Catalyst- and acid-free Markovnikov hydration of alkynes in a sustainable H2O/ethyl lactate system

Article abstract of DOI:10.1016/j.molliq.2021.115758

An efficient and sustainable protocol for the hydration of alkynes has been developed under metal/acid/catalyst/ligand-free conditions in a water/ethyl lactate mixture. The hydrogen-bond network in the ethyl lactate and water mixture plays a crucial and decisive role in activating the alkynes for hydration to afford the corresponding methyl ketones. This strategy gives the Markovnikov (ketone) addition product selectively over other possible products. The essential role of hydrogen bonding has been confirmed by experimental and theoretical techniques. A probable mechanism has been suggested by various control tests. The efficacy of the method has been further explored for the competent production of value-added α,β-unsaturated carbonyl compounds through the reaction of aldehydes with alkynes as ketonic surrogates. The environmentally benign hydration method takes place under mild conditions, has broad functional-group compatibility, and uses the ethyl lactate/water (1:3) medium as a “green alternative” in the absence of any hazardous, harmful, or expensive substances.

Full text of DOI:10.1016/j.molliq.2021.115758

Journal of Molecular Liquids 331 (2021) 115758
Contents lists available at ScienceDirect
Journal of Molecular Liquids
journal homepage: www.elsevier.com/locate/molliq
Catalyst- and acid-free Markovnikov hydration of alkynes in a sustainable
H2O/ethyl lactate system
a
b
b
a,
Anshu Dandia a, , Pratibha Saini , M.J. Chithra , Sivaranjana Reddy Vennapusa , Vijay Parewa
⁎
⁎
a
Centre of Advanced Studies, Department of Chemistry, University of Rajasthan, Jaipur, India
Indian Institute of Science Education and Research Thiruvananthapuram, Maruthamala PO, Vithura, Thiruvananthapuram 695551, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and sustainable protocol for the hydration of alkynes has been developed under metal/acid/catalyst/
ligand-free conditions in a water/ethyl lactate mixture. The hydrogen-bond network in the ethyl lactate and
water mixture plays a crucial and decisive role in activating the alkynes for hydration to afford the corresponding
methyl ketones. This strategy gives the Markovnikov (ketone) addition product selectively over other possible
products. The essential role of hydrogen bonding has been confirmed by experimental and theoretical tech-
niques. A probable mechanism has been suggested by various control tests. The efficacy of the method has
been further explored for the competent production of value-added α,β-unsaturated carbonyl compounds
through the reaction of aldehydes with alkynes as ketonic surrogates. The environmentally benign hydration
method takes place under mild conditions, has broad functional-group compatibility, and uses the ethyl lac-
tate/water (1:3) medium as a “green alternative” in the absence of any hazardous, harmful, or expensive
substances.
Received 25 November 2020
Received in revised form 16 February 2021
Accepted 22 February 2021
Available online 2 March 2021
Keywords:
Ethyl lactate and water mixture
Alkynes
Catalyst free
α,β-Unsaturated compounds
Hydration
© 2021 Elsevier B.V. All rights reserved.
1. Introduction
Cautious scrutiny of the documented methodologies illustrates that
all existing processes for the hydration of alkynes have restricted effi-
The development of atom-economic and selective organic transfor-
mations is one of the most demanding tasks for chemists in modern sce-
narios [1]. The selective addition of H2O to unsaturated bonds provides a
platform for the construction of most prevalent feedstocks [2]. In partic-
ular, the straight conversion of alkynes into carbonyl compounds by hy-
dration demonstrates high atom economy and synthetic aptitude [3].
The vital and crucial event in alkyne hydration is the effective activation
of the alkyne and subsequent quick addition of a water molecule.
Hydration of alkynes is traditionally catalyzed by HgO–BF3 (the
Hennion–Nieuwland reaction) or HgO–H2SO4 (the Kucherov reaction)
in a strongly acidic environment [4]. Although these procedures give
good yields, pollution issues related to taking care of and disposing of
toxic Hg salts have restricted their use for broad applications in large-
scale industrial syntheses of value-added carbonyl compounds. To over-
come the disadvantages of the strongly acidic conditions and the use of
poisonous Hg salts, a variety of transition-metal catalysts containing Rh,
Pd, Ru, Cu, Pt, Ir, Fe, Ag, Sn\\W, Co, Ga, Au, and Os, as well as other metal
centers, have been widely studied for the hydration of alkynes to form
carbonyl compounds [5–8].
ciency because of the use of transition-metal complexes, which are
toxic and expensive catalysts, and the additional steps for the synthesis
of catalyst requiring hazardous and undesirable additives. In addition,
strongly acidic conditions have been used to promote the hydration re-
action [9]. Although some less hazardous acids have been used to im-
prove the reaction conditions, they still lack adaptability. In all cases, a
catalyst or acid was needed for further activation of the alkynes for hy-
dration. Moreover, it is extremely hard to perform hydration of alkynes
in an acid- or catalyst-free environment because of the poor nucleophi-
licity of water molecules and requirement for appropriate activation
procedures. To our knowledge, only two reports are available describing
the use of water in supercritical conditions and water with a toxic vola-
tile organic solvent for catalyst-free hydration of alkynes [10]. These
methods required specific experimental tools with tedious conditions
to maintain a high temperature and pressure for the reaction under mi-
crowave irradiation or an inert atmosphere. Therefore, there is rising
demand for the development of an acid- or catalyst-free greener proto-
col for the hydration of alkynes.
Ethyl lactate (EL) is a biomass-derived platform solvent, which is
nontoxic, potentially cheap, and entirely biodegradable [11]. As a result
of the excellent compatibility of EL with water, EL and water mixtures
have been significantly used in organic synthesis. Recently, we sug-
gested a crucial and unprecedented role of hydrogen bonding and hy-
drophobicity in aqueous-mediated synthesis [12].
⁎
Corresponding authors.
E-mail addresses: dranshudandia@yahoo.co.in (A. Dandia),
parewavijay.parewa@gmail.com, parewavijay@uniraj.ac.in (V. Parewa).
https://doi.org/10.1016/j.molliq.2021.115758
0167-7322/© 2021 Elsevier B.V. All rights reserved.

