Serendipitous Observation of Liquid-Phase Size Selectivity inside a Mesoporous Silica Nanoreactor in the Reaction of Chromene with Formic Acid

Article abstract of DOI:10.1002/cctc.201701975

An unprecedented product shape/size selectivity in the hydrolysis/decarboxylation reaction sequences of chromene with formic acid within MCM-41 as a nanoreactor in the liquid phase is observed. Chromene is expected to form pyrimidine in the reaction with

Full text of DOI:10.1002/cctc.201701975

Accepted Article
Title: A Serendipitous Observation of Liquid Phase Size Selectivity
inside Mesoporous Silica Nanoreactor in the Reaction of
Chromene with Formic Acid
Authors: Paramita Das, Suman Ray, Piyali Bhanja, Asim Bhaumik, and
Chhanda Mukhopadhyay
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Link to VoR: http://dx.doi.org/10.1002/cctc.201701975
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10.1002/cctc.201701975
ChemCatChem
1
A Serendipitous Observation of Liquid Phase Size Selectivity
inside Mesoporous Silica Nanoreactor in the Reaction of
Chromene with Formic Acid
Paramita Das,[a] [b] Suman Ray,[a] Piyali Bhanja,[c] Asim Bhaumik,[c] and Chhanda Mukhopadhyay*[a]
Abstract: Unprecedented sharp product shape/size selectivity in the
hydrolysis/decarboxylation reaction sequences of chromene with
formic acid within MCM-41 as nanoreactor in liquid phase is
observed. Chromeneis expected to form pyrimidine in the reaction
with HCOOH. However, here, serendipitously the product switches
oxidations and reductions, hydrogenations and C-C bond-
formation reactions etc.2 This effect stems from (i) selective
ingress of guest molecules inside nanoreactor according to
size/shape of the molecules, (ii) diffusion barrier caused by the
nanoreactor, and (iii) restriction imposed by the nanoreactor on
from pyrimidine to enol lactones and δ-keto acids inside nanoreactor. rotational and translational motions of the included guest
The shape/size selectivity in liquid medium is a highly desired
phenomenon in organic synthesis. We have prepared four different
varieties of porous silica materials to fetch this product selectivity.
Very high yields of these biologically relevant compound surpass the
existing methodologies. Again, though there are few reports of
coumarin-fused enol lactone, this approach enables the easy
synthesis of naphthalene-fused enol lactones which is rarely
reported. Moreover, this is the first generalized synthesis of δ-keto
molecules and intermediates or products.3 Both the effects
depend on size and shape of the molecules accommodated
inside nanoreactor. Owing to the impact of nanoreactor on
product selectivities, the efficacious design of nanoreactors may
provide efficient tools for performing organic reactions in a
selective and very competent way. Again, the mesoporous
materials provide a size/shape and functional group selective
microenvironment that allows encapsulation of guest molecules
for confined synthesis and catalysis.4 In this context, ordered
mesoporous silicas5-10 having highly ordered pore structures,
high specific surface area, tunable morphology, and high
thermal stability have enthused significant research efforts in
shape-selective heterogeneous catalysis.11 The pores that
control the transport pathways act as a diffusion barrier to
reactants and products and consequently impact on the product
selectivity. The morphological features of silica have been
known to influence the hydrocarbon selectivity in Fischer-
Tropsch synthesis.12 For example, SBA-15 with large pore
diameter (6-10 nm) was reported to have heavy hydrocarbon
acids following
a
number of hydrolysis/decarboxylation/ring
opening/tautomerization/decarboxylation steps.
Introduction
Selectivity in organic synthesis continues to be one of the key
concerns of the synthetic chemists. Of the various strategies
employed, the use of nanoreactors to control the product
selectivity has shown significant prospects.1 Two main types of
selectivities are frequently practiced in the design of
nanoreactors, either the preferential formation of a particular
molecule among two or more possible products or the
preference for one of the stereoisomers.2 The term nanoreactor
selectivity
whereas
short-pore
SBA-15
has
C5+
selectivity.12,13 Chen et al. have recently reported the shape
selectivity of a Suzuki cross-coupling reaction using mesopores
Pd on mesoporous silica as nanoreactors in liquid
medium.3 Furthermore, in heterogeneous asymmetric catalysis,
the effect of pore confinement on improving enantoselectivity
has been studied.14 Despite this breakthrough, achieving
size/shape selectivity in liquid phase in organic synthesis using
nanoreactor is an appealing approach and a fascinating theme.
In this study, we observed unprecedented sharp product
shape/size selectivity in the reaction of chromene with formic
acid within the mesoporous pores of MCM-41 nanoreactor and it
occurred in liquid phase.
indicates
a constrained and organized space where the
chemical reactions occur. It is previously demonstrated that
organic photochemical reactions inside nanoreactors show
deviance in product distribution and follow reaction pathways
that are not otherwise seen.1 Selectivities in organic synthesis
has been achieved inside nanoreactors in different organic
transformations including but not limited to chemoselective
[a]
[b]
[c]
P.Das, S. Ray, C.Mukhopadhyay
Department of Chemistry, University of Calcutta,
92, APC Road, Kolkata-700009, India.
