reaction conditions for the addition of ethynide ions to the
carbonyl group of ketones (ethynylation reaction).8 It should
be noted that the presence of neutral ketone molecules under
superbasic conditions is associated with the reversible nature of
the deprotonation reaction (see Scheme 1, reaction i).
Thus, in superbasic media, the ambident properties of
ketones are enhanced and potentially favorable conditions are
created for aldol condensation as well as for the autoconden-
sation reaction of ketones.
Autocondensation processes can accompany other reactions
of ketones in superbasic media. In such a case, the
autocondensation reaction can be either a side (undesirable)
reaction or it can be one of the stages in the synthesis of the
target product. For example, decrease in the yields of
tetracyclic derivatives of frontalin,11 possessing high antimicro-
bial,12,13 antiviral,14,15 anticancer,16,17 and cardio stimulating
activity,18,19 in the reactions of cycloaliphatic ketones and
acetylenes is presumably associated with the autocondensation
reaction. On the contrary, the aldol reaction is considered one
of the key steps in the superbase-promoted cascade assembly
of terphenyls from acylarenes and arylacetylenes.11 Terphenyls
belong to a class of practically important compounds, being
widely used in materials science for the manufacture of laser
dyes, scintillators, heat-resistant polymeric materials,20 tribolu-
minescent sensors,21 and anion-exchange membranes;22 they
also exhibit neuroprotective, antithrombotic, cytotoxic,23,24 and
anti-HIV25,26 activities.
It is worth noting that both of the abovementioned reactions
relate to the recently discovered and rapidly developing
superbase-promoted reactions involving self-organization of
several equivalents of acetylenes and ketones to afford
synthetically and pharmaceutically valuable carbo- and hetero-
cycles (Scheme 2). In this case, acetylenes can also be
considered as synthetic equivalents of ketones, as described in
the work.27 Notably, these reactions are realized as pot-, atom-,
and step-economical processes (PASE paradigm).11
For a number of ketone/acetylene reaction pairs, non-
quantitative yields in these reactions may be due to the parallel
aldol condensation of the starting ketones. To further optimize
these new, synthetically important reactions, which are now
increasingly widely used for the synthesis of various
heterocyclic compounds,28−30 it is necessary to understand
the role of aldol condensation of ketones and propose possible
ways to suppress it.
Surprisingly, despite the prevalence of aldol condensation,
we did not find a reliable experimental and quantum-chemical
description of the base-catalyzed reaction in solution. The
enthalpy of the reaction for the formation of diacetone alcohol
from acetone is estimated on the basis of the tabulated
enthalpies of the formation of reagents and products, while in
more complex cases, some theoretical estimates are used.31,32
At the same time, the experimental study of the kinetics of the
autocondensation reaction is difficult even in the case of
acetone because the equilibrium of the first stage of this
reaction is shifted toward the reagents, and in order to study it,
it is necessary to monitor the temporal variation of low
concentrations of the resulting ketol.33
The goal of this work is to provide the reliable quantum-
chemical description of the aldol condensation mechanism,
accounting for the experimental results on the autocondensa-
tion reaction of acetone in the KOH/DMSO superbase
medium. This study has solved two main tasks. First, the
kinetic and thermodynamic features that are characteristic of
the aldol reaction in a superbasic medium are described and
the thermodynamic characteristics of the autocondensation of
a number of alkylaryl ketones, dialkyl ketones, and cyclo-
aliphatic ketones are estimated. Second, the effect of aldol
condensation on superbase-promoted cascade assemblies of
ketones with acetylenes is considered. While addressing these
issues, we were especially interested in answering the following
question: why the interaction of acetone with acetylene fails to
give 6,8-dioxabicyclo[3.2.1]octanes or acylcyclopentenols, for
example (Scheme 2), which are characteristic of the reactions
of other ketones with acetylene.11
RESULTS AND DISCUSSION
■
Autocondensation of Acetone. One of the necessary
conditions for the base-catalyzed aldol condensation of ketones
is generation of an enolate ion, which subsequently attacks the
carbonyl group of the neutral ketone molecule.3 We have
previously shown that enolate ions are easily formed as
[enolate]−K+·DMSO·H2O complexes upon interaction of
ketones with the KOH·DMSO superbase complex, which is
a thermodynamically favorable process.34 Within the adopted
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Figure 1. Reaction profile of autocondensation of two acetone molecules. The structures of the transition states are indicated. See Supporting
Information for the Cartesian coordinates of stationary points.
