Beyond acid strength in zeolites: Soft framework counteranions for stabilization of carbocations on zeolites and its implication in organic synthesis

Article abstract of DOI:10.1002/anie.201500864

The generation of a carbocation with an acid depends not only on the acid strength but also on the ability of the counteranion to stabilize the positive charge left behind. Here we report that despite their relatively weak acidity, zeolites are able to ge

Full text of DOI:10.1002/anie.201500864

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201500864
German Edition: DOI: 10.1002/ange.201500864
Heterogeneous Catalysis
Beyond Acid Strength in Zeolites: Soft Framework Counteranions for
Stabilization of Carbocations on Zeolites and Its Implication in Organic
Synthesis**
Jose R. Cabrero-Antonino, Antonio Leyva-Pꢀrez,* and Avelino Corma*
Abstract: The generation of a carbocation with an acid
depends not only on the acid strength but also on the ability
of the counteranion to stabilize the positive charge left behind.
Here we report that despite their relatively weak acidity,
zeolites are able to generate and stabilize medium-size
(molecular weight ꢀ 300 Da) delocalized carbocations on
their surface under mild reaction conditions, as it can be
done by strong Brønsted or Lewis acids in solution. The zeolite
thus acts as a soft macroanion, prolonging the lifetime of the
carbocation sufficiently to perform multifunctionalization
reactions with amides, thioamides, and phenols, with high
yield and selectivity. Biological studies show that some of the
products obtained here present significant inhibition activity
against colon cancer cells, illustrating the new possibilities of
zeolites to prepare complex organic molecules.
processes for medium-size molecules with molecular weights
> 300 Da is still limited due to pore size restrictions and
relatively low acid strength.[3] However, zeolites can stabilize
carbocations by the high degree of delocalization of the
negative charge across the zeolite framework, so if a zeolite
with larger external surface area could efficiently form and
stabilize carbocations of synthetic interest on the surface, the
number of catalytic transformations for advanced organic
synthesis with zeolites would increase significantly. Such well-
stabilized carbocation intermediates are also found in some
“transition-metal-catalyzed” reactions where in situ-gener-
ated acids are the catalytically active species.[4]
Here we show that different zeolites can generate and
stabilize delocalized carbocations after dehydration of prop-
argyl alcohols, under mild reaction conditions, and then
catalyze the synthesis of a variety of bioactive oxazoles,
thiazoles, and indenols with high yield, selectivity, and
turnovers, giving water as the only by-product. Most impor-
tantly, the catalysts are very stable toward deactivation.
Scheme 1 shows the equilibrium reaction of propargyl
alcohol 1 with a proton to generate a delocalized carbocation.
Propargyl alcohols have been presented in the last years as
C
arbocations are valuable intermediates in organic syn-
thesis with a tendency to easily accept incoming nucleo-
philes.[1] When the positive charge is delocalized, the carbo-
cation can act as an ambident electrophile that performs
multifunctionalizations in one-pot. Among the myriad of
methods to generate carbocations, the most common is the
removal of a leaving group on the carbon atom by acidifica-
tion and stabilization of the positive charge left behind by
a suitable counteranion. Because carbocations are soft in
nature, soft counteranions with highly delocalized electron
clouds such as triflate (OTfÀ), triflimide (NTf2 ), tetrafluoro-
À
À
À
borate (BF4 ), and hexafluoroantimonate (SbF6 ) are com-
monly employed, despite the inherent difficulties to handle
such strong acids in solution (H0 < 12).
Aluminosilicates are solid acids with industrial applica-
tions for ion-exchange, gas separation, and catalysis.[2]
Between them, zeolites are by volume the most used catalysts
worldwide, with an important impact in both petrochemical
and fine chemical industries, but its use in advanced organic
Scheme 1. Formation of a delocalized carbocation from propargyl
alcohol 1 with an acid, and catalytic addition of amides, thioamides,
and phenols to give oxazoles, thiazoles, and indenols, respectively. In
the absence of another nucleophile water often re-enters to give the
Meyer–Schuster rearrangement to ketone 1a.
[*] Dr. J. R. Cabrero-Antonino, Dr. A. Leyva-Pꢀrez, Prof. A. Corma
Instituto de Tecnologꢁa Quꢁmica, Universidad Politꢀcnica de
Valencia-Consejo Superior de Investigaciones Cientꢁficas
Avda. de los Naranjos s/n, 46022, Valencia (Spain)
E-mail: anleyva@itq.upv.es
acorma@itq.upv.es
[**] This work was supported by Consolider-Ingenio 2010 (proyecto
MULTICAT) and Severo Ochoa program. J.R.C.-A. and A.L.-P. thank
ITQ for a fellowship. We thank Dr. S. Valencia for providing H-Beta
nanocrystalline zeolite and Dr. U. Dꢁaz for providing ITQ-2 zeolite.