*Tel: +91-9433019610; *Email: cmukhop@yahoo.co.in
P. Das
“The design of chemical products and processes that reduce or
eliminate the use or generation of hazardous substances”
fosters the principle and practice of sustainable chemistry, as
defined by U.S. Environmental Protection Agency (EPA).15,16
The most pivotal area of chemistry dealing with the
development of medicinally and pharmaceutically relevant
molecules, with their traditionally large volume of waste/product
ratio, is perhaps most ripe for sustainability.17 In addition, it is
possible to apply the tenets of sustainability to the generation of
biologically interesting products using aqueous medium
approaches. Therefore, development of synthetically useful,
elegant and convergent reactions in water is appealing to an
environmentally cognizant society. Again “Organocatalysis” has
Asutosh College
Department of Chemistry
92, S. P. Mukherjee Road, Kolkata-700026, India
A. Bhaumik, P.Bhanja
Department of Materials Science,
Indian Association for the Cultivation of Science, Jadavpur,
Kolkata-700032, India
Supporting information for this article is given via a link at the end of
the document (CCDC: 1408025, 1408026, 1407896,
1407897,1407898, and 1408296).
This article is protected by copyright. All rights reserved.

10.1002/cctc.201701975
ChemCatChem
2
emerged during the last decade as one of the major issues in Results and Discussion
the development of catalytic chemical technology because of its
suntanibility perspectives and analogy to eon-perfected enzyme
catalysis.18 Organocatalytic methods are especially attractive for
the preparation of compounds that must not tolerate metal
Characterization of Silica
We have prepared four different varieties of porous silica
materials namely large pore MCM-41 (LP-MCM-41),
microporous silica nano particle (Micro-SNP), small pore MCM-
41 (SP-MCM-41) and mesoporous silica nano particle (Meso-
SNP). Among them small pore MCM-41 (SP-MCM-41)
andmesoporous silica nano particle (Meso-SNP) worked
efficiently as a size selective reaction vessel for preferential
formation of enol lactones instead of pyrimidine in the reaction of
chromene with HCOOH. The characterizations of these two
materials are given below. Characterizations of the other two
materials are presented in Supporting Information I.
contamination,
such
as
pharmaceutically
relevant
molecules.19 Thus, the challenge of developing efficient
aqueous-phase organocatalytic processes has been posed.20
O
O
C7H15_n
O
n_C7H15
O
O
O
O
O
O
MeO
O
O
O
O
OH
frutinone A
fordianin A
HO
norneolambertellin
O
n_C7H15
O
OH
n-H15C7
O
O
HO
Nitrogen adsorption analysis.
O
MeO
MeO
MeO
O
O
O
Nitrogen adsorption analysis has been carried out using a
Quantachrome Autosorb 1-C surface area analyzer at 77 K after
outgassing the samples at 130 °C under high vacuum. Figure 2a
represents the N2 adsorption-desorption isotherm of SP-MCM-
41 which is classified as typical type IV isotherm with H4
hysteresis loop according to IUPAC nomenclature. In Figure 2a,
the capillary condensation at a relatively low partial pressure
(P/P0) region of 0.05 to 0.23 of nitrogen, indicates the presence
of small mesopores.36 The material exhibits H4 hysteresis loop
at high pressure region 0.46-0.98 bar, suggesting the existence
of uniform large pore size throughout the whole material. The
BET (Brunauer-Emmett-Teller) surface area of SP-MCM-41 was
found to be 833 m2g-1. For Meso-SNP irreversible type IV
adsorption isotherm with H1 hysteresis loop are observed, that
is a typical characteristic of mesoporous materials (Figure 2c).
BET Surface area was calculated to be 556 m2g-1. This is a
reasonably high value and also a characteristic feature of MCM-
41 type silica materials. The pore volume of SP-MCM-41 and
Meso-SNP were 0.386 ccg-1 and 0.52 ccg-1 respectively.
arisugacin A
fordianin B
Figure 1. Significant examples of biologically active enol lactones.
Naturally occurring biologically active molecules are outstanding
source of lead compounds in drug disocovery.21 Enol lactones,
such as the derivatives of coumarin,22 flavonoids,23 and
neoflavonoids,24 comprise ubiquitous structural motifs in a
number of biologically active natural products.25 In particular,
annulated enol lactones exhibit outstanding natural and
biological activities. For instance, frutinone A has antibacterial
and antioxidant activity,26 fordianin A and fordianin B have
cytotoxicity against A549 (human lung cancer) and human
cervical carcinoma,27 norneolambertellin functions as an
antifungal,28 coumestrol acts as an anti-breast cancer27,29 and
Arisugacin
A possesses significance in the treatment of
Alzheimer's disease30 (Figure 1).