Table 1. Equilibrium Mixture Content (%) and Relative Free Energies ΔG (kcal/mol, in Parentheses) of the Starting Reagents
a
of Ketone and Its Enolate Ion (I) and Their Condensation Products, the Complex of Ketol (II) and Croton (III)
a
In the case of alicyclic ketones (see Table 1, entries 1 and 2), quite significant amounts of aldol condensation products (up to 70%) are observed
in the initial reaction system. These products can enter into further, deeper condensation processes.
B2PLYP-D/6-311+G**//B3LYP/6-31+G* approach, depro-
tonation of the acetone molecule 1, followed by the formation
of the enolate complex [CH2C(O)CH3]−K+·DMSO·H2O (2),
proceeds through an activation barrier ΔG⧧ = 8.0 kcal/mol and
is associated with a decrease in the free energy of the system by
ΔG = −2.8 kcal/mol.
Acetone molecule 1 forms with complex 2 a pre-reaction
complex 2′ (ΔG = 0.4 kcal/mol), where the interaction of
acetone with its enolate leads to the formation of the
potassium 2-methyl-3-oxobutane-2-olate complex [CH3C(O)-
CH2C(CH3)2O]−K+·DMSO·H2O (3) (Figure 1). The reac-
tion proceeds through a small activation barrier ΔG⧧ = 10.7
kcal/mol and is accompanied by a slight increase in the free
energy of the system (ΔG = 0.4 kcal/mol). Note that complex
3 can decompose as readily as it is formed because the reverse
activation barrier is ΔG⧧ = 10.3 kcal/mol (Figure 1).
Protonation of 2-methyl-3-oxobutane-2-olate by a water
molecule in complex 3, which completes the formation of ketol
[CH3C(O)CH2C(CH3)2OH]·KOH·DMSO (4), is thermody-
namically unfavorablethe free energy of the system further
increases by 0.7 kcal/mol (Figure 1).
The reversibility of the first stage of aldol condensation is in
fact a “characteristic problem” of the autocondensation
reaction of ketones in the presence of bases.2,35 To overcome
this difficulty, various methods to remove ketol from the
reaction mixture are used in chemical practice. For example,
the best yield (75%) of the autocondensation product of
acetone (diacetone alcohol) can be obtained by using a Soxhlet
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Scheme 3. Addition of One and Two Acetone Molecules to Mesityl Oxide Leading to (a) Isophorone, (b) 4,4,8-Trimethylnon-
7-ene-2,6-dione, and (c) Phorone
extractor to separate the catalyst (Ba(OH)2) and the resulting
ketol.3 It is also pointed out that additional stabilization of
ketolates and the shift of the equilibrium toward adducts can
be achieved by using bases with more strongly coordinating
cations, for example, boron or zinc cations.35 We hypothesized
that an alkali metal cation with a small radius can increase the
stability of the complex. Indeed, our calculations indicate that
replacement of the superbase complex KOH·DMSO by
NaOH·DMSO leads to a complex of sodium 2-methyl-3-
oxobutane-2-olate [CH3C(O)CH2C(CH3)2O]−Na+·DMSO
that is stable, ΔG = −1.8 kcal/mol relative to the acetone
molecule and the enolate complex [CH2C(O)CH3]−Na+·
DMSO·H2O.
Under the action of a base, further dehydration of ketol in
complex 4 is possible, which leads to the mesityl oxide complex
[CH3C(O)CHC(CH3)2]·KOH·DMSO·H2O (6′). This re-
action proceeds through successive stages of deprotonation of
the methylene group and elimination of the hydroxide anion.
The resulting activation barrier for 6′ is ΔG⧧ = 15.9 kcal/mol,
while the free energy of the system increases by ΔG = 2.9 kcal/
mol relative to complex 3 (Figure 1). Note that the
dissociation of 6′ resulting in the formation of mesityl oxide
6 and the base complex with a water molecule (KOH·DMSO·
H2O) is associated with a slight decrease in the free energy of
the system ΔG = −2.4 kcal/mol. This value is, however, still
0.6 kcal/mol higher than the free energy of the potassium
ketolate complex 3.
The stage of water elimination is characterized by a barrier,
that is, by ΔΔG⧧ = 4.8 kcal/mol higher than the barrier for the
stage of ketol formation. At the same time, the water
elimination stage is readily reversible, with the reverse
activation barrier being ΔG⧧ = 14.9 kcal/mol (Figure 1).
