Iron(III)-Catalyzed Hydration of Unactivated Internal Alkynes in Weak Acidic Medium, under Lewis Acid-Assisted Br?nsted Acid Catalysis

Article abstract of DOI:10.1002/adsc.201900633

Alkylarylalkynes are converted with full regioselectivity into the corresponding arylketones by formal hydration of the triple bond under weak acidic conditions, at times and temperatures (≤95 °C) comparable to those used for terminal alkynes. The process catalyzed by Fe₂(SO₄)₃nH₂O in glacial acetic acid exhibits good functional group compatibility, including that with bulky triple bond substituents, and can be extended to the one-pot transformation of aryltrimethylsilylacetylenes into acetyl derivatives via a desilylation-hydration sequence. The overall reactivity pattern along with proton affinity data indicate that the triple bond is activated by proton transfer rather than by π-interaction with the metal ion. This mechanistic feature, at variance with that of noble metal catalysts, accounts for the total regioselectivity and the insensitivity to steric hindrance exhibited by the Fe₂(SO₄)₃nH₂O/AcOH catalytic system. (Figure presented.).

Full text of DOI:10.1002/adsc.201900633

Title: Iron(III)-Catalyzed Hydration of Unactivated Internal Alkynes in
Weak Acidic Medium, under Lewis Acid-Assisted Brønsted Acid
Catalysis
Authors: Achille Antenucci, Piergiorgio Flamini, Marco Valerio
Fornaiolo, Sergio Di Silvio, Sara Mazzetti, Paolo Mencarelli,
RICCARDO SALVIO, and Mauro Bassetti
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900633
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10.1002/adsc.201900633
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iron(III)-Catalyzed Hydration of Unactivated Internal Alkynes
in Weak Acidic Medium, under Lewis Acid-Assisted Brønsted
Acid Catalysis
Achille Antenucci,a Piergiorgio Flamini,a Marco Valerio Fornaiolo,a Sergio Di Silvio,a
Sara Mazzetti,a Paolo Mencarelli,a,b Riccardo Salvio,b,c Mauro Bassettib,*
a
Dipartimento di Chimica, Università di Roma La Sapienza, P.le A. Moro 5, 00185 Roma, Italy
CNR, Istituto per i Sistemi Biologici, Sezione Meccanismi di Reazione, c/o Dipartimento di Chimica, Università La
b
Sapienza, P.le A. Moro 5, 00185 Roma, Italy
Dipartimento di Scienze e Tecnologie Chimiche, Università "Tor Vergata", Via della Ricerca Scientifica 1, 00133
c
Roma, Italy.
E-mail: mauro.bassetti@cnr.it
Received: ((will be filled in by the editorial staff))
Dedicated to Professor Barbara Floris
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. Alkylarylalkynes are converted with full
regioselectivity into the corresponding arylketones by formal
hydration of the triple bond under weak acidic conditions, at
times and temperatures (≤ 95 °C) comparable to those used
for terminal alkynes. The process catalyzed by
Fe2(SO4)3nH2O in glacial acetic acid exhibits good
functional group compatibility, including that with bulky
triple bond substituents, and can be extended to the one-pot
transformation of aryltrimethylsilylacetylenes into acetyl
derivatives via a desilylation-hydration sequence. The
overall reactivity pattern along with proton affinity data
indicate that the triple bond is activated by proton transfer
rather than by -interaction with the metal ion. This
mechanistic feature, at variance with that of noble metal
catalysts, accounts for the total regioselectivity and the
insensitivity to steric hindrance exhibited by the
Fe2(SO4)3nH2O/AcOH catalytic system.
Keywords: alkynes; trialkylsilylacetylenes; iron catalysis;
protodesilylation; one-pot reactions
possible in the case of gold,[5] silver,[6] or platinum
complexes.[7] The search for efficient and selective
catalytic systems at increasingly lower costs, toxicity
Introduction
The hydration of the triple bond represents a
straightforward and atom economic transformation of
alkynes into carbonyl compounds.[ 1 ]Although the
process is exergonic, the activation of the unsaturated
group toward attack by oxygen nucleophiles requires
an electrophilic species, i.e. a Brønsted acid alone,[1,2]
or in presence of a Lewis acid co-catalyst. This
combination allows to lessen the harsh conditions
imposed by concentrated aqueous solutions of strong
acids, as originally obtained with the use of mercury
compounds.[ 3 ] The high toxicity associated with
large-scale applications of mercuric salts[4] prompted
for the investigation of alternative catalysts.[1] Among
the most relevant developments, it should be
evidenced that acid-free catalysis is nowadays
and overall environmental impact remain
a
challenging field of investigation.[8]
While terminal alkynes can be selectively
converted into the corresponding ketones, or
aldehydes under specific ruthenium catalysts,[1] the
transformations of internal alkynes poses additional
concerns (Scheme 1). Due to inherently lower
reactivity, non-activated internal alkynes are either
unreactive[6,8b,8d]
or
require
more
forcing
conditions.[2b,2d,2e] The reaction scope is further
hampered by difficult regioselectivity which is faced
by most catalytic systems.[3c,5a,b,c,g,7,8a,8e,f, 9 ] Specific
attention has been given recently to these issues,[10]
and the following are cases of significant
achievements. Arylketones, which are the favored
1
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10.1002/adsc.201900633
Advanced Synthesis & Catalysis
products
when
starting
from
asymmetric
Assisted Brønsted Acid (LBA) catalysis have also
been addressed in comparison with transition metal
catalysis.