A. Dandia, P. Saini, M.J. Chithra et al.
Journal of Molecular Liquids 331 (2021) 115758
Scheme 1. Strategies toward alkyne hydration methods.
Inspired by this work and our earlier studies [13], we demonstrate
that hydration of alkynes can be performed very efficiently in the pres-
ence of water by tuning its properties with EL under metal/acid/
catalyst/ligand-free conditions. We anticipate that the hydrogen-bond
network in the EL and water mixture plays a crucial and decisive role
in activating the substrate for hydration of the alkyne. Product forma-
tion in the hydration of alkynes is strongly dependent on the reaction
parameters, which raises the issue of regioselectivity. Both types of
product, that is, the Markovnikov (ketones) and anti-Markovnikov (al-
dehydes) products, have been reported under various conditions [14].
Our method is highly regioselective and forms Markovnikov-type prod-
ucts. Furthermore, the efficacy of the protocol has also been ensured
for the competent production of α,β-unsaturated carbonyl compounds
by the reaction of aldehydes with alkynes as ketonic surrogates
(Scheme 1).
When EL is added to an aqueous reaction mixture, the intramolecu-
lar hydrogen bonding vies with the intermolecular hydrogen bonding of
the water molecules and forms a complex hydrogen-bonding network
that provides specific assistance to the mixture. EL molecules have
four key sites through which they can connect with H2O molecules
(Scheme 2): (a) the hydroxy oxygen atom (complex 1), (b) the hydroxy
hydrogen and keto oxygen atoms (complex 2), (c) the keto oxygen
atom (complex 3), and (d) the alkoxy oxygen atom. As a result of the
steric hindrance of the alkoxy group in EL, the latter is a less favorable
site for hydrogen bonding, which led us to exclude the probability of
the development of complex 4.
Table 1
Screening of the hydration of phenyl acetylene to form 2i under various conditionsa.
Entry
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
H2O
EL
72
72
72
72
72
72
24
24
72
72
72
72
72
72
72
72
72
72
72
57
48
41
32
28
64
84
84
56
72
81
–
2. Results and discussion
EL:H2O (1:1)
EL:H2O (2:1)
EL:H2O (3:1)
EL:H2O (1:2)
EL:H2O (1:3)
EL:H2O (1:4)
EL:H2O (1:3)c
EL:H2O (1:3)d
EL:H2O (1:3)e
CH3CN:H2O (1:3)
DMF:H2O (1:3)
CH2Cl2:H2O (1:3)
MeOH:H2O (1:3)
EtOH:H2O (1:3)
iPrOH:H2O (1:3)
EtOAc:H2O (1:3)
Salicylic acid (SA):H2O (1:3)
We first examined the possibility of an aqueous method for the hy-
dration of alkynes under catalyst- and acid-free conditions at 110 °C
by using phenyl acetylene as a model substrate. In this trial, formation
of the desired product was not observed because of the poor nucleophi-
licity of the water. Hence, there is a great need for an alternative green
system that appropriately activates the substrate.
Fascinated by the solvent-tuning approach with a biomass-based
sustainable solvent, we performed the model reaction by employing
EL as a co-solvent with water in assorted ratios (Table 1). We found
that a 1:3 ratio of EL:H2O gave the desired product 2i in excellent
yield relative to other proportions for the EL and water mixture. From
these results, we observed that a larger amount of water was necessary
in the EL/H2O system for alkyne hydration.
The distinctive role of EL in promoting the hydration of alkynes in
aqueous media can be attributed to its ability to alter the intermolecular
hydrogen bonding of water molecules [15]. In a pure EL phase, strong
intramolecular hydrogen bonding between the hydroxy and carbonyl
groups of the EL molecules enables them to interact with phenyl
acetylene.
9
10
11
12
13
14
15
16
17
18
19
–
–
26
24
21
30
–
a
Reactions were performed with phenyl acetylene (2 mmol) in various solvents at
110 °C.
b
Isolated yield.
c
Reaction at 70 °C.
Reaction at 90 °C.
Reaction at 120 °C.
d
e
2

