Molecules 2021, 26, 2864
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environmental concerns [27]. Recently, numerous transition metal salts and complexes
were found applicable as catalysts for Markovnikov-type alkyne hydration—among these,
gold, silver, platinum, palladium, rhodium and ruthenium compounds [29–38]. Although,
these represent great progress compared to the classical methodologies, such reactions
are generally promoted by soluble catalytic sources typically in the presence of various
ligands. This fact, along with the high price of the catalytic metal, should be considered as
a significant drawback.
Bismuth subnitrate (Bi O(OH) (NO ) ) is a commercially available bismuth(III) com-
5
9
3 4
pound that bears significant medical uses (e.g., as an antidiarrheic agent) [39]. It can readily
be prepared by the controlled thermal decomposition of Bi(NO3)3 5H O [40], and it is
·
2
practically insoluble in most typical organic solvents. In spite of its beneficial properties,
such as ready availability, nontoxicity and low price, it has scarcely been investigated as
a heterogeneous bismuth catalyst in organic synthesis [41,42]. Earlier, we reported that
various soluble bismuth salts are useful as homogeneous catalysts in alkyne hydration [20].
We speculated that bismuth subnitrate may be applicable as a heterogeneous source for
catalytic bismuth(III) and that it may prove useful as an efficient heterogeneous catalyst
for Markovnikov-type alkyne hydrations. The application of heterogeneous catalysts in
continuous flow systems have received an upsurge of interest, which is due to numerous
benefits, such as facile catalyst handling, recycling and reuse, as well as simple product
isolation [43
interact with a superstoichiometric amount of catalyst species, which enhances the reaction
rates considerably [50 51], while the improved control over temperature and residence
time ensures a high selectivity and low waste generation [52 55]. We therefore intended
–49]. Additionally, in loaded catalyst columns, continuous substrate streams
,
–
to study the reactions not only under the traditional batch conditions but, also, within a
continuous flow packed-bed reactor environment. Our results are presented herein.
2. Results and Discussion
As the starting point of our study, the catalytic activity of different bismuth(III) com-
pounds was compared using the Markovnikov-type hydration of p-methoxyphenylacetylene
as the model reaction (Table 1). The reaction mixture containing the alkyne (1.0 M), together
with 15 mol% of the selected catalyst, was refluxed for 24 h in MeOH as the solvent. Having
confirmed the lack of conversion without any catalyst present (entry 1), we were delighted
to find that, in the presence of bismuth subnitrate as the catalyst, the corresponding methyl
ketone was formed in a quantitative and selective reaction (entry 2). Bi(OTf) also furnished
3
the quantitative conversion; however, dimethyl acetal
an extent of 12% (entry 3). According to the reaction mechanism suggested earlier [56
is, in fact, an intermediary product, which is formed by the hydroalkoxylation of the
alkyne with methanol; is then hydrolyzed to yield methyl ketone as the desired product.
BiBr proved less reactive as a catalyst and furnished only 45% conversion, along with
2
was detected as a side product to
,
57],
2
2
1
3
some notable amount (8%) of
2 formed as a side product (entry 4). Bi(OAc) and Bi O
3 2 3
proved inactive as a catalyst in the model reaction (entries 5 and 6).
Next, the effects of the most important reaction conditions were investigated carefully.
As concerns the reaction time, it was found that 24 h is necessary for completion of the
model reaction under reflux conditions in MeOH (further conditions: 15 mol% catalyst
loading and 1 M substrate concentration). Shorter reaction times gave lower conversions—
for example, 73% in the case of 12 h and 18% in the case of 3 h (Table 2, entries 1–5). Upon
investigating the effects of catalyst loading (entries 6–8), the best results were achieved
with 15 mol%; however, with only 2 mol% of bismuth subnitrate catalyst present, an
acceptable conversion of 62% could still be achieved. Importantly, in the cases of 2 and
5
mol% catalyst loading, dimethyl acetal 2 appeared as a side product to an extent of 29%
and 12%, respectively. Heating at reflux temperature was found to be necessary for efficient
alkyne hydration, since only traces of product formation occurred at room temperature
(entry 9). Upon increasing the substrate concentration to 2 M, a notable decrease of the