However, despite the importance of these compounds in the
field of medicine, unexpectedly, there are only few novel reports
available in the literature documenting the synthesis of enol
31
lactones. Moreover, some of the experimental conditions have
not been optimized on the sustainability point of views. The
most effective access to these class of compounds, so far
reported, is the condensation reactions of isopropylidene
malonate with aromatic aldehydes followed by the Michael
32
addition of dimedone and/or 4-hydroxycoumarin. Moreover,
they suffer from the use of a limited number of C-H-activated
acids, mainly, activated 1,3-diketo systems. Reports with
unactivated α- and β-naphthol to produce naphthalene-fused
enol lactones are even rarer,33 which is far from the demand of
diversity-oriented target synthesis. This may be due to the
absence of a convenient protocol for preparing naphthalene-
fused enol lactones. Kanemasa34 and Biju35 independently
reported convenient and elegant approach towards enol
lactones. Despite this advance, metal-free reaction in
environmentally benign solvent using simplest catalyst and
starting material is an attractive approach.
Figure 2. (a) N2 adsorption isotherm and (b) pore size distribution of SP-MCM-
41; (c) N2 adsorption isotherm and (d) pore size distribution of Meso-SNP.
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10.1002/cctc.201701975
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Non-Local Density Functional Theory (NLDFT) method was
used to estimate the pore size distribution plots of SP-MCM-41
and Meso-SNP, shown in Figure 2b and 2d respectively. A
sharp peak is observed in the PSD of SP-MCM-41 indicating
uniform mesopores having dimension of 3.0 nm. This data
matches well with the value obtained from UHR TEM analysis of
the sample. Whereas for Meso-SNP, the pore size distribution is
little broad with peak pore diameter of 2.6 nm.
The small angle powder X-ray diffraction pattern of SP-MCM-41
is shown in Figure 5a. As seen from the figure, SP-MCM-41
material displays three characteristic diffraction peaks centered
at 2θ values of 2.4, 4.2 and 4.8° which can be attributed for the
distinct planes i.e.,100 (strong), 110 (weak), and 200 (weak)
reflections. This implies the presence of two dimensional
hexagonal mesopores.37 However, in the small angle powder
XRD pattern of Meso-SNP only a single peak is observed
(Figure 5b). The d spacing calculated using Bragg's equation
depicts the value as 3.08 nm which is in close agreement with
the individual UHR-TEM analysis.
UHR-TEM analysis
Representative UHR-TEM images of SP-MCM-41 are shown in
Figure 3a-b. In Figure 3b, regularly arranged ordered hexagonal
pores which are perpendicular to the pore axis with a dimension
of ~2.8 nm are clearly observed. This indicates the existence of
mesoporosity in the SP-MCM-41 material. The FFT (Fast Fourier
Transform pattern) given in the inset of Figure 3b, represents the
highly ordered hexagonal array of the material.
Figure 5. Small angle XRD pattern of SP-MCM-41 (a); and Meso-SNP (b).
Synthetic application of nanoreactor
In our recent paper we have reported experimentally and
environmentally convenient approach towards the library
synthesis of 88 different chromene compounds using
38
heterogeneous ZnFe2O4 nano-powder in water. Consequently,
Figure 3. UHR-TEM images of SP-MCM-41 (a, b).
our long-term quest was directed at exploring further application
of the pyrano-chromene and benzo-chromene systems. Since
the pyrimidine ring is an integral part of various natural products
of therapeutic importance,39 we therefore, first refluxed the
Again, the UHR-TEM image analysis of Meso-SNP reveals that
this mesoporous silica material is composed of uniform spheres
having dimension of around 800 nm (Figure 4a-b). In these
figures low electron density spots (pores) are seen throughout
the specimen, and pores of dimensions ca. 2.6 nm are observed.
chromenes with excess HCOOH to afford pyrimidine as stated in
39a,b
literature.
But to our surprise, along with the expected
pyrimidine, a trace amount of an unanticipated product was also
formed ( Scheme 1). Albeit, the 1H NMR spectrum of the
unexpected molecule was very simple, we could not
unambiguously determine the structure only from NMR
spectroscopy. Finally, the formation of the unanticipated enol-
lactones
through
an
unexpected
triple
hydrolysis/decarboxylation cascades were confirmed from X-ray
single crystal analyses. Hence, we comprehended that this
would be a new chemistry, and if the reaction conditions could
be optimized, a novel strategy for the synthesis of enol lactones
would be established.
Optimization of Reaction Conditions
Figure 4. UHR-TEM images of Meso-SNP (a, b).