A. Dandia, P. Saini, M.J. Chithra et al.
Journal of Molecular Liquids 331 (2021) 115758
Scheme 2. Hydrogen bonding in water and EL.
Table 2
Interaction energies of the three complexes corrected with the BSSE and ZPE.
Ecomplex (au)
EEL+W (au)
BSSE (au)
ΔZPE (au)
Eint (au)
Eint (kcal mol−1
)
Complex 1
Complex 2
Complex 3
−498.8392
−498.8421
−498.8385
−498.8296
−498.8296
−498.8296
0.0010
0.0014
0.0008
0.0029
0.0041
0.0025
−0.0057
−0.0070
−0.0056
−3.6071
−4.3718
−3.5207
Fig. 1. Structures of complexes 1–3 (along with atom numbering) optimized at the B3LYP/6-311++G(d,p) level of theory.
The interaction energies (Eint) [16] of the three complexes were de-
termined as the difference between the energy of the complex
(Ecomplex) and the added energies of EL and H2O (EEL and EW, respec-
tively; Table 2, Fig. 1). The energies were corrected by incorporating
the basis set superposition error (BSSE) computed by utilizing the coun-
terpoise procedure [17] and zero-point energy (ZPE).
those on X and Y decrease (Δq < 0). This shows the presence of an H-
bond [16]. Furthermore, we note interactions between the lone pair of
the H-bond acceptor and the anti-bonding orbital of the H-bond donor
(nO → σ*O–H). The stabilization energy (E(2)) reveals the strength of
the hydrogen-bonding interaction [16,18,19]. Based on the E(2) values,
it can be inferred that nO(21)9 → σ*O10–H11 is the relatively stronger interac-
tion and, hence, complex 2 is relatively more stable than complexes 1
and 3.
Eint ¼ Ecomplex−ðEEL þ EWÞ þ BSSE þ ΔZPE
Through the above calculations, we established that complex 2 is
the most contributing hydrogen-bonding network in the mixture.
This hydrogen-bonding network activates the water molecule and
brings it extremely close to the phenyl acetylene molecule for the
hydration reaction. These hydrogen-bonding interactions predomi-
nantly occur with a higher water concentration relative to the EL
concentration [15]. A few reports are available for the hydrogen-
in which ΔZPE = ZPEcomplex − (ZPEEL + ZPEW
)
The interaction energy calculations summarized in Table 2 show
that complex 2 is themost stable among the three complexes with Eint
=
−4.3718 kcal mol−1. NBO analysis (see Table 3) indicates that, in all
three complexes, the atomic charge on H in the X–H···Y hydrogen
bond increases upon hydrogen-bond formation (Δq > 0), whereas
3