The obtained values of the relative free energies of the
starting reagents, 1 + 2 (ΔG = 0.0 kcal/mol), and their
condensation products, 3 (ΔG = 0.4 kcal/mol) and 6 (ΔG =
1.0 kcal/mol), show that at the equilibrium at room
temperature, the reaction mixture contains 59% of the starting
acetone 1 and its enolate ion 2, 30% of the complex of the
anion of ketol 3, and 11% of mesityl oxide 6. Similarly, we
estimated the composition of the mixtures formed under the
action of a superbase from aliphatic, cycloaliphatic, and
alkylaryl ketones, which are differently (readily or hardly)
involved in the cascade assemblies with acetylenes (Table 1).
In most cases, it was found that the formation of the
condensation products is either only slightly thermodynami-
cally favorable or completely unfavorable relative to the
starting ketones and their enolate ions. In particular, the
condensation is unfavorable in the case of alkylaryl ketones
(see Table 1, entry 5). Indeed, the yields of the products of the
cascade reactions for these ketones with acetylene [6,8-
dioxabicyclo(3.2.1)octanes, acylcyclopentenols and furans] in
superbasic media are invariably high (60−98%).11
The thermodynamic stability of the condensation products
of cycloaliphatic ketones is significantly different (see Table 1,
entries 3, and 4). The formation of a croton as a result of the
condensation of cyclopentanone in a superbasic medium leads
to a significant decrease in the free energy of the system, ΔG =
−5.1 kcal/mol, relative to the initial ketone and its enolate ion,
while for cyclohexanone, on the contrary, there is a slight
increase in the free energy, ΔG = 0.2 kcal/mol. The obtained
ratios of the free energy values explain the lower yields of
tetracyclic derivatives of frontalin obtained from cyclo-
pentanone and acetylene (34%) as compared to the yields of
the corresponding derivative of frontalin obtained from
cyclohexanone (51%).11
Addition of More Acetone Molecules. We investigated
further the addition of one and two acetone molecules to
mesityl oxide to obtain isophorone, 4,4,8-trimethylnon-7-ene-
2,6-dione, and phorone (Scheme 3).
At the first stage of isophorone assembly, mesityl oxide 7
forms with an enolate ion 2 a pre-reaction complex 6″ (ΔG =
0.3 kcal/mol), where the enolate ion is added to the Cβ-atom
of the double bond of mesityl oxide (Michael reaction). This
transformation is associated with an activation barrier ΔG⧧ =
13.1 kcal/mol (Figure 2), which does not exceed any of the
previously discussed activation energies. The reaction leads to
the formation of the 1,5-diketone carbanion complex [CH3C-
(O)CH2C(CH3)2CHC(O)CH3]−K+·DMSO·H2O (7) and is
associated with a decrease in the free energy by 6.3 kcal/mol.
Next, the intramolecular transfer of a proton of the terminal
methyl group to the carbanion center in 7 takes place through
a barrier ΔG⧧ = 17.5 kcal/mol, leading to the formation of the
[CH3C(O)CH2C(CH3)2CH2C(O)CH2]−K+·DMSO·H2O
complex (8) (Figure 2). This isomerization results in the
thermodynamically more stable 1,5-diketone carbanion cen-
tered on the terminal atom. The decrease in the free energy of
the system during the formation of 8 is ΔG = −8.4 kcal/mol
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isophorone 12a proceeds with a significant decrease in the
energy of the system (ΔG = −10.7 and −19.5 kcal/mol,
respectively). In addition, this transformation is associated with
small activation barriers to cyclization (intramolecular addition
at the carbonyl group) ΔG⧧ = 5.4 kcal/mol and dehydration
ΔG⧧ = 12.6 kcal/mol.
The total decrease in the free energy of the system upon the
formation of isophorone 12a from three acetone molecules 1,
under the action of two complexes of the KOH·DMSO base, is
ΔG = −22.3 kcal/mol.
An alternative direction for the interaction of mesityl oxide
with acetone is the formation of phorone initiated by the
addition of the carbanion of mesityl oxide to the carbonyl
group of acetone (Scheme 3c). The deprotonation of the α-
CH3 group of mesityl oxide 6 under the action of the KOH·
DMSO complex leads to the formation of the mesityl oxide
anion in the complex [(CH3)2CCHC(O)CH2]−K+·DMSO·
H2O (6c). The process is associated with an activation barrier
ΔG⧧ = 8.8 kcal/mol and leads to a decrease of the free energy
of the system by 2.4 kcal/mol. Further, the acetone molecule 1
forms with complex 6c a pre-reaction complex 6c′ (ΔG = 0.2
kcal/mol). In complex 6c′, the addition of the mesityl oxide
anion to the carbonyl group of the acetone molecule, leading
to the ketolate complex [(CH3)2CCHC(O)CH2C-
(CH3)2O]−K+·DMSO·H2O (9c), and subsequent dehydration,
resulting in the formation of phorone 12c, proceed through
activation barriers ΔG⧧ = 10.6 kcal/mol and ΔG⧧ = 16.6 kcal/
mol, respectively, which are close to similar barriers for
condensation of two acetone molecules (Figure 4). In this case,
the formation of linear condensation products of three acetone
molecules (9c−12c), as in the cases of condensation of two
and four molecules, is thermodynamically unfavorable (Figure
4).