arylalkylalkynes,[2d,2f] are also accessible under metal-
free conditions in presence of directing hydroxyl[11] or
carbonyl groups.[ 12 ] Appropriate co-catalysts can
switch the selectivity toward the otherwise disfavored
α-aryl ketones.[13 ] In the case of diarylalkynes, an
electron donor group in one aryl ring favors the
formation of only one regioisomer.[14]
Results and Discussion
Hydration of Alkylarylalkynes
To test the activity of Fe2(SO4)3·nH2O (1) in AcOH
for the hydration of internal alkynes, 1-
phenylpropyne (2) was chosen as the model substrate
for control experiments. The conditions (95 °C)
which had allowed for near quantitative formation of
acetophenone from phenylacetylene (2a) left a
significant amount of unreacted 1-phenylpropyne.
The conversion into 1-phenylpropanone (3) improved
significantly upon raising the temperature from 95 to
120 °C, in presence of 10 mol% of 1 (Table 1, entries
1-2). Lowering the content of the iron salt gave
reduced conversion into the hydration product (Table
1, entries 2-4), as well as the use of d4-acetic acid as
solvent or of the ironII salt FeSO4·7H2O as catalyst
(Table 1, entries 5-6). The addition of H2O, 1 equiv
or up to H2O:AcOH, 10:90 v/v, did not show any
significant change with respect to the result of entry 2.
When the reaction of 2 was performed on 3.4
mmol in presence of 10 mol% of 1 in AcOH (7.0 mL),
at 120 °C for 24 h, the work-up afforded a crude
mixture containing the arylketone as the only
hydration product accompanied by traces of substrate
and unidentified by-products. Elution by column
chromatography gave pure 3 in 61% yield. Though
the low yield was not an encouraging result, the
observed regioselectivity prompted us to expand
further on the reactivity of alkylaryl alkynes. To this
aim, a series of compounds ArCCR were prepared
under Sonogashira-Hagihara conditions (Table in SI).
current state
O
H2O
R
+
R
R
R'
R'
Mn+ + H+
R'
O
low regioselectivity, costly metalsor strong acids, extra steps catalyst synthesis
this work
AcOH
O
Ar
Ar
R
Lewis acid (FeIII)
R
full regioselectivity, handablecatalyst, weak acids, LBAcatalysis
Scheme 1. Hydration of Internal Alkynes.
In the mainstream of emerging iron catalysis in
organic synthesis,[ 15 ] iron salts have been used as
promoters in the hydration of terminal alkynes.
Following from those seminal works based on
stoichiometric[16] or catalytic FeCl3,[17] the extension
to few cases of internal alkynes was achieved in
presence of FeCl3/3·AgNTf2 in dioxane/H2O,[18] or of
FeCl2·4H2O/methanesulfonic
acid
in
1,2-
dichloroethane (DCE).[19] Alkynyl chlorides can also
be converted into α-chloromethylketones using
FeCl3·6H2O in DCE.[20] We have shown that ironIII
sulfate hydrate added to glacial acetic acid promotes
the hydration of terminal alkynes.[ 21 ] In this case
acetic acid serves as the proton donor and the iron
salt, in the form of easily handable whitish crystals, is
the co-catalyst. Neat AcOH can be regarded as a mild
acidic medium because its low dielectric constant
suppresses the proton dissociation equilibrium. This
catalytic system has also been adopted to the
formation of seven membered cyclic ketones along
the synthesis of (+)-Dalesconol A and B,[ 22 ] thus
indicating compatibility with chemical complexity.
The system Fe2(SO4)3·nH2O/AcOH represents an
example of combined acid catalysis, where the
effectiveness of a proton source is exalted by
associative interaction with a Brønsted or a Lewis
acid,[ 23 ] an approach successfully applied in the
context of alkyne activation and hydration
reactions.[24,25] It is also recognized that mechanistic
details involved in the cooperative effects of the
combined acids remain rather elusive.[24]
Table 1. Reaction Optimization and Control
Experiments.[a]
Entry Iron salt (mol%)
T, °C 2[b] 3 [b]
1
2
3
4
5
6
1 (10)
1 (10)
1 (5)
–
95
66 18
2 78
36 43
96 < 1
68 16[c]
98 < 1
120
120
120
1 (10) in CD3CO2D 120
FeSO4·7H2O (10)
120
[a] Conditions: 2 in AcOH 0.5 M (1.0 mmol in 2 mL), 24 h
in air, in presence of 1,2-diphenylethane as internal
[b]
standard.
GC percentages of 2 and 3. [c] PhCOCD2Me
We wish to report our investigation on the activity
of this iron-based catalytic system in the hydration of
internal alkynes, in particular of non-activated and
sterically hindered alkylaryl substrates and of
aryltrimethylsilylacetylenes,
desilylation-hydration sequence
conditions. Mechanistic issues related to Lewis Acid-
(m/z = 136).