Since our group is actively working for long on silica based
heterogeneous catalyst40 for greener reaction protocols and
stimulated by our previous experience regarding switchable shift
in product selectivity inside the silica meso/nano pores while
using the same precursor, we decided to use the porous silica
as a size selective nanoreactor.40a We anticipated that if the
X-ray diffraction analysis
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10.1002/cctc.201701975
ChemCatChem
4
(temperature, solvent etc.) for the formation of enol lactones
using the previously optimized nanoreactor, SP-MCM-41 (Table
1, entry 5). Gratifyingly, by decreasing the quantity of HCOOH
from excess to 10 mol%, boosted up the yield from 55% to 84%
since pyrimidine formation is greatly prevented (Table 1, entry
6). Temperature dependence on the yield of enol lactone (2f) to
the pyrimidine (P) was probed with the same test reaction with
10 mol% of catalyst HCOOH, SP-MCM-41 as nanoreactor (40
mg) in H2O. The reaction performed best when the temperature
is 80 °C ( Table 1, entry 7). However, the reaction did not
proceed at 70 °C (Table 1, entry 8). Again, in absence of silica,
neither the enol lactone nor the pyrimidine derivative was formed
at 80 °C even in presence of excess HCOOH (Table 1, entry 9).
This essentially reflects the role of confined space inside the
silica mesopore in endorsing such reactions at a relatively lower
temperature. Screening of the reaction conditions further
established that the yield decreased substantially with stronger
inorganic acids as they required recurrent work-up procedures,
neutralization steps and extensive chromatographic purification
(Table 1, entries 10-14). However, relatively weaker acids
afforded better yield because of their less extensive work-up
(Table 1, entries 7, 15-18). Therefore, we found that HCOOH is
the most efficient catalyst for this reaction among all the
screened Brønsted acids. The reaction was unsuccessful in
common organic solvents like DMSO, toluene, ACN, EtOH,
acetone and DCM which verified that water was indispensable
for this transformation and 80 °C as the most effective reaction
temperature (Table 1, entries 7). We conducted the reaction in
presence of varied amount of SP-MCM-41 from 40 mg to 5 mg
keeping the reaction time unaltered (Table 1, entries 7, 20-22).
Since at 80 °C pyrimidine formation is totally stopped, so if we
decrease the amount of silica from 40 mg to 5 mg only the yields
of enol-lactone gradually decreases (93%–19%) if the reaction
time is fixed. Therefore, 40 mg SP-MCM-41 was optimum
amount since increasing amount to more than 40 mg did not
improve the yield of enol-lactone. The enol-lactone can also be
afforded with porous alumina, however in comparatively less
yield than SP-MCM-41 (Table 1, entry 23). Thus, the reaction
parameters given in Table 1, entry 7, were the optimal reaction
conditions. Diminishing the amount of HCOOH loading below 10
mol% resulted in incomplete conversion with decreased yield
(Table 1, entry 19).
Scheme 1. The possible products formed in the reaction between chromenes
and HCOOH.
reaction is performed in water, the hydrophobic organic
chromene compounds will preferably enter the channels of silica
since the environment inside the pores are little less hydrophilic
than the sea of water outside the pores and the reaction will
ensue inside the pores. Accordingly, depending on the size of
pores one particular transition state or product will be favored
because of the constraint imposed by the silica wall. To
authenticate this proposition, a series of experiments were
conducted with
a representative reaction of 2-amino-4-(4-
nitrophenyl)-5-oxo-4H,5H-pyrano[3,2-c]chromene-3-carbonitrile
(1f) in presence of four different porous silica materials with
varied pore diameter, pore volume and surface area (Table 1).
The chromene derivative (1f) was first refluxed with excess of
HCOOH in water at 100 °C in presence of large pore MCM-41
(LP-MCM-41) with pore diameter 3.56 nm and pore volume 1.79
ccg-1. Disappointingly, we isolated the pyrimidine compound (P)
as the exclusive product ( Table 1, entry 2). Therefore, we
assumed that large pore silica as reaction vessel could not
impose any product selectivity by preferentially stabilizing one
particular transient state or product. Keeping this in mind we
next prepared microporous silica (Micro-SNP) with pore
diameter 1.0-1.2 nm and pore volume 0.65 ccg-1 instead of
mesoporous silica with large pore diameter. Yet again we
isolated only the pyrimidine compound ( Table 1, entry 3). We
understood that in this instance, the reaction might have taken
place at the external surface of the particles, since ingress of
starting materials was not possible through these small pores
thereby, giving no product selectivity. Subsequently, we thought
of venturing silica having pore diameter in-between the two
extremes. We thus, prepared spherical mesoporous silica nano-
particles (Meso-SNP) of around 800 nm size having pore
diameter 2.6 nm with pore volume of 0.52 ccg-1 by adopting
different synthetic procedure than used for previously mentioned
silica materials. Remarkably, on refluxing 1f with excess