Figure 2. Reaction profile of the formation of 1,5-diketone carbanion
8. The structures of the transition states are indicated. See Supporting
Information for the Cartesian coordinates of the stationary points.
relative to the initial mesityl oxide 6 and acetone carbanion 2
(Figure 2).
Further, in 1,5-diketone carbanion 8, intramolecular
addition at the neighboring carbonyl group can occur, leading
to cyclization of isophorone (Scheme 3a). On the other hand,
carbanion 8 can undergo addition to the carbonyl group of the
next acetone molecule, condensing into a linear product with a
longer carbon chain (Scheme 3b). Figure 3 depicts cross
sections of these two reaction pathways.
The estimates obtained show that the formation of the linear
products 9b−12b is thermodynamically unfavorable, while the
formation of the complex of cyclic ketol 10a and the final
Figure 3. Reaction profiles of the formation of isophorone 12a (blue line) and linear products 8-hydroxy-4,4,8-trimethylnonane-2,6-dione 10b and
4,4,8-trimethylnon-7-ene-2,6-dione 12b (light blue line). The structures of the transition states are indicated. See Supporting Information for the
Cartesian coordinates of the stationary points.
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Figure 4. Reaction profile of the formation of phorone. The structures of the transition states are indicated. See Supporting Information for the
Cartesian coordinates of the stationary points.
Scheme 4. KOH/DMSO-Promoted Reactions of Methyl-3-butyn-2-ol (the Product of Ethynylation of Acetone with Acetylene)
and Acetone with Acetylene
Summarizing, from both thermodynamic and kinetic points
of views, the formation of cyclic condensation products (10a−
12a) is preferred, and the most favorable of them is the
formation of isophorone 12a. Note that the formation of such
a cyclohex-2-enone structure as in isophorone is often
thermodynamically favorable, but it is possible only for
alicyclic ketones that can form CHR (R = H, Alk, (Het) Ar)
carbanions of 1,5-diketone of type 8. For example, a significant
decrease in the free energy ΔG = −15.6 kcal/mol takes place in
the case of a similar condensation of three cyclohexylmethyl
ketone molecules into 3,5-dicyclohexyl-5-methylspiro[5.5]-
undec-2-en-1-one. This circumstance may explain the decrease
in the yields of 6,8-dioxabicyclo[3.2.1]octanes when going
from adamantyl methyl ketone (54%), which cannot form
isophoronic structures, to cyclohexyl methyl ketone (25%).11
Interaction of Acetone with Acetylene. Acetone, in
turn, cannot be altogether involved in the cascade reactions to
form 6,8-dioxabicyclo[3.2.1]octanes or acylcyclopentenols.11
For example, the synthesis of 7-methylene-6,8-
dioxabicyclo[3.2.1]octanes in the KOH/DMSO system at 80
°C,36 initiated by the decomposition of tertiary propargyl
alcohols to the corresponding ketones and acetylene (reverse
ethynylation reaction), leads, in the case of 2-methyl-3-butyn-
2-ol (the product of acetone ethynylation with acetylene), to
the formation of only the products of O-vinylation A and
autovinylation B of the starting alcohol (within 10−15 min,
Scheme 4a). Upon increasing the reaction time to 1 h, 2,5-
dimethyl-5-(vinyloxy)hex-3-yn-2-ol C (the product of vinyl-
ation of Favorsky diol) and 2,2,4,4-tetramethyl-5-methylidene-
1,3-dioxolane D are also obtained (Scheme 4b).37
According to the method of gas chromato-mass spectrom-
etry, the direct reaction of acetone with acetylene in the KOH/
DMSO system at 80 °C (Scheme 4b), performed in this work,
leads, along with the formation of products B−D, also to the
formation of 1,3,5-trimethyl-7-methylene-6,8-
dioxabicyclo[3.2.1]octane E (19% B + C + D + E total
content) and different products of the acetone aldol
condensation. The latter include 6-hydroxy-4,4,6-trimethy-
loct-7-yn-2-one F (the product of the ethynylation of 1,5-
diketone 7, 11%), phorone G (12c), isophorone H (12a)
(17% G + H total content), and in addition the products of
further interactions with the participation of isophorone [such
as 3,3,6,8-tetramethyl-3,4-dihydronaphthalen-1(2H)-one (5%),
5,5-dimethyl-3-(2-methylpenta-1,4-dien-1-yl)cyclohex-2-en-1-
one (10%), and 3-(2,4-dimethylpenta-1,3-dien-1-yl)-5,5-dime-
thylcyclohex-2-en-1-one (38%)]. Thus, under the interaction
of acetone with acetylene, the reactions of aldol condensation
and ethynylation, as well as further transformations with the
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Figure 5. Reaction profiles and reaction schemes of competing directions of the interaction of acetone with acetylene in KOH/DMSO superbase;
the forward (black color) and reverse (gray color) activation barriers (ΔG⧧, kcal/mol) are indicated. All the values of ΔG along the reaction profile
are given in kcal/mol relative to a sum of acetone 1, acetylene 13, and KOH·DMSO complex. See Supporting Information for the Cartesian
coordinates of the stationary points.