The catalytic hydration reactions on these
substrates were then performed using the conditions
adopted for the hydration of 2, while making changes
of temperature, reaction time, or catalyst loading
whenever convenient (Table 2). The reaction of 1-
undergoing
under
a
mild
2
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10.1002/adsc.201900633
Advanced Synthesis & Catalysis
Table 2. Hydration of Arylalkylalkynes Promoted by
Fe2(SO4)3·nH2O/AcOH.[a],[b]
methyl-3-(oct-1-ynyl)-benzene (4a), 1-methyl-2-(oct-
1-ynyl)-benzene (4b), or o-tolyl-t-butylacetylene (4c),
at first performed at 120 °C, gave excellent isolated
yields (80-90%) of the corresponding arylketones.
The reactivity of the triple bond did not suffer the
steric hindrance by the methyl group in ortho-
position, neither was affected upon increased
congestion from a t-butyl group in place of the linear
n-hexyl chain. Due to the high yields obtained, the
reactions of compounds 4a-c were repeated at lower
temperatures. In the case of compound 4c, traces of
ketone were observed at 70 °C whereas full
conversion was obtained after 18 h at 90 °C, and
similar results were found for 4a,b. These conditions
are comparable to those used for the hydration of
terminal alkynes.[21] Regarding the higher conversion
of these alkylarylalkynes vs 1-phenylpropyne, it is
worth mentioning that an increase of yield at
increasing length of the alkyl chain of PhCCR (R =
Me, Et, Bu) was also found under catalysis of
FeCl3/3·AgNTf2.[18] 1-Dec-1-ynylnaphtalene (4d)
also reacted smoothly at 95 °C. Whereas the
entry Alkyne
1
conditions Ketone
yield
2
3
4
5
6
7
efficiency
of
the
catalytic
system
Fe2(SO4)3·nH2O/AcOH for alkyne 4a can be
compared with the conversion of 1-phenyl-1-heptyne
in formic acid (100 °C, 5 h, 89% GC yield),[2b] and of
1-phenyl-1-hexyne in dioxane/H2O (FeCl3/3·AgNTf2,
95 °C, 60 h, 99%)[18] or in ethanol with 1 equiv of p-
toluensulfonic acid (PTSA) under microwave
irradiation (170 °C, 30 min, 89%),[2d] reactions under
hydrative conditions of sterically hindered triple
bonds as in 5b-d have not been reported for
unactivated alkynes. Although compatible with
hydration under Brønsted acidic conditions, ortho-
substitution even with activating groups implies more
forcing conditions.[2d] The bifunctional and highly
congested diyne 4e was slowly (50 h) converted into
the corresponding diketone 5e, found in a mixture
with the monohydrated product at shorter reaction
times. The isolated yield (55%) reflected the lower
reactivity of the 1-propynyl group with respect to the
longer chain alkynyls.
The substrates activated by the electron donating
groups p-OMe (4f, p = 0.27) or p-OH (4g, p =
0.37) gave high yields of the hydration product
under milder conditions, i.e. 70 °C and < 6 mol% of
catalyst loading. Further reduction of the reaction
temperature to 50 °C still allowed for a good
conversion of the phenol but not anymore of the
methyl ether. Only traces of the ketone derived from
4g were found in absence of the iron salt under same
conditions. The reactivity of the activated alkynes
4f,g can be compared with that of p-MeO-
C6H4CCC4H9 (PTSA 20%, boiling ethanol, 60 h,
90%) or of o-MeOC6H4CCC4H9 (PTSA 20%,
boiling ethanol, 144 h, 80%) in stronger acidic
conditions.[2d] On the other hand, the aryl bromide 4h
(m-Br = 0.39) required 120 °C and longer reaction
time for a modest conversion (42%) into the
hydration product, in presence of unreacted alkyne.
8
9
10
11
12
13
14
15
16
[a] Conditions: Alkyne 1.0 – 2.0 mmol in AcOH (2.0 – 4.0
mL), salt 1 (10 mol%). [b] Isolated yields. [c] GC yield.
3
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10.1002/adsc.201900633
Advanced Synthesis & Catalysis
1-(Thiophen-2-yl)-1-octyne (4i) allowed to react
represented in the graph of Figure 1 which shows the
disappearance of the silylated alkyne, the formation
of acetophenone as well the formation and
consumption of phenylacetylene as an intermediate.
at 80 °C gave high yield of the hydration product, as
evidence of compatibility of the catalytic system with
sulfur donor atoms. Conversely, compound 4j did not
react under any circumstances, due to protonation of
the pyridinyl ring and deactivation of the triple bond.
In the case of the homopropargylic alcohol (4k), the
acetylated arylketone 5k was obtained in 45% yield.