OIDD screening data supplied by courtesy of Eli Lilly and
Company—used with Lilly’s permission.
synthons for many organic reactions catalyzed by Brønsted
and Lewis acid catalysts,[5] because they are dual proelectro-
philes[6] that react with various nucleophiles in atom-econom-
ical processes. Because water can re-enter in the absence of
any other nucleophile, the formation of the carbocation can
be indirectly observed by the presence of the Meyer–Schuster
product 1a.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201500864.
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Though reactant 1 is too large to diffuse through the pores
of a large-pore zeolite like faujasite, it may react on the acid
sites accessible through the external surface of the zeolite and
may generate the corresponding carbocation. To test that
possibility, we selected an USY acidic zeolite (Si/Al ratio =
15) that presents mesopores, giving larger external surface
area than the starting NaY zeolite. Then, an ethanolic
solution of compound 1 was added on H-USY and a rapid
change of color was observed. In situ infrared experiments
(IR, Figure S1 in the Supporting Information, SI) showed the
formation of minor amounts of ketone 1a,[7] which may
indicate that the delocalized carbocation given in Scheme 1 is
being formed and, at some extent, reacting with H2O. To
further confirm this, we synthesized the isotopically-labeled
13C-propargyl alcohol 1 (13C-1,1,3-triphenylpropargyl alcohol
1; Scheme S1)[8] and the evolution of the marked substrate in
solution in the presence of catalytic amounts of H-USY
(5 wt%) or triflic acid (HOTf, 20 mol%) was followed by
in situ 1H and 13C NMR spectroscopy. The results in Figure 1
Figure 2. Diffuse-reflectance (A) and UV/Vis (B–E) (in 1,4-dioxane)
spectra of compound 1 under acidic conditions: A) compound
1 impregnated in H-USY zeolite as an ethanolic solution, of which the
ethanol was evaporated by drying at 608C; B) compound 1 in solution
after addition of 5 mol% of triflimidic acid HNTf2 at 1008C; C) com-
pound 1 after addition of 5 mol% of HCl at 1008C; D) compound
1 after addition of 5 mol% of p-TSA at 1008C; and E) compound 1.
spectrum of the H-USY zeolite after impregnation with
1 (line A), and this band nicely fits with that of the
carbocation generated in solution with a catalytic amount of
a very soft acid such as triflimidic acid (line B). Notice that the
intensity of the band decreases for harder acids than
triflimidic acid such as HCl and para-toluenesulfonic acid
(p-TSA; lines C and D). These results are in line with the
lower amount of ketone 1a detected by NMR with the H-
USY zeolite and triflimidic acid, suggesting that the carbo-
cation forms and stays longer with the softer acids. Thus, we
can say that the carbocation of 1 can be formed on H-USY
with an efficiency that is, at least, comparable with typical
strong Brønsted acids such as HCl, p-TSA, HOTf, and HNTf2.
If the formation of the carbocation would exclusively
depend on the acid strength of the catalyst, the weaker acidity
of the H-USY zeolite should hardly promote the reaction
according to its much lower pKa (or H0) value.[9] Thus another
factor such as the properties of the counteranion is playing
a key role on the formation and stabilization of the
carbocation on the zeolite. A possible way to determine the
influence of the proton and of the counteranion on the
formation of the carbocation separately would consist in
correlating the activation energy (Ea) of the reaction with an
acidity parameter (H0 or pKa) of the catalyst.[10] If the acid
strength is the only responsible factor for the formation of the
carbocation, a linear relationship between Ea and the acid
strength should be found. On the other hand, if the counter-
anion is further stabilizing the carbocation, a lower Ea of that
expected from the corresponding pKa of the acid will be
observed.
Figure 1. In situ 1H NMR experiments of the isotopically labeled 13C-
propargyl alcohol 1 in acid conditions using 1,4-dioxane-d8 as a solvent.
A) compound 13C-1; B) compound 13C-1 in the presence of 5 wt% of
H-USY zeolite at 1008C after 15 min; C) compound 13C-1 in the
presence of 5 wt% of H-USY zeolite at 1008C after 20 h; and D) com-
pound 13C-1 in the presence of 20 mol% of HOTf at 1008C after
15 min.