Figure 6. Theoretical kinetic curves of the products accumulation of the interaction of acetone with acetylene in KOH/DMSO superbase (80 °C, 1
h) at initial concentrations (a) from work37 (CKOH (const.) = 0.037 mol/L, C13 = 0.4 mol/L, C16 = 0.4 mol/L, CHOH = 0.1 mol/L) and (b) at this
work (CKOH (const.) = 0.037 mol/L, C1 = 2.0 mol/L, C13 = 0.5 mol/L, CHOH = 0.1 mol/L). See Supporting Information for the rate constants
values.
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participation of the products of these reactions predominate.
However, to initiate cascade assemblies leading to the
formation of 6,8-dioxabicyclo[3.2.1]octanes and acylcyclopen-
tenols, it is required that at the first stage, acetone interacts
with acetylene in the direction of nucleophilic addition to the
triple CC bond of acetylene (C-vinylation reaction).11,38
To understand the reasons of this atypical behavior of
acetone in the superbase-promoted reactions with acetylene, it
is reasonable to compare the kinetic characteristics of all three
competing reactions that can occur in the acetone/
unsubstituted acetylene system. These are (i) the acetone C-
vinylation reactions, (ii) the reaction of acetone aldol
condensation into isophorone, and finally (iii) the ethynylation
reactions followed by alcohol autovinylation. Note that the
mechanisms of the reactions of ethynylation and C-vinylation
of acetone with unsubstituted acetylene were studied in detail
in our earlier works,34,38 and in the present work, they were
only recalculated within the adopted B2PLYP(D2)/6-
311+G**//B3LYP/6-31+G* approach. Additionally, in this
work, the forward and reverse activation barriers for
autovinylation of methyl-3-butyn-2-ol were calculated. The
resulting reaction profile representing the energetic character-
istics of the compared competing reactions is shown in Figure
5.
It is clearly seen that at the initial stage of transformations,
the action of the KOH·DMSO complex on both the acetone
molecule and the acetylene molecule leads to the formation of
the corresponding stable complexes of anions 2 and 14 (Figure
5). The formation of these starting nucleophiles (enolate ion
and ethynide ion) is a necessary step for carrying out C-
vinylation and ethynylation reactions. Moreover, the differ-
ences in the decrease of the free energy of the system upon the
formation of complexes 2 and 14 are in qualitative agreement
with the pKa values (of the acids conjugated with these
anions) in the DMSO solution, which decrease in the series
31.4 (H2O) > 29.9 (HCCH 13) > 26.5 (acetone 1). Note that
the formation of these anions in an aqueous solution is
thermodynamically extremely unfavorable; in this case, water is
a much stronger acid than acetone and acetylene [pKa
decreases in the series 26.0 (HCCH 13) > 20.0 (acetone 1) >
15.7 (H2O)]. Indeed, the reactions of ethynylation and C-
vinylation of ketones with acetylenes do not occur in aqueous
media.
unfavorable (ΔG = 7.5 kcal/mol and 9.6 kcal/mol,
respectively) and does not increase the amount of alcohol
16. Thus, only a small part of alcoholate 15 is spent for the
interaction with alcohol 16 to form the product of
autovinylation 17. According to the obtained theoretical
estimates, a significant part of alcoholate 15 decomposes
with the formation of the starting acetone and acetylene and
ultimately transforms into the products of aldol condensation
of acetone.