A. Dandia, P. Saini, M.J. Chithra et al.
Journal of Molecular Liquids 331 (2021) 115758
Table 3
Hyperconjugative interactions, stabilization energies, E(2), and variations in the charges of atoms X, Y, and H with H-bond formation.
Complex
1
X–H···Y bond
Interaction
E(2) (kcal mol−1
)
ΔqX
ΔqH
ΔqY
(1)
O19–H20···O10
O19–H20···O10
O10–H11···O19
O10–H11···O19
n
n
n
n
→ σ*O19–H20
4.09
3.59
0.13
9.99
−0.0356
–0.0356
−0.0356
–0.0356
0.0268
0.0268
0.0124
0.0124
−0.0283
–0.0283
–0.0447
–0.0447
O10
(2)
→ σ*O19–H20
→ σ*O10–H11
→ σ*O10–H11
O10
(1)
2
O19
(2)
O19
(1)
O2
O19–H20···O2
O19–H20···O2
O19–H20···O2
O19–H20···O2
n
n
n
n
→ σ*O19–H20
→ σ*O19–H20
→ σ*O19–H20
→ σ*O19–H20
2.57
5.41
2.75
3.09
−0.0447
− 0.0447
−0.0360
–0.0360
0.0386
0.0386
0.0266
0.0266
−0.0335
–0.0335
−0.0440
–0.0440
(2)
O2
(1)
O2
3
(2)
O2
To further confirm the specific assistance of the EL/H2O system, var-
ious aqueous systems with other co-solvents were studied. Aqueous
mixtures of alcohols produced moderate yields of desired product
(Table 1, entries 15–17). Similar results were found with an aqueous
mixture of an ester (Table 1, entry 18). These outcomes confirmed the
synergic effect of the hydroxy and ester carbonyl groups of the EL mol-
ecules in the EL/H2O system. No hydration of alkyne to form the corre-
sponding methyl ketone was observed in the presence of an H2O/
salicylic acid system (Table 1, entry 19). Salicylic acid has predomi-
nantly strong intramolecular H-bonding and is not involved in strong
intermolecular hydrogen bonding with the water molecules. As a result
of this, SA was unable to activate the water molecules for alkyne hydra-
tion. Moreover, the desired product was not formed in aqueous mix-
tures of CH2Cl2, CH3CN, and DMF (Table 1, entries 12–14). The effect
of temperature on the reaction was also examined (Table 1, entries
9–11). At lower temperatures, inferior yields of the product were ob-
served. The conversion was extraordinarily enhanced by increasing
the reaction temperature. The optimum temperature for the reaction
was found to be 110 °C. Further increases in temperature did not ad-
vance the outcome to a significant amount.
Scheme 3. Control experiments.
bond-driven activation of alkynes [20] for nucleophilic addition, but
the hydration of alkynes remains unexplored under these
conditions.
Fig. 2. Gibb's free energy profiles calculated for the addition pathway. The relative energy values with respect to the sum of the energies of reactants (∑E(EL + H2O + PhCCH)) in kcal
mol−1 are given for each reaction point.
4