A complex mixture was also observed in the
reaction of propargylic alcohol (4l) which afforded
the cis-enyne 5l as the only isolable product. The
activated diaryl alkyne p-MeOC6H4CCPh (4m)
reacted easily, though with formation of both
regioisomers; only the diketone 5m could be isolated
after a prolonged reaction time.[26]
The reaction of symmetric alkynes did not
proceed efficiently under catalysis of Fe2(SO4)3·nH2O
(10 mol%) in AcOH. From diphenylacetylene (4n),
PhCOCH2Ph (5n) was isolated in 50% yield (120 °C,
18 h) with no further improvement due to subsequent
conversion into the corresponding 1,2-diketone
(PhCO)2 at prolonged reaction times.[2b] The
conjugated diyne PhCC-CCPh (4o) was totally
inert toward hydration or any other transformation
under the conditions of this work, while 4-octyne
(4p) gave low conversion into 4-octanone (5p) even
at 120 °C. All the reactions here described proceeded
under heterogeneous conditions due to the low
solubility of the iron salt in AcOH. Various attempts
to obtain homogeneous solutions by the use of AcOH
mixtures with more polar solvents corresponded to
drastic reduction of activity. Moreover, the solid
material recovered by filtration at the end of reaction
exhibited poor activity in subsequent runs.
Figure 1. Transformation of PhCCSiMe3 (, 1 mmol)
into PhCOMe () in presence of Fe2(SO4)3nH2O (10
mol%) in AcOH (2.2 mL), 85 °C; concentration values
calculated from response factors with respect to 1,2-
diphenylethane as internal standard; best line fitting of
PhCCH () with equation 2.
By assuming that the overall process
corresponds to a sequence of two consecutive and
irreversible first-order reactions (equation 1), and by
the use of equation 2,
k1
k2
PhCCSiMe3
PhCCH
PhCOMe (1)
Hydration of Aryltrimethylsilylalkynes
푘1 × [ퟔ풂]
푘2−푘1
2푡
1
[
]
ퟐ풂 =
(푒−푘 푡 − 푒−푘
)
(2)
The scope of the reaction was investigated on
aryltrimethysilylalkynes. When PhCCSiMe3 (7a)
was treated with the iron salt (10 mol%) in acetic acid
(16 h, 90 °C) the GC-MS analysis revealed the
selective formation of acetophenone (8a, 98% GC
yield) in presence of traces of phenylacetylene (2a),
indicating a one-pot desilylation-hydration process.
Since -SiMe3 is a protective group of the ethynyl
function and aryltrialkylsilylacetylenes are more
stable and easily handable materials than the
corresponding terminal alkynes,[27] the direct
transformation into the acetyl derivatives is a
desirable chemical process. While trialkylsilyl groups
are easily removed by nucleophiles (OH- or F-), the
acid hydrolysis requires more vigorous conditions.
For comparison, compound 7a gave acetophenone
it is possible to estimate the following values of rate
constants: k1 = 2.8 (±0.9)  10-4 s-1 and k2 = 4.0 (±
1.5)  10-5 s-1, indicating a relatively faster
desilylation process than alkyne hydration. The same
reaction performed in absence of ironIII sulfate
showed the presence of unreacted silyl substrate and
only traces of PhCCH, pointing out that acetic acid
alone cannot perform the desilylation step. This one-
pot procedure catalyzed by Fe2(SO4)3nH2O under the
mild acidic conditions of neat AcOH can be extended
to other trimethylsilylated acetylenes including those
with electronwithdrawing aryl substituents (Table 3).
The scope of the hydration for terminal alkynes
catalyzed by Fe2(SO4)3nH2O/AcOH was described in
our previous work.[21]
when treated with
a
sulfonated condensed
polynuclear aromatic resin in water for 72 h at
120 °C.[28] Other cases of ArCC-TMS
transformation into the acetyl derivative have been
reported under strong acidic conditions[2d,29] or gold
catalysis.[8e]
The reaction of compound 7a was monitored as
a function of time by sequential GC analysis. The
results of this experiment, performed at 85 °C, are
4
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10.1002/adsc.201900633
Advanced Synthesis & Catalysis
the role of the metal ion are still under consideration,
even with respect to the limiting cases outlined in
Scheme 2.[18,32]
Table
3.
One-Pot
Desilylation-Hydration
of
Aryltrimethylsilylacetylenes Promoted by Fe2(SO4)3·nH2O
in AcOH.[a],[b]
The reactivity pattern exhibited by the catalytic
system Fe2(SO4)·nH2O/AcOH, e.g. effect of
CD3CO2D vs AcOH as solvent (Table 1, entry 5),
regioselectivity and no inhibition by steric hindrance,
suggest that the hydration process promoted by
Fe2(SO4)3nH2O/AcOH proceeds via
a
rate-
determining protonation step, as a consequence of
Lewis acid-assisted Brønsted acid catalysis. In
particular, the proton addition is expected to yield
preferred
formation
of
an
intermediate
[a]
[b]
arylvinylcation with respect to an alkylvinylcation,
due to stabilization by an aryl substituent of the
positive charge at the adjacent carbon atom.[33] In a
theoretical calculation performed on 1-phenylpropyne,
the stability of the two carbocations that can be
formed upon protonation of 2 was evaluated at the
HF/6-311G(d,p) level of theory. The results indicate
that carbocation PhC(+)=CHCH3 (2_2H+) is more
stable than PhCH=CH(+)CH3 (2_1H+) by 20.6
kcal/mol in vacuum and by 15.8 kcal/mol in acetic
acid, which is in agreement with the observed
regioselectivity.