HCOOH in presence of Meso-SNP, enol-lactone ( 2f) was
obtained in (51%) yield (Table 1, entry 4). Being enthued by this
consequence, we next prepared another variety of small pore
MCM-41 (SP-MCM-41) with pore diameter 3.0 nm and pore
volume 0.39 ccg-1 by fine tuning the synthetic parameters like
temperature, ratio of surfactant to tetraethylorthosilicate (TEOS)
concentrations, pH of the medium etc. to check the effect on
product yield on further decreasing the pore volume. However,
yield increased only marginally (55%) with this new variation of
silica (Table 1, entry 5). This puts a termination to our search for
ideal silica material as nanoreactor. Invigorated by this success,
we next attempted to screen the other reaction parameters
Origin of selectivity
We next turned our attention to find the root why enol lactone is
being formed instead of pyrimidine when the reaction is carried
out in presence of mesoporous silica. We therefore, primarily
wanted to confirm that the reaction is taking place inside the
silica pores. To verify this proposition, when chromene with
bulkier aromatic group (Ar) like α-naphthalene (1j), β-
naphthalene (1k) or pyrene derivatives (1l) were used, the
relative reaction rate decreased, as evident from the time
required for the reaction to reach the completion (12 h, 12 h and
16 h respectively; Scheme 2). Therefore, this size-dependent
reaction rate provides indirect evidence for the involvement of
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10.1002/cctc.201701975
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Table 1. Screening of Reaction Conditions.a
O
NH2
N
NH
CN
O
O
O
O
O
O
Conditions
+
O
NO2
O
O
NO2
O
NO2
(P)
(2f)
(1f)
Entry
Type of silica
(40 mg)
Textural properties
Catalyst(mol %)
Temp. (°C)
%YieldbP
%Yieldb2f
SA(m2g-1)
─
Dp(nm)
─
Vp(ccg-1)
─
1
2
─
HCOOH(excess)
HCOOH(excess)
HCOOH(excess)
HCOOH(excess)
HCOOH(excess)
HCOOH(10)
HCOOH(10)
HCOOH(10)
HCOOH(excess)
HClO4 (10)
100
100
100
100
100
100
80
>90
>90
>90
45
42
13
trace
─
<10
<10
<10
51
55
84
93
─
LP-MCM-41
Micro-SNP
Meso-SNP
SP-MCM-41
SP-MCM-41
SP-MCM-41
SP-MCM-41
─
1057
739
556
833
833
833
833
─
3.56
1.0
2.61
3.0
3.0
3.0
3.0
─
1.79
0.65
0.52
0.39
0.39
0.39
0.39
─
3
4
5
6
7
8
70
9
80
─
─
10
11
12
13
14
15
16
17
18
19
20
21
22
23
SP-MCM-41
SP-MCM-41
SP-MCM-41
SP-MCM-41
SP-MCM-41
SP-MCM-41
SP-MCM-41
SP-MCM-41
SP-MCM-41
SP-MCM-41
833
833
833
833
833
833
833
833
833
833
833
833
833
279
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
4.94
0.39
0.39
0.39
0.39
0.39
0.39
0.39
0.39
0.39
0.39
0.39
0.39
0.39
0.29
80
─
25
27
32
19
22
45
41
64
79
70
65
41
19
76
HCl (10)
80
─
H2SO4 (10)
80
─
HNO3 (10)
80
─
H3PO4 (10)
80
─
Lactic (10)
80
─
Ascorbic (10)
PhCOOH (10)
AcOH (10)
80
─
80
─
80
─
HCOOH (5)
100
80
trace
─
SP-MCM-41 (20 mg)
SP-MCM-41 (10 mg)
SP-MCM-41 (5 mg)
Meso-Al2O3 (40 mg)
HCOOH (10)
HCOOH (10)
HCOOH (10)
HCOOH (10)
80
─
80
─
80
─
aReaction conditions: 1f (1 mmol), silica (40 mg), water (5 mL), time (6 h).
bIsolated yields.
the cavity of mesoporous silica. Again, the formation of enol
lactones at a relatively low temperature (80 °C) in presence of
silica, indicates that the silica meso channel is facilitating the
reaction probably by confinement effect. This defines the
significance of the confined cavity in promoting such reactions in
aqueous media at a relatively low temperature. This proposition
is further validated by the non-formation of any enol lactones
when the reaction was carried out in presence of non-porous
silica at 80 °C probably due to the absence of confinement effect,
because, in the case of non-porous materials, the reaction takes
place at the external surface of the particles. These facts
together with the previously discussed phenomenon of pore size
dependent product selectivity reinforce the involvement of silica
pores in this reaction. Grounded on these results, we
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10.1002/cctc.201701975
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6
bIsolated yields.
hypothesized that in case of formation of pyrimidine, the size of
the parent chromenes is further increased since one additional
ring is formed. However, in case of silica with medium pore size
this pathway (pyrimidine formation) is highly prohibited due to
the constraint imposed by nanoreactor on rotational and
translational motions of the products/intermediates aiding the
other pathway to afford the enol lactones having size
comparable to the parent chromenes. This may be the reason of
Substrate Scope for the Synthesis of Enol Lactones
Having obtained the optimized reaction conditions, the scope of
the reaction was subsequently investigated, and the
representative results are summarized in Scheme 2. Regardless
of the electronic nature and the position of substituent on the
aromatic ring (Ar) the reaction afforded the corresponding enol
lactones in good to excellent yields. When Ar (aromatic) is
replaced by R ( aliphatic) the reaction was still successful,
however, showed a modest decline in yield. It was pleasing to
find that cyanide moiety on the aromatic ring was not affected
under the present HCOOH mediated hydrolysis condition.