1
show that the signal in the H NMR spectrum at 5.52 ppm
corresponding to the hydroxy group of the alcohol slighty
decreases for the zeolite (B and C) and disappears for triflic
acid (D). Additionally, an increase of the water signal at
2.15 ppm was observed for the zeolite (B and C) and aromatic
signals of ketone 1a appeared at ca. 8 ppm for triflic acid (D).
These results indicate that a minor product is formed with H-
USY that cannot be detected by NMR spectroscopy. A
13C NMR measurement (Figure S2) confirms this point.
To directly detect the carbocation, we performed diffuse-
reflectance UV/Vis spectroscopy measurements of the zeolite
impregnated with the propargyl alcohol. We expected that the
delocalized carbocation would have a long enough lifetime to
observe the extinction molar coefficient, even at very low
concentration. Figure 2 shows a new band in the UV/Vis
Figure 3 shows that a straight line is found for different
sulfonic acids (methylsulfonic MeSA, p-TSA, and TfOH)
indicating that mainly the acid strength controls the carbo-
cation formation when sulfonate is the counteranion. How-
ever, triflimidic acid HNTf2 shows a similar activation energy
than TfOH despite having a much lower acidity,[11] with an
additional stabilization of ca. 30–60 kJmolÀ1 (depending on
the acid parameter considered) due to the highly delocalized
triflimidate anion. Remarkably, the H-USY zeolite behaves
like HNTf2, with a stabilization of about 40 kJmolÀ1.
2
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Figure 3. Activation energy–acidity values (H0, top; pKa, bottom) plot
for different acids and H-USY zeolite. The activation energies of the
reaction are calculated from the initial rate of the Meyer–Schuster
rearrangement, by in situ NMR measurements (see Figure S3 for
calculations). High catalytic loadings of H-USY (120 wt%) and HNTf2
assure rapid formation of the ketone.
The results in Figure 3 would indicate that the efficient
formation of the carbocation of 1 on H-USY occurs after
stabilization by the delocalized framework of the solid, thus
overriding the necessity of having a strong acidity in the
reaction medium. In other words, the softness of acid zeolites
helps to stabilize soft carbocation intermediates, giving
a chance to the zeolites for catalyzing reactions occurring
through such a type of carbocations.
Figure 4 shows the results for the reaction between
different propargyl alcohols and nucleophiles such as aryl
and alkyl amides, aryl and alkyl thioamides, and mono- or
dimethyl-substituted phenols when catalyzed by 5–10 wt% of
H-USY (Si/Al = 15). For instance, when 1 was reacted with
benzamide 2 the corresponding oxazole 3 was cleanly formed
in 94% yield. A variety of oxazoles (compounds 3–8),
thiazoles (compounds 10–12 and 14–15), and indenols (com-
pounds 16–17) can be constructed from trisubstituted prop-
argyl alcohols with high conversions and selectivities. Mean-
while, the products obtained for disubstituted propargyl
alcohols (compounds 9, 13, and 18–20) are those correspond-
ing to simple nucleophilic substitutions.[12] Notice that this
modular approach is suitable for the synthesis of compound
libraries.
The products in Figure 4 have further synthetic use and
a potential biological activity. For instance, oxazoles consti-
tute an important member of the aromatic heterocycle
family[13] with wide use as building blocks in organic syn-
thesis[14] and as biologically active molecules.[15] Thiazoles and
indenols are also important heterocycles in organic synthesis,
present in many natural products and in biologically and
pharmaceutically active compounds.[16] A list with some
reported synthetic methods for these molecules is included
in the SI (Table S1) and, despite the plethora of Brønsted and
Figure 4. Scope of the cyclization reaction between substituted prop-
argyl alcohols and various nucleophiles, catalyzed by H-USY zeolite
(Si/Al=15). GC yields [%], yields [%] of isolated products in paren-
theses. For the reaction of substituted propargyl alcohols with thio-
amides and phenols, the previous dehydration of the H-USY zeolite
was not necessary. Reaction conditions for compounds 3 and 6–11:
H-USY zeolite (5 wt%) previously dehydrated under vacuum at 3008C
for 2 h, propargyl alcohol (0.5 mmol), amide (1 mmol), and anhydrous
1,4-dioxane (4 mL) at 1008C for 24 h. For compounds 9–11 reaction
time was 75 h. For compounds 5 and 12–16 the solvent was 1,2-DCE
(1,2-dichloroethane, 4 mL). For 15 the reaction time was 48 h and for
16 it was 100 h. For compounds 17–21: H-USY zeolite (10 wt%),
propargyl alcohol 1 (0.5 mmol), phenol (1 mmol), and anhydrous 1,2-
DCE (4 mL) at 808C for 72 h. For compounds 17–18 the reaction time
was 24 h.