Conditions: Alkyne 1.0 mmol in AcOH (2.0 mL).
Isolated yields. [c] GC yield based on 1,2-diphenylethane as
internal standard.
Mechanism of Alkyne Hydration under LBA
Catalysis
The mechanism of hydration of the triple bond
depends largely on the reaction conditions and the
adopted catalytic system.[1] Two simplified extremes
can be envisaged in the acid- or in the metal ion-
catalyzed hydrations, which are depicted in Scheme 2
for unsymmetrical alkynes. The Brønsted acid acts as
proton source to form the C-H bond of an incipient
vinyl cation, subject to attack by water and formation
of enolic species. When a carboxylic acid is present
in absence of added water, the addition step yields an
enol ester which evolves further into the ketone, as
extensively documented in the literature (Scheme 2,
path a).[2b,3c,8c,19,25,30,31] On the other hand, a transition
metal ion forms with the triple bond an intermediate
π-complex, characterized by charge delocalization
within the charge-transfer adduct. Addition of water
to either carbon atom and subsequent demetallation
steps afford the carbonyl products (Scheme 2, path b).
Most of the metal promoted processes including those
with mercury and noble metal catalysts fall into this
scheme which accounts for the formation of both
regioisomeric products for compounds of type
ArCCR.[3c,5a,b,c,g,7,8e,9a]
As acetic acid alone does not provide access to
the hydration products, the presence of the Lewis acid
implies enhanced acidity of the proton donor, as in
the definition of LBA catalysis. To find experimental
evidence in this respect, the acidity constant of acetic
acid was measured as a function of [Fe2(SO4)3·nH2O],
using a mixture of DMSO/H2O 80:20 (v/v) (hereafter
referred to as 80% DMSO),[34] in which the salt was
found to be soluble. In this medium, used for the
determination of acidity constants and the study of
reaction mechanisms,[35] the pKw for water
autoprotolysis rises to 18.4 and the pK values of
neutral acids rise compared to those in pure water.[36]
This acidity inhibition results in more evident effects
of an interacting additive on the dissociation of acid
species.[36]
Apparent acidity constants of acetic acid in the
presence of ironIII sulfate hydrate at different
concentrations were determined by potentiometric
titrations, carried out on 1.0 mM solutions of AcOH
using Me4NOH as base and Et4NClO4 (5.0 mM) as
ionic strength buffer (titration plots in SI). Analogous
measurements were carried out in the presence of
FeSO4·7H2O, for comparison. The results shown in
the plot in Figure 2 indicate that the acidity of AcOH
is affected by the presence of Fe2(SO4)3·nH2O. The
apparent pK of the acid decreases from 8.19 down to
7.35 upon addition of increasing amount of the salt
up to its solubility limit observed at ≤ 20 mM. On the
other hand, the addition of FeII sulfate, which did not
catalyze the reaction of 2 (Table 1, entry 6), gave no
appreciable change of the measured acidity.
path a
H3O+
O
R'O
Ar
R
H
R
H
R'OH
- H+
Ar
Ar
Ar
R
Ar
R'
H2O
HO
R
HO
Ar
M(n-1)+
Mn+
+
R
- H+ Ar
M(n-1)+
R
Mn+
path b
O
O
+
Ar
R
R
Ar
Scheme 2. General Mechanisms for Hydration of Internal
Alkynes (R’ = H, Ac).
The observed enhanced acidity can thus be
explained in terms of interaction of acetic acid with
FeIII and generation of free hydronium ions and
acetate species, as exemplified in equation 3 (sulfate
ions omitted for clarity), in which the equilibrium is
Since the advent of iron salts as alkyne hydration
catalysts is rather recent, mechanistic issues regarding
5
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10.1002/adsc.201900633
Advanced Synthesis & Catalysis
driven by the affinity of the acetate ligand for the FeIII
centre. The low coordinating ability and basicity of
the sulfate ions may assist both coordination of
AcOH as well as protonic release. Iron salts with
more basic counterions were indeed found to be poor
catalysts.[21]
Table 4. Relative Proton affinity (PAR) of Internal Alkynes
vs PhCCH.
[a]
[a]
entry RCCR’
PAR
PAR
(vacuum) (AcOH)
1
2
3
4
5
6.35
0
0.48
0.61
0.98
1.46
0
 1.35
 3.82
 7.13
o-tolylCCBut (4c)
PhCCH (2a)
PhCCMe (2)
PhCCPh (4n)
PhCCCCPh(4o)
(AcOH)Fe3+(H2O)x + H2O
(AcOFe)2+(H2O)x + H3O+ (3)
[a] kcal/mol.
In vacuum all the PAR values are positive, thus
indicating that the internal alkynes are more basic
than PhCCH, due to charge stabilization of the
protonated species by increased molecular
dimensions. In acetic acid, an opposite trend is
observed which may be rationalized by taking into
account two structural features that may influence
proton affinity. The first one is the capability to
stabilize the positive charge in the carbocation, which
increases on increasing of molecular dimension. The
second and opposing effect is the partial loss of
conjugation due to protonation, which increases at
increasing extension of the -system in the alkyne. In
vacuum the two factors partially compensate even if
stabilization of the positive charge by molecular
dimension prevails over loss of conjugation. In acetic
acid the latter factor becomes dominant, stabilization
of positive charge being provided, at least in part, by
the solvent. Accordingly, the alkynes with more
extended -system become less basic (4n and 4o).