A. Dandia, P. Saini, M.J. Chithra et al.
Journal of Molecular Liquids 331 (2021) 115758
Scheme 4. Probable mechanism.
In control experiments, the addition of a radical scavenger (TEMPO)
did not affect the yield of the reaction (Scheme 3a). Furthermore, no
products from the radical pathway were obtained under these condi-
tions. These results ruled out the possibility of a radical mechanism.
The reaction was also carried out under an inert atmosphere (Scheme
3b). An excellent yield of desired product was obtained, which ruled
out the probable involvement of any oxidative pathway. Deuterated
product was formed when the reaction was performed with D2O in-
stead of H2O under analogous conditions (Scheme 3c). However, a
lower yield of the desired compound was detected with D2O because
of the less effective H-bonding relative to that of H2O [12]. This test
shows that both hydrogen atoms participate in the reaction. Any associ-
ation of the hydroxy group of the EL molecule direct to the phenyl acet-
ylene is ruled out because only deuterated product is formed. We did
Table 4
Scope of the alkyne hydration reactiona.
aReactions were performed with aryl alkyne (2 mmol) in the EL:H2O (1:3) system at 110 °C.
5

A. Dandia, P. Saini, M.J. Chithra et al.
Journal of Molecular Liquids 331 (2021) 115758
not observe any peak of a vinylic ether in the GC–MS spectrum, which
confirms that there is no direct participation of EL molecules in the
reaction.
Markovnikov addition in the present case (Fig. 2). However, it should
be noted that the activation energy (Ea) of the anti-Markovnikov route
is only slightly higher (~1.6 kcal mol−1) than that of the Markovnikov
pathway. Based on the Ea values and the energies of the products, it
can be inferred that the Markovnikov product is both kinetically and
thermodynamically controlled.
Therefore, in the present case, only Markovnikov adducts (ketones)
have been regioselectively formed. A literature survey indicated that the
hydration of alkynes also competes with the formation of homocoupled
alkynes [22]. The present protocol gave exclusively Markovnikov ad-
ducts (ketones). The formation of homocoupled alkynes was not ob-
served in the current case. Based on the above observation, we
propose that the hydrogen-bonding network between the EL and H2O
molecules interacts with the alkyne via a hydrogen-bond donor–
acceptor interaction and brings the H2O molecules into close proximity
of the alkynes to form enolic intermediates. Subsequent
tautomerization of the enolic intermediates gives the final product 2i
(Scheme 4).
For further confirmation of the formation of hydrogen bonds in the
reaction mixture, NMR experiments were carried out [21] (see the
ESI). We prepared the samples, that is, H2O + phenyl acetylene,
EL + phenyl acetylene, and EL + H2O + phenyl acetylene, and recorded
their 13C NMR spectra. If the phenyl acetylene molecules interacted with
any of these solvent systems, a downfield shifting of the triple-bond car-
bon atoms would be observed in the 13C NMR spectra. As anticipated,
the NMR spectrum of the EL + H2O + phenyl acetylene sample shows
downfield shifting of phenyl acetylene triple-bond carbon atoms 1
and 2 from δ = 83.62 and 80.52 ppm to δ = 83.93 and 80.81, respec-
tively. The other two samples did not show any significant downfield
shifting of the triple-bond carbon atoms. These experiments confirm
the possible hydrogen-bonding interaction between the alkyne mole-
cules and the EL/H2O mixture.
Hydration of alkynes is regioselective. Both types of product, that is,
Markovnikov (ketones) and anti-Markovnikov (aldehydes), have been
reported under various conditions [14]. From the theoretical calcula-
tions, we observed that the transition state associated with
Markovnikov addition is more stable than the transition state of anti-
After confirming our hypothesis, the hydration of a diversity of aro-
matic terminal alkynes with different functional groups was accom-
plished, and the outcomes are presented in Table 4. Alkyne electronic
density is expected to be a key contributor for establishing H-bonding.
Table 5
Synthetic application of the procedure for the production of α,β-unsaturated carbonyl compoundsa.
aReactions were performed with benzaldehyde (2 mmol) and phenyl acetylene (2 mmol) in the EL:H2O (1:3) system at 110 °C.
6