The theoretically obtained ratios of the condensation
products 12a (H), ethynylation 15 (anionic complex of A),
autovinylation 17 (anionic complex of B), and C-vinylation 18
(precursor of E) reactions in this case are 0.62 mol/L (88.6%),
0.03 mol/L (4.3%), 0.04 mol/L (5.7%), and 0.01 mol/L
(1.4%), respectively. These results are in qualitative agreement
with the experimental data from Scheme 4b (81% F + G + H +
isophorone conversion products and 19% B + C + D + E).
The presented theoretical results explain and supplement the
experimental data. Based on different experimental approaches
to the reaction and theoretical kinetic models of interactions in
the acetone/unsubstituted acetylene system, it was found that
autovinylation and aldol condensation reactions impede the
selective realization of the C-vinylation reaction of acetone
with acetylene and of the cascade assemblies triggered by this
reaction.
CONCLUSIONS
■
The mechanism of condensation involving two, three, and four
acetone molecules, as well as the thermodynamic stability of
condensation products of a number of aliphatic, cycloaliphatic,
and alkylaryl ketones, have been investigated and described in
some detail employing methods of quantum chemistry.
It is shown that the condensation of two acetone molecules
proceeds through small activation barriers, not exceeding 15.5
kcal/mol. In this case, the products of addition and elimination
of water turn out to be thermodynamically unstable relative to
the initial ketone and its enolate ion. Similar results are found
for other dialkyl and alkylaryl ketones. A significant decrease in
the free energy (ΔG = −5.1 kcal/mol) is observed only upon
condensation of two cyclopentanone molecules, resulting in
the formation of a croton, which in this case explains the
decreased yields of bicyclooctanes.
It has been demonstrated that the interaction of three
ketone molecules resulting in the formation of the cyclohex-2-
enone structure leads to thermodynamically stable autocon-
densation products. This is typical, for example, for
isophorone, a condensation product of acetone, and for 3,5-
dicyclohexyl-5-methylspiro[5.5]undec-2-en-1-one, a condensa-
tion product of cyclohexylmethyl ketone. In these cases, aldol
condensation in the reactions promoted by superbases can
have a significant effect on the ability of ketones to form 6,8-
dioxabicyclo[3.2.1]octanes or acylcyclopentenols when react-
ing with acetylenes.
The free energies of the activation of the competing
reactions (Figure 5) and kinetic curves of the product
accumulation modeled with the KINET39 program (Figure
6) indicate that the reaction of C-vinylation of acetone in the
KOH/DMSO superbase is impeded by the autovinylation
reaction of 2-methyl-3-butyn-2-ol and by the reaction of aldol
condensation of acetone into isophorone.
In the case when propargyl alcohol 16 acts as the initial
reagent, the formation of solely the alcohol autovinylation
product 17 (anionic complex of B) is predicted (Figure 6a),
which is indeed observed in the experimental data.37
Using quantum-chemical calculations, we have identified
factors that impede the C-vinylation of acetone by acetylene
and evaluated the degree of their influence on the C-vinylation
reaction. These are (i) the kinetic preference of the
ethynylation reaction, followed by thermodynamically favor-
able autovinylation of the resulting alcohol, and (ii) the
possibility of carrying out the aldol condensation of acetone,
which is the next kinetically preferable reaction after the
ethynylation.