Despite the mild conditions, even sterically bulky 1-naphthyl, 2-
naphthyl aldehydes and 1-pyrenealdehyde were easily
transformed into the desired products in moderate yields.
However, the relative reaction rate was decreased with bulkier
aldehydes as evident from the reaction completion time.
Moreover, much to our satisfaction, the present protocol is mild
enough to sustain both the lactone rings in the product as well
as acid-sensitive functional groups. In order to guarantee a high
flexibility of substitution patterns we addressed the synthesis of
enol lactones from α- and ß-naphthol-4H-pyrans (Scheme 3).
The structures of enol lactones were confirmed unambiguously
from X-ray single crystal analysis of four distinct compounds 4j,
4l, 4t, 4u. ORTEP plots of 4j (CCDC 1408025), 4l (CCDC
1408026), 4t ( CCDC 1407896) and 4u (CCDC 1407897) are
given in Figure 6. The scope of this reaction was subsequently
extended to bis enol lactone systems (Scheme 4).
product selectivity inside nanoreactor.
The diffusion barrier
caused by the nanoreactor pores also influences the product
and thus also impact product selectivity. These also explicate
why silica with very large and very small pore volume and pore
diameter could not impart any selectivity for enol lactones.
Effect of heat treatment of silica on product selectivity
Another indirect proof which can support the involvement of
silica pore in the reaction and validate the proposed hypothesis
is the observed effect of heat treatment of silica on product
selectivity. When the silica materials were washed with HCl to
remove the TEOS and used as nanoreactor prior to heat
treatment, they could not show any selectivity for enol lactones.
However, after heating at 600 °C for 8 hours, we reached the
above mentioned selectivity for enol lactones. Prior to the heat
treatment because of presence of more number of silanol
groups, the silica cavity was not sufficiently hydrophobic to
promote the reaction preferentially inside the silica pores leaving
no selectivity for enol lactones. But after heating it at 600 °C for
8 hours, removal of water from adjacent silanol groups makes
the silica pores comparatively more hydrophobic for the organic
molecules to enter inside and the reaction to occur favorably
inside pores. Therefore, reaction inside pores bestows special
selectivity for enol lactones. In Table 2, the effect of heat
treatment time on product selectivity is presented which shows
that with increasing heat treatment time the selectivity for enol-
lactone increases. This may be because of greater extent of
silanol condensation and thereby, a decrease in the
NH2
O
HCOOH (10 mol%)
SP-MCM-41 (40 mg)
CN
Ar
O
O
Ar
H2O
80 °C, 6 h.
O
(1)
O
O
(2)
O
O
O
O
hydrophilicity inside silica pores promoting the organic
molecules to diffuse inside the nanoreactor for size selective
catalysis .
O
O
O
Br
O
H
H
H
NO2
Br
O
O
O
O
O
2b (91 %)
O
2a (90 %)
O
2c (92 %)
O
Table 2. Effect of heat treatment on enol-lactone selectivity.a
O
O
H
O
H
O
NH2
N
NH
H
SP-MCM-41
(40 mg)
CN
O
O
O
O
O
O
HCOOH
(10 mol%)
H2O
O
O
NO2
O
O
Cl
O
O
CN
+
2f (93 %)
2e (87 %)
O
2d (91 %)
O
O
NO2
O
(1f)
O
NO2
O
NO2
O
(P)
(2f)
%YieldbP
%Yieldb2f
O
H
O
H
O
Entry
Time (h)
H
1
2
3
4
5
0
2
4
6
8
90
70
46
23
11
<10
26
N
O
O
OCH3
O
O
O
O
2h (81 %)
O
2i (78 %)
O
2g (89 %)
O
O
H
O
O
O
49
H
H
72
O
O
O
O
O
2l (71 %)c
85
2k (77 %)b
2j (75 %)b
aReaction conditions: 1f ( 1 mmol), water ( 5 mL), time (6 h), temperature
(100 °C), reaction performed with SP-MCM-41 (40 mg) pre-heated at 600 °C
for different time.
a
Reaction conditions: Pyran 1 (1 mmol), SP-MCM-41 (40 mg)
and 10 mol% HCOOH catalyst in water (5 mL) was heated at 80
°C for 6 h. btime: 12 h. ctime: 16 h. d Isolated yields.
This article is protected by copyright. All rights reserved.

10.1002/cctc.201701975
ChemCatChem
7
Scheme 2. One-pot Synthesis of Enol Lactones.
Scheme 3. Substrate Scope of Enol Lactones.
O
O
O
O
O
O
O
H
O
NO2
O
Cl
O
O
Br
H
H
H
H
O
O
O
H
H
O
O
O
O
H
H
4c (89 %)
O
4b (91%)
O
4a (89 %)
O
6a (89 %)
6b (85 %)
6c (88 %)
O
O
O
H
H
H
a
Br
NO2
Reaction conditions: Pyran 5(1 mmol), SP-MCM-41(40 mg)
and 10 mol% HCOOH catalyst in water (5 mL) was heated at 80
NO2
b
4d (88 %)
O
4e (88 %)
4f (92 %)
°C for 8 h. Isolated yields.