Alkyne 4c is the most basic, both in vacuum and
acetic acid, because, with the same degree of
conjugation of phenylacetylene, its greater molecular
dimension helps in stabilizing the positive charge.
The reactivity of the compounds shown in Table
4 was further investigated by competition reactions
between couples of alkynes, which were performed at
120 °C in order to observe conversion for all the
Figure 2. Apparent pK values of AcOH versus the
concentration of iron ions in DMSO/H2O 80:20 (v/v)
(20 °C).
The assumption that the activation stage of the
reaction is due to protonation of the triple bond
should be reflected in the substrate selectivity of the
hydration process. As a matter of fact, the alkynes
studied in this work vary largely in reactivity which is
satisfactory for arylalkynes 4a-d but of decreasing
interest for 1-phenylpropyne and the symmetric
diaryl or dialkyl alkynes, while the diyne 4o is
unreactive. In the search of a parameter that may
reflect such a wide difference, we examined the
proton affinities of o-tolylCCBut, PhCCMe,
PhCCPh and PhCC-CCPh with respect to that of
phenylacetylene, taken as a reference of a reactive
terminal alkyne. The relative proton affinity (PAR)
should correlate with the tendency of a substrate to
undergo a reactive process via initial protonation
compared to phenylacetylene (2a). The PAR values
were obtained by ab-initio calculations performed at
the HF/6-311G(d,p) level in vacuum and in acetic
acid, and are expressed as the negative of the E
value of the isodesmic reaction shown in eq 4. [37]
1
compounds in the series. The H NMR spectrum of
the reaction mixture after work-up afforded the molar
ratio of the two hydration products (P’ and P’’) from
each alkyne couple (Table 5), a value reflecting the
relative reactivity of the substrates.
Table 5. Competition Experiments for the Hydration of
Alkynes Catalyzed by Fe2(SO4)3·nH2O in Acetic Acid.[a]
entry Alkyne’
Alkyne’’ [P’]/[P’’][b] Time (h)
Ph(+)C=CH2 + RCCR’
PhCCH + R(+)C=CHR’
1
2
3
4
5
4.0
5.5
5.0
8.0
19
PhCCH
o-tolCCBut PhCCMe
PhCCH
PhCCMe
PhCCPh
o-tolCCBut
11
25:1
20:1
100:1
2:1
(4)
PhCCMe
PhCCPh
PrCCPr
A positive PAR indicates that a given alkyne is
more basic than the reference, and vice versa. The
calculated values show opposite trends in vacuum
and in the solvent (Table 4), a case that is not
uncommon for proton affinities of organic
compounds.[37b]
[a]
[b]
1 (5 mol%), alkynes (1.0 M in AcOH), 120 °C.
1
Determined by H NMR analysis of the reaction mixture,
after work-up.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900633
Advanced Synthesis & Catalysis
These results indicate an analogy between the
does not limit the activity of the catalytic system.
Interaction of the iron salt with acetic acid provides a
stronger Brønsted acidic species under catalytic
conditions suitable for either hydration or sequential
protodesilylation/hydration of internal alkynes. The
nature of the mechanism of LBA catalysis explains
both the corresponding advantages as well as the
limitations in the substrate scope.
proton affinity of the alkynes in acetic acid and the
experimental trend of reactivity, which varies in the
order o-tolCCBut ≥ PhCCH > PhCCMe >
PhCCPh >> PhCC-CCPh. The analysis based on
proton affinities explains the unexpected reactivity of
compound 4c and the inertness of 1,4-diphenylbuta-
1,3-diyne under the conditions of this work. Thus the
substrate scope and its limits depend essentially on
the mechanistic nature of the process. Due to the
large substrate selectivity here observed, the catalytic
system may find application for chemioselective
hydration of alkyne moieties in different chemical
environments.
Experimental Section
For details of materials, instruments, general experimental
1
procedures, and figures of H and 13C NMR spectra of
compounds, see the Supporting Information.
It is worth mentioning that the role of protons
has also been specifically discussed in the context of
homogeneous gold catalysis.[38]
6-(m-Tolyl)hex-5-yn-3-ol (4k): an oven dried Schlenk
tube was charged under nitrogen with [PdCl2(PPh3)2] (300
mg, 0.43 mmol) and CuI (134 mg, 0.70 mmol). After two
nitrogen/vacuum cycles, NH(iPr)2 (12 mL), 3-iodotoluene
(1.50 g, 6.9 mmol) and 5-hexyn-3-ol (0.91 mL, 8.2 mmol),
were added by syringe. The tube was sealed with a rubber
septum, immersed in an oil bath, and the mixture kept
under magnetic stirring at 50 °C for 6h. When cooled, a
saturated aqueous solution of ammonium chloride (20 mL)
was poured into the tube and the mixture extracted with
diethyl ether (20 mL  2). The organic phase was washed
with NH4Cl (10 mL), with brine, dried over sodium sulfate
and the solvent evaporated off under vacuum. The brown
oily residue was purified by column chromatography over
silica using hexane/CHCl3 (4:6) as eluent to give the
Catalytic cycle
The overall catalytic cycle, postulated on the basis
of reactivity data and mechanistic investigation, may
be summarized as shown in Scheme 3.