A different composition of the products is predicted by the
modeled kinetic curves shown in Figure 6b when acetone is
directly introduced into the interaction with acetylene in a
significantly larger amount (C1 = 2.0 mol/L). Initially, all of
the acetylene is spent for the formation of alcoholate 15 and a
small amount of alcohol 16. Alcohol 16 is formed from 15
solely by protonation with water (CHOH = 0.1 mol/L in a
DMSO solution). The protonation of alcoholate 16 with an
excess of acetone and acetylene is thermodynamically
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orienting the methyl groups to the boundaries of the cavity where the
solvated complex is placed within the framework of the PCM model
used. The water molecule in this complex is coordinated by one of the
hydrogen atoms to the oxygen of the DMSO molecule, and the
second hydrogen atom is coordinated to the atom, which is bound to
EXPERIMENTAL SECTION
■
Computational Details. Estimation of the enthalpy of the aldol
reaction is associated with certain difficulties when using many
popular density functionals.31 In particular, for the aldol reaction of
two acetone molecules, the enthalpy change calculated on the basis of
the heats of formation is ΔH = −10.5 0.2 kcal/mol; the CBS-QB3
method predicts an exothermicity of the reaction ΔH = −9.2 kcal/
mol. At the same time, the B3LYP/6-31+G (d, p) approach estimates
this reaction as endothermic with ΔH = +1.0 kcal/mol. Extension of
the basis set to the triple-zeta further deteriorates the estimatefor
B3LYP/6-311+G (2df, 2p), ΔH increases to +2.4 kcal/mol. The same
trend is typical for such functionals as B3PW91, B1B95,
MPW1PW91, PBE1PBE, and only M06-2X gives a sufficiently
adequate value. The latter is most likely due to the fact that this
reaction was included in the training set when parametrizing this
functional.31
the potassium cation in Nu·K+ (see e.g.,, the transition states TS2′→3
,
TS6″→7, and TS7→8 in Figures 1 and 2). Thus, when searching for
minima and transition states on the PES, we considered the
conformations that concerned only the Nu·K+ fragment. The number
of localized conformations at the stationary points on the PES usually
did not exceed three. The search for transition states, characterized by
a variety of possible mutual orientations of the reagents (trans-
formations 2′ → 3, 6″ → 7, 8′ → 9b, and 6c′ → 9c), was carried out
in a special way. In the cases 2′ → 3, 8′ → 9b, and 6c′ → 9c, scanning
of the dihedral angle involving the CO bond of the acetone
molecule 1 and the CC double bond of the anions 2, 8, and 6c was
carried out, while for the search along the path 6″ → 7, the dihedral
angle involving the CC double bonds of croton 6 and enolate ion 2
was scanned. In all the cases, the interatomic distances between the
bonded atoms were additionally frozen at 2.05 Å, which corresponds
to a somewhat larger distance that is characteristic of the transition
state geometry. The minima obtained for a particular PES cross
section were selected for the optimization of the transition states
followed by energy refinement using the adopted B2PLYP//B3LYP
approach.
The B2PLYP functional,40 which provides “chemical” accuracy in
various tests,41−43 was not among the functionals studied in ref 31. In
our recent studies, the B2PLYP/6-311+G**//B3LYP/6-31+G*
approach has been successfully used to describe various reactions of
ketones with acetylenes carried out in superbasic media, including the
steps of vinylation and ethynylation, isomerization of the multiple
bond position, reactions of nucleophilic addition to a double bond, in
which unsaturated ketones act as the Michael acceptors, and so
forth.38 For the aldol reaction of acetone in the gas phase, this
approach with the inclusion of the D2 Grimme dispersion
correction44 gives the estimate ΔH = −8.2 kcal/mol, which is in
good agreement with the data of the reference calculation CBS-QB3
(ΔH = −9.2 kcal/mol). For this reason, the B2PLYP(D2)/6-
311+G**//B3LYP/6-31+G* approach was chosen to describe the
energy profiles of the aldol−croton condensation.
Optimization of the structural parameters of the molecular species
involved in the reaction was carried out, accounting for solvent effects
at the level of the polarization continuum model IEFPCM45 using
density functional theory at the B3LYP46,47 level of theory with the 6-
31+G* basis set. The vibrational corrections to enthalpies and Gibbs
free energies were calculated at the same level of theory (B3LYP/6-
31+G*) for a standard temperature 298.15 K.
For all stationary points, the number of negative eigenvalues of the
Hessian matrix was analyzed; the connection of the transition states
with the corresponding potential energy surface (PES) minima was
proved by the reaction coordinate following, using the local quadratic
approximation algorithm.48
The energies of the stationary points were further refined using the
double-hybrid functional B2PLYP with Grimme’s dispersion
correction D249 in combination with the 6-311+G** basis set. In
addition, the solvation energies in DMSO were calculated within the
framework of the polarizable continuum model IEFPCM,45 using the
B3LYP/6-31+G* approach. Modeling of the cavity was performed
within the approach GEPOL50 using the universal force field radii and
universal scaling factor for the solvent α = 1.1.51 For the calculation of
the solvation energy, the dimethyl sulfoxide dielectric constant ε =
46.8 was used.
All the kinetic curves were modeled at T = 353 K to the Arrhenius
equation k(T) = kBT/h × exp(−ΔG⧧/RT), using the KINET
program.39 All quantum chemistry calculations were performed with
Gaussian 09.54
Reaction of Acetone with Acetylene in the KOH/DMSO
System. A mixture of acetone (5.81 g, 0.1 mol) and KOH·0.5H2O
(6.50 g, 0.1 mol) in DMSO (50 mL) was placed into a 0.25 dm3 steel
rotating autoclave. The autoclave was fed with acetylene up to 14 atm
and then decompressed to atmospheric pressure to remove air. The
autoclave was fed with acetylene again (initial pressure at ambient
temperature was 14 atm) and heated to 80 °C for 1 h. The pressure
reached its maximum (18−20 atm) as the temperature was raised to
80 °C and then dropped upon acetylene consumption in the course of
the reaction. The final pressure at ambient temperature was 2 atm.