O
O
O
O
O
Scheme 4. Synthesis of bis Enol Lactones.
H
H
H
CN
Cl
Br
4g (92 %)
O
4i (90 %)
O
4h (88 %)
O
(b)
(d)
(a)
(c)
O
O
O
H
H
H
OCH3
OCH3
OCH3
CH3
4j (93 %)
O
4k (90 %)
4l (87 %)
Br
H
NO2
H
H
O
O
O
O
OCH3
O
Br
H
O
O
O
4m (85 %)
H
4o (90 %)
H
OCH3
Br
4n (91 %)
4p (92 %)
H
Cl
O
H3C
O2N
H
O
O
O
O
O
O
4t (90 %)
4r (91 %)
4s (92 %)
4q (93 %)
MeO
Figure 6. ORTEP representation of (a) 4j (CCDC 1408025), (b) 4l (CCDC
1408026), (c) 4t ( CCDC 1407896) and (d) 4u (CCDC 1407897) ( thermal
ellipsoids at 50% probability in all cases).
OMe
N
O
H
H
H
O
O
O
O
O
Synthesis of δ-keto acids
4u (88 %)
4v (84 %)
4w (79 %)
a
Reaction conditions: Pyran 3 (1 mmol), SP-MCM-41 (40 mg)
and 10 mol% HCOOH catalyst in water (5 mL) was heated at 80
°C for 6 h. bIsolated yields.
Based on the above promising results, we thought to further
extend the reaction time to monitor any change in the nature of
the product. Inspiringly when continued the reaction of 1 with
HCOOH for 20 h, we observed an unprecedented reactivity that
provided
hydrolysis/decarboxylation/double
opening/tautomerization/decarboxylation
the
δ-keto
acids
(7)
hydrolysis/double
cascades,
through
triple
ring
thus
unfolding an unrecognized opportunity for their synthesis. Upon
the observation of the serendipitous reaction sequences, we
shout that this is the first generalized report for the synthesis of
δ-keto acids (Scheme 5).
Till date no general scheme for their synthesis has been
reported and only a few isolated examples are available as side
41
products. It further demands to be the simplest approach to be
This article is protected by copyright. All rights reserved.

10.1002/cctc.201701975
ChemCatChem
8
adopted by the scientific community. The final structure of
compound 7f was confirmed by X-ray crystallographic analysis
(CCDC 1407898) (Figure 7).
NMR Study to Monitor Time-Dependent Conversion of Enol
Lactone to δ-Keto Acid
The time-dependent conversion of enol lactone (2b) to δ-keto
NH2
1
acid (7e) was carefully monitored by taking H NMR spectra of
HCOOH (10 mol%)
SP-MCM-41 (40 mg)
CN
Ar
1
O
O
Ar
crude reaction mixture. The H NMR spectra taken at 6, 9, 12,
γ
α
δ
β
15 and 20 h showed that the integration of benzylic C-H peak of
enol lactone (Figure 8, red dot) gradually diminished and that of
-OH peak of δ-keto acid gradually intensified (Figure 10, blue
star) in the crude 1H NMR spectra.
H2O, 80 °C, 20 h.
COOH
O
(1)
O
OH
(7)
NO2
Cl
Br
O
O
H
O
H
H
COOH
COOH
COOH
OH
OH 7b (92 %)
Br
7c (90%)
NO2
OH
7a (94 %)
CN
O
O
H
O
H
H
COOH
COOH
COOH
OH 7f (92 %)
OCH3
OH 7e (91 %)
OCH3
7d (91 %)
OH
OH
OCH3
O
O
H
O
H
H
COOH
COOH
COOH
OH
O
OH
OH 7i (88 %)
7h (90 %)
N
7g (89 %)
Br
H
O
O
H
H
COOH
COOH
COOH
OH
7k (88 %)
OH
OH
7j (91 %)
7l (78 %)
O
O
O
H
H
H
COOH
COOH
COOH
OH 7m (74 %)b
OH 7o (70 %)c
OH 7n (75 %)b
a
Reaction conditions: Pyran 1 (1 mmol), SP-MCM-41 (40 mg)
and 10 mol% HCOOH catalyst in water (5 mL) was heated at 80
b
c
d
°C for 20 h. time:30 h. time:42 h. Isolated yields.
Scheme 5. Synthesis of δ-keto acids.
Figure 8. 1H NMR monitoring of the conversion of lactone (2b) (red ball) to δ-
keto acid (7e) (blue star).
Control Experiment
Unlike compound 1 in case of compound 3 even after 48 h, no
ring opened product (8) was formed (Scheme 6). In case of
pyran (1) the conversion from enol lactone (2) to δ-keto acid (7)
goes via ß-keto acid (D) ( Scheme 7) which is easily
decarboxylated and subsequently converted to δ-keto acid.