Ar
R
3+
(AcOH)Fe(H2O)x
R
H
AcOH
2+
(AcO)Fe(H2O)x + Ar
1
desired product (oil, 0.85 g, 66% yield). H NMR (300
MHz, CDCl3): = 7.26-7.07 (m, 4H), 3.76 (m, 1H), 2.60
(m, 2H), 2.32 (s, 3H), 2.0 (br s, 1H), 1.64 (m, 2H), 1.00 (t,
J = 7.0 Hz, 3H). 13C {H} NMR (75 MHz, CDCl3):  =
137.7, 132.1, 128.6, 128.5, 128.0, 122.9, 85.5, 82.9, 71.4,
29.0, 27.7, 21.0, 9.8. HRMS (ESI-TOF) m/z for (C13H16O
+ H+) calc 189.1279, found 189.1219.
3+
Fe(H2O)x
+
Ar
O
H
R
Ar
R' = H, Ac
R
R'O
Procedure for Alkyne Hydration
Scheme 3. Plausible catalytic cycle.
The reactions were carried out on a 1-2 mmol scale of
alkyne, as exemplified in the case of compound 4a.
Different conditions for the reactions of alkynes 4b-p and
7b-d are specified in Tables 2 and 3, respectively.
Protonation of the alkyne by hydronium ions or by
FeIII-activated AcOH yields intermediate alcohol or
vinylic ester,[1c,30,39] which undergo rapid tautomeric
rearrangement or hydrolysis to afford the final
hydration product.
m-Methyloctanophenone (5a):[40] Ferric sulfate hydrate (1,
68 mg, 0.125 mmol), glacial acetic acid (2.5 mL) and 1-
methyl-3-(oct-1-yn-1-yl)benzene (4a, 250 mg, 1.25 mmol)
were introduced into a 25 mL round bottom flask,
equipped with a magnetic bar and a water condenser. The
flask was immersed into an oil bath set at 95 °C. The
reaction mixture was left under stirring until consumption
of the substrate (16h), as evidenced by TLC and GC-MS.
Upon cooling, the heterogeneous mixture was filtered
through a Celite pad and rinsed with diethyl ether (20 mL).
The organic solution was washed twice with a saturated
aqueous solution of NaHCO3 (2 10 mL), then with water
and dried over sodium sulfate. After filtration and removal
of solvent under vacuum, the oily residue was filtered
through a short chromatographic column using petroleum
Conclusion
Alkylaryl alkynes are transformed into the
corresponding aryl ketones in presence of the Lewis
acid Fe2(SO4)3nH2O in AcOH. The nature of the
mechanism due to combined acid catalysis under
gentle conditions accounts for the complete
regioselectivity, unattainable by the most active
catalytic systems. Costly transition metals, strong
inorganic acids or halogenated materials are not
involved in the procedure, based on easily available
reagents. Invasive steric hindrance in the substrate
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900633
Advanced Synthesis & Catalysis
ether as eluent to give 218 mg of 5a (light yellow oil, yield
80%). H NMR (300 MHz, CDCl3):  7.79-7.71 (m, 2H),
7.3 Hz, 3H) ppm. 13C {H} NMR (75 MHz, CDCl3): 
199.6, 171.0, 138.4, 136.8, 133.8, 128.5, 128.4, 125.2, 74.9,
34.5, 27.9, 27.2, 21.3, 21.2, 9.6 ppm. GC-MS: (m/z, M+ =
248.14): 205 (M+ – Ac, 30%), 188 (28%), 134 (35%), 119
(100%), 91 (32%), 65 (10%). HRMS (ESI-TOF) m/z for
(C15H20O3 + Na+) calc 271.1310, found 271.1266.
1
7.39-7.30 (m, 2H), 2.94 (t, J = 6.2 Hz, 2H), 2.41(s, 3H),
1.73 (m, 2H), 1.44-1.22 (m, 8H), 0.88 (t, J = 7.0 Hz, 3H)
ppm. 13C NMR (75 MHz, CDCl3):  200.8, 138.3, 137.2,
133.6, 128.6, 128.4, 125.3, 38.7, 31.7, 29.3, 29.1, 24.4,
22.6, 21.3, 14.1 ppm. GC-MS: (m/z, M+ = 218.0): 218
(19%), 147 (12%), 134 (93%), 119 (100%), 91 (12%), 65
(9%).
General Procedure of Competition Experiments
A round bottom 10 mL flask equipped with a water
condenser was charged with two different alkynes (1.0
mmol each), 1.0 mL of acetic acid, salt 1 (28 mg, 0.05
mmol) and a magnetic bar, then immersed in an oil bath set
at 120 °C. The mixture was kept under stirring in air and
the reactions were stopped at different times depending on
the chosen alkyne couple (see Table 5), in order to ensure
detection of both hydration products in presence of
residual substrates. After work-up, as described in the
alkyne hydration procedure, the crude was analyzed by 1H-
NMR (CDCl3) to obtain the signal intensities of the
methylene protons –CH2CO– of each product.