Lewis acid catalysts previously used for these reactions,[17] the
turnover numbers (TON) and turnover frequencies (TOF,
hÀ1) achieved to date are always < 100, selectivity and catalyst
amount varies widely, and no solid catalysts have been
reported.[18,19]
H-USY gives a TOF0 = 845 hÀ1 (Figure S4) for the syn-
thesis of oxazole 3, which is significantly higher than that for
any other acid catalyst reported to date and for any other
nucleophilic addition to a propargyl alcohol, as far as we
know. Since even in the mesoporous H-USY zeolite there is
an important part of the microporous surface that is not
accessible to the bulky reactant, a 2D-layered ITQ-2[20]
delaminated zeolite with a higher external surface area was
also used as a catalyst (see Tables S2 and S3 and Figures S5–
S8 for characterization data of the solid acid catalysts). Note
that the delaminated zeolite has a higher Si/Al ratio and
a lower amount of acid sites. ITQ-2 (Si/Al = 25) with large
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accessibility gives a TOF0 of ca. 600 hÀ1; nevertheless, the
much lower number of acid sites in ITQ-2 gives a lower
reaction rate compared to that of H-USY. The benefits of
accessibility of the acid sites are also illustrated by the
increase in TOF0 found for the H-Beta zeolite in nanocrystal-
line form[21] when compared with the regular H-Beta zeolite.
Amorphous aluminosilicates such as silica-alumina and
standard MCM-41 were tested and their activity was lower
than that of H-USY (Table S4). Besides that, H-USY is
recyclable without loss of yield throughout six reuses (Fig-
ure S9).
Following previously proposed mechanisms for homoge-
neous acid catalysts[17j–l] and the above experiments in which
the intermediate carbocation was detected, Scheme 1 shows
what could be a general mechanism for the nucleophilic
addition to propargyl alcohols with a zeolite catalyst. The first
step is the formation of the carbocation on the acid sites,
followed by nucleophilic attack and cyclization.
Complementary to the catalytic work, the biological
activity against colon cancer cells for a series of molecules
synthesized by the above zeolite-catalyzed procedure is
presented (Figure S10 and Tables S5 and S6).[22] The inhib-
ition percentages in Colo 320 KrasSL cells at a concentration
of 0.2 mm were significant for most of the compounds, and 16
and 20 showed IC50 values for hNCI-H716 and mSTC-1 cell
lines similar to those of the currently used drugs Irinotecan
and 5-fluorouracil.[23] These results show the possibilities of
using zeolites for the preparation of bulky bioactive anti-
cancer molecules.
In summary, delocalized carbocations can be formed after
dehydration of propargyl alcohols on the surface of the H-
USY zeolite due to the stabilization of the carbocation by the
highly delocalized negative charge of the solid framework.
The in situ addition of different amides, thioamides, and
phenols to the carbocations proceeds with a catalytic effi-
ciency comparable to much stronger homogeneous acids to
give a variety of heterocycles, fused cycles, and other products
of interest for organic synthesis in high yields and selectivity.
Some of these compounds show significant biological activity
as anticancer agents. The experimental procedure shown here
is simple, sustainable, and effective, and opens a new way to
prepare complex organic molecules with zeolite catalysts.
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Keywords: carbocations · cycloaddition reactions ·
heterogeneous catalysis · propargyl alcohols · zeolites
&&
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Received: January 29, 2015
Published online: && &&, &&&&
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Communications
Heterogeneous Catalysis
J. R. Cabrero-Antonino, A. Leyva-Pꢁrez,*
A. Corma*
&&&& — &&&&
Beyond Acid Strength in Zeolites: Soft
Framework Counteranions for
Stabilization of Carbocations on Zeolites
and Its Implication in Organic Synthesis
Stabilized carbocations: Zeolites are able
to generate and stabilize medium-size
(molecular weight ꢀ300 Da) delocalized
carbocations on their surface under mild
conditions to perform multifunctionali-
zation reactions with catalytic activities
comparable to that of strong homoge-
nous Brønsted acids. Some of the prod-
ucts obtained here exhibit significant
inhibition percentages against colon
cancer cells.
6
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