However, in case of pyran 3 to acribe the non-formation of (8),
we heated the reaction mixture at 80 °C with piperadine and
isolated the compound 9. The interpretation of the above results
Figure 7. ORTEP Representation of 7f (CCDC 1407898) (thermal ellipsoids at
50% probability).
indicates that in
8
the carboxylic acid is not easily
decarboxylated and it prefers to stay as stable 6-membered
This article is protected by copyright. All rights reserved.

10.1002/cctc.201701975
ChemCatChem
9
lactone. When piperidine is added the equilibrium is shifted
towards right since the free carboxylic acid forms amide
resulting compound 9. The formation of compound 9 was
unambiguously confirmed by X-ray crystal structure (CCDC
1408296) (Scheme 6).
reaction occurs inside the pores of MCM-41 nanoreactor, the
product switches from pyrimidine to enol lactones and δ-keto
acids. In case of formation of pyrimidine the size of the parent
chromenes is further increased since one additional ring is
formed. Inside the silica pore, this pathway is highly prohibited
due to the constraint imposed by nanoreactor on rotational and
translational motions of the products/intermediates aiding the
other pathway to afford the enol lactones having size
comparable to the parent chromenes. This may be the reason of
product selectivity inside nanoreactor.
The diffusion barrier
caused by the nanoreactor pores also influences the product
egress and thus also impact product selectivity. The shape/size
selectivity in liquid medium is a much desired effect. Moreover,
this
is
a
new
mild
and
metal-free
tandem
hydrolysis/decarboxylation methodology that can override the
existing procedures and subsequently persuade synthetic
applications of pyrano-chromene and benzo-chromene in
organic chemistry towards the synthesis of biologically relevant
coumarin and naphthalene-fused enol lactones. The reaction
described here is a rare successful example of enol lactones
synthesis in water. Further, the present protocol is mild enough
to sustain both the lactone rings in the product as well as acid-
sensitive functional groups. More importantly, the import of these
discoveries extends beyond simply providing a new synthetic
strategy for enol lactones. Finally, we observed an
unprecedented reactivity that provide the δ-keto acids through
Scheme 6. Control Experiment.
Plausible mechanism
A
plausible synthetic mechanistic route, underpinning the
an
intramolecular
tandem
hydrolysis/double
triple
ring
formation of enol lactones and δ-keto acids is depicted in
Scheme 7. Our approach could comprise the relay processes of
the following domino sequences: three sequential hydrolyses,
followed by decarboxylation to form enol lactone (2). This enol
lactone undergoes double hydrolysis followed by ring opening of
hydrolysis/decarboxylation/double
opening/tautomerization/decarboxylation, thus unfolding an
unrecognized opportunity for their synthesis. This is the first
generalized report for the synthesis of δ-keto acids. We hope
that these reactions will find use outside the academic
environment for the synthesis of medicinally important molecular
structures.
dual lactone ring to form intermediate D.
D
endures
tautomerization and finally decarboxylation to form δ-keto acid
(7). Notably, this is the first report of tandem triple
hydrolysis/decarboxylation/double hydrolysis and double ring
opening/tautomerization/decarboxylation to afford δ-keto acids.
Acknowledgements
O
O
NH2
NH2
We would also like to thank CAS-V (UGC), DST-FIST and DST-
PURSE, Department of Chemistry, University of Calcutta, for
funding as departmental projects.
CN
Ar
C
O
CN
Ar
O
O
O
Hydrolysis
Hydrolysis
Ar
O
(A)
O
O
O
O
(1)
O
(B)
Hydrolysis
Keywords: mesoporous silica nanoreactor, size/shape
selectivity, cascade reaction, enol lactones, δ-keto acids
O
O
OH
C
O
OH Ar
O
O
O
Double Hydrolysis
and Double
Decarboxylation
Ar
Ar
CO2H CO2H
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O
O
O
OH
(D)
(C)
Enol Lactone (2)
Tautomerization
Ar
O
Ar
O
Decarboxylation
γ
α
β
δ
COOH
CO2H CO2H
OH
OH
δ -Keto Acid (7)
(E)
Scheme 7. Plausible Reaction Pathway.
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shape selectivity in the hydrolysis/decarboxylation reaction
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Y. Ji, W. G. Song, Y. Luo, J. Phys. Chem.
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FULL PAPER
Unprecedented sharp product
Paramita Das, Suman Ray,
Piyali Bhanja, Asim Bhaumik,
Chhanda Mukhopadhyay*
shape
selectivity
in
the
hydrolysis/decarboxylation
reaction sequences of chromene
with formic acid within MCM-41
as nanoreactor in liquid phase
affording enol lactones and δ-
keto acids.
Page No. – Page No.
A Serendipitous Observation
of Liquid Phase Size
Selectivity inside
Mesoporous Silica
Nanoreactor in the Reaction
of Chromene with Formic
Acid
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Author(s), Corresponding Author(s)*
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Title
Text for Table of Contents
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