A. Dandia, P. Saini, M.J. Chithra et al.
Journal of Molecular Liquids 331 (2021) 115758
As a consequence, aryl alkynes with strong electron-donating groups
generated the final compounds in outstanding yields under the opti-
mized conditions. Electron-withdrawing groups on aryl alkynes needed
longer reaction times for the transformation to the analogous aryl ke-
tones in good yield. Moreover, aliphatic and internal alkynes were
inert under the employed conditions. Further investigation is under
way in our laboratory.
Encouraged by these outcomes, we extended the synthetic scope of
the above procedure for the synthesis of value-added α,β-unsaturated
carbonyl compounds [23]. According to the existing literature proce-
dures [24], the synthesis of these compounds requires a base, an acid,
or a catalyst. We successfully applied the above protocol for the produc-
tion of α,β-unsaturated carbonyl compounds through the reaction of al-
dehydes with alkynes as ketonic surrogates. In a tentative experiment,
benzaldehyde (2 mmol) and phenyl acetylene (2 mmol) were submit-
ted to the optimized reaction conditions. After 48 h, α,β-unsaturated
compound 3i was isolated in good yield. The reaction tolerated a wide
variety of groups on the phenyl ring and gave the analogous compounds
in excellent yields (Table 5). All of these reactions were accomplished in
48–60 h.
3.4. General process for the production of α,β-unsaturated carbonyl
compounds 3
Alkynes (2 mmol) and aldehydes (2 mmol) were added to a stirred
35 mL solution of EL:H2O (1:3). The reaction mixture was stirred at
110 °C for a suitable time. After successful conversion, the resultant so-
lution was cooled to room temperature and extracted with ethyl acetate
(4–6 mL). The combined organic phases were dehydrated over anhy-
drous sodium sulfate and filtered. The filtered solution was concen-
trated under reduced pressure and purified by column
chromatography on silica gel (hexane:EtOAc as the eluent) to give the
pure desired product.
4. Conclusions
In summary, we have shown regioselective Markovnikov-type al-
kyne hydration in an ethyl lactate/water (1:3) medium. By various ex-
perimental and theoretical techniques, the critical role of the
hydrogen-bonding network in the ethyl lactate and water mixture for
the hydration of alkynes has been established. This strategy was also
used for the production of α,β-unsaturated carbonyl compounds
through the reaction of aldehydes with alkynes as ketonic surrogates.
Broad substrate applicability and excellent yields without the addition
of metals, catalysts, acids, and additives make the process
eye-catching. To widen the application of the above procedure and un-
derstand the mechanism of this system in more detail, further work is
ongoing in our laboratory and will be reported in due course.
In a successive mechanism, the alkyne molecule first undergoes a
hydration reaction and produces the corresponding methyl ketone.
The hydrogen-bonding network between the EL and H2O molecules ac-
tivates the aldehyde molecule through cooperative hydrogen bonding
and facilitates the Claisen–Schmidt condensation [25] with the resulting
methyl ketone to construct the desired α,β-unsaturated carbonyl com-
pound. Overall, the reaction follows the hydration/condensation
sequence.
Author statement
A.D. and V.P. developed the idea; V.P. designed the concept; P.S.
completed review of literature, V.P. and P.S. analyzed the results; P.S.
was involved in the data analysis, P.S. and V.P. completed the manu-
script CMJ and SRV analyze and conclude computational details. All
the authors discussed the results and commented on the paper.
3. Experimental section
3.1. General
See the ESI.
Declaration of Competing Interest
There are no conflicts to declare.
Acknowledgments
3.2. Computational details
The ground-state equilibrium structures of the hydrogen-bonded
complexes were optimized by using the DFT functional B3LYP [26]
with the 6–311++G(d,p) basis set. To estimate the strength of inter-
molecular H-bonding in these complexes, NBO analysis is conducted
at the same level of theory. Furthermore, to understand whether the ad-
dition reaction of complex 2 to phenyl acetylene follows the
Markovnikov or anti-Markovnikov pathway, the two plausible
transition states were optimized by using the Berny algorithm. An in-
trinsic reaction coordinate scan was conducted to confirm that the ob-
tained transition states associate the reactants and products in the
potential energy surface. The reactants, products, and transition states
were optimized at the B3LYP/6-31G(d) theoretical level. All analyses
were achieved in the gas-phase by utilizing the Gaussian 09 rev A.02
[27] program package.
DST-SERB, C.S.I.R., and U.G.C., New Delhi, are acknowledged for fi-
nancial assistance. The authors are grateful to MNIT, Jaipur, for the spec-
tral studies.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.molliq.2021.115758.
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as the eluent) to provide the pure desired product.
7

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