3,3-Dimethyl-1-(2-methylphenyl)butan-1-one (5c): clear
oil, eluent petroleum ether, mg 212 from 240 mg of 4c,
82% yield. H NMR (300 MHz, CDCl3):  7.59-7.51 (m,
1H), 7.38-7.29 (m, 1H), 7.28-7.19 (m, 2H), 2.79 (s, 2H),
2.47 (s, 3H), 1.04 (s, 9H). 13C {H} NMR (75 MHz,
CDCl3
1
125.3, 53.6, 31.5, 29.8, 20.7. GC-MS: (m/z, M+ = 190.0):
190 (7%), 175 (14%), 134 (9%), 119 (100%), 91 (28%), 65
(10%). HRMS (ESI-TOF) m/z for (C13H18O + Na+) calc
213.1255, found 213.1208.
1-(1-Naphthyl)-decan-1-one (5d):[41] clear oil, eluent
petroleum ether, mg 47 from 55 mg of 4d, 81% yield. 1H
NMR (300 MHz, CDCl3):  8.57 (dd, J = 8.4, 0.6 Hz, 1H),
7.96 (d, J = 8.2 Hz, 1H), 7.91-7.82 (m, 2H), 7.63-7.45 (m,
2H), 3.05 (tr, J = 7.4 Hz, 2H), 1.80 (m, 2H), 1.49-1.19 (br
m, 12H), 0.90 (tr, J = 6.7 Hz, 3H). 13C {H} NMR (75
MHz, CDCl3): 204.9, 136.2, 133.8, 132.1, 129.9, 128.2,
127.6, 126.9, 126.2, 125.6, 124.2, 42.2, 31.7, 29.30, 29.29,
29.2, 29.1, 24.6, 22.5, 13.9. HRMS (ESI-TOF) m/z for
(C20H26O + Na+) calc 305.1881, found 305.1908.
Computational Details
The calculations were carried out at the HF/6-311G(d,p)
level of theory by using the Gaussian 09 D1 package with
keyword scf=tight.[42] Harmonic vibrational frequencies
were calculated at the HF/6-311G(d,p) level of theory to
confirm that the stationary points found correspond to local
minima and to obtain the zero-point vibrational energy
(ZPVE) corrections. The solvent effect was taken into
account by using the Polarizable Continuum (PCM)
1-(3-Bromophenyl)-1-octanone
(5h):
oil,
eluent
model.[43] The keyword SCRF=(PCM,SOLVENT
=
petroleum ether/CHCl3 (1:2), mg 115 from 256 mg of 4h,
42% yield. H NMR (300 MHz, CDCl3):  8.07 (s, 1H),
AceticAcid) was used. When, upon protonation of the
alkyne, two different carbocations can be formed, the most
stable was taken into account for the calculation of the
relative proton affinity (PAR).
1
7.86 (d, J = 3.0 Hz, 1H), 7.68-7.65 (m, 1H), 7.33 (m, 1H),
2.92 (t, J = 7.3 Hz, 2H), 1.71 (t, J = 7.1 Hz, 2H), 1.31 (m,
8H), 0.87 (t, J = 6.9 Hz, 3H) ppm. 13C {H} NMR (75 MHz,
CDCl3): 
122.9, 38.6, 31.7, 29.2, 29.1, 24.1, 22.6, 14.0 ppm. GC-
MS: (m/z, M+. = 282.06): 282-284 (9%), 198-200 (100%),
183-185 (83%), 157, 159 (27%), 132 (11%), 76 (13%).
HRMS (ESI-TOF) m/z for (C14H19BrO + K+) calc
321.0256, found 321.0261.
Acknowledgements
The research was performed under the joint project (CNR-
Dipartimento di Chimica)“Sistemi catalitici innovativi per lo
sviluppo di processi sostenibili” and further supported by Fondi
di Ateneo La Sapienza 2016 and 2017.
2,5-Dicyclohexyl-1,4-di-(1-propanone)benzene
yellow solid, eluent chloroform, mg 49 from 82 mg of 4e,
crystallized from MeOH/CH2Cl2, mp = 156 – 162 °C. H
(5e):
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10.1002/adsc.201900633
Advanced Synthesis & Catalysis
FULL PAPER
Iron(III)-Catalyzed Hydration of Unactivated
Internal Alkynes in Weak Acidic Medium,
under Lewis Acid-Assisted Brønsted Acid
Catalysis
R = alkyl
H
R
Ar
Ar
R
O
R
AcO
Ar
Ar
Adv. Synth. Catal. Year, Volume, Page – Page
Ar
R = SiMe3
O
weak acids, full regioselectivity, combined acid catalysis
Achille Antenucci, Piergiorgio Flamini, Marco
Valerio Fornaiolo, Sergio Di Silvio, Sara Mazzetti,
Paolo Mencarelli, Riccardo Salvio, Mauro
Bassetti*
11
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