The reaction mixture, after cooling to room temperature, was diluted
with cold (5−10 °C) water (100 mL) and extracted with Et2O (5 ×
25 mL). The combined organic extracts were washed with H2O (3 ×
20 mL) and dried over K2CO3. Et2O was evaporated, and the crude
product (4.96 g, viscous, light brown oil) was analyzed by GC MS
(Shimadzu GCMSQP5050A spectrometer).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00388.
Description of Wertz52 entropy correction for dimethyl
sulfoxide, complete ref 54, details of modeling the
kinetic curves of the interaction of acetone with
acetylene in KOH/DMSO superbase, calculated imag-
inary frequencies of transition-state species, and tables of
the Cartesian coordinates and electronic energies of all
the stationary points (PDF)
To estimate the activation free energy in solution, we used an
approach that is based on results proposed by Wertz52 in ref 53. When
applied to dimethyl sulfoxide, this approach suggests that the entropy
in the DMSO solution Ssol can be obtained from the entropy for ideal
gas in the harmonic approximation (Sharm) as follows
Ssol = 0.74Sharm − 3.21 cal·mol−1·K−1
(1)
(See Supporting Information for details).
AUTHOR INFORMATION
The superbasicity was taken into account at the level of the
monosolvate model, with the KOH·DMSO complex being explicitly
included in the calculation (MONOPCM model).38 It should be noted
that in ref 38 we determined the most preferable mutual orientation of
the molecules in the monosolvate complexes of the type Nu·K+·
DMSO·H2O (where Nu stands for nucleophile), as well as in the
transition states connecting these complexes. The DMSO molecule is
coordinated by the oxygen atom to the potassium cation of Nu·K+,
■
Corresponding Author
Nadezhda M. Vitkovskaya − Laboratory of Quantum-
Chemical Modeling of Molecular Systems, Irkutsk State
University, 664003 Irkutsk, Russian Federation;
orcid.org/0000-0002-3001-082X; Phone: +7-3952-521-
211; Email: vita@cc.isu.ru
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pubs.acs.org/joc
Article
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Authors
Vladimir B. Orel − Laboratory of Quantum-Chemical
Modeling of Molecular Systems, Irkutsk State University,
664003 Irkutsk, Russian Federation; A.E. Favorsky Irkutsk
Institute of Chemistry, Siberian Branch of the Russian
Academy of Sciences, 664033 Irkutsk, Russian Federation;
orcid.org/0000-0003-2834-6700
Alexander S. Bobkov − Laboratory of Quantum-Chemical
Modeling of Molecular Systems, Irkutsk State University,
664003 Irkutsk, Russian Federation; orcid.org/0000-
0001-8901-3577
Nadezhda V. Semenova − A.E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch of the Russian Academy of
Sciences, 664033 Irkutsk, Russian Federation
Elena Yu. Schmidt − A.E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch of the Russian Academy of
Sciences, 664033 Irkutsk, Russian Federation
Boris A. Trofimov − A.E. Favorsky Irkutsk Institute of
Chemistry, Siberian Branch of the Russian Academy of
Sciences, 664033 Irkutsk, Russian Federation; orcid.org/
0000-0002-0430-3215
(16) Corsano, S.; Mellor, J. M.; Ourisson, G. The Structure of
Cimigenol. Chem. Commun. 1965, 10, 185−186.
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and Phytotoxic Metabolite from Cladobotryum rubrobrunnescens. J.
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00388
Notes
(19) Chou, T.; Osamu, K.; Uemura, D. Relative Stereochemistry of
Pinnatoxin A, a Potent Shellfish Poison from Pinna Muricata.
Tetrahedron Lett. 1996, 37, 4023−4026.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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■
V.B.O., N.M.V., and A.S.B. gratefully acknowledge grant no.
FZZE−2020−0025 from the Ministry of Science and Higher
Education of the Russian Federation. E.Y.S. and B.A.T. thank
the Baikal Analytical Centre of collective use for the
equipment. The authors are grateful to Dr., Prof. Vladimir B.
Kobychev for useful discussions and recommendations as well
as to Dr. Evgeniy V. Gromov for proofreading the manuscript.
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