Cross-linked polystyrene-TiCl4 complex as a reusable Lewis acid catalyst for solvent-free Knoevenagel condensations of 1,3-dicarbonyl compounds with aldehydes

Article abstract of DOI:10.1016/j.catcom.2018.11.001

Cross-linked polystyrene copolymer beads with the average particle size in the range of (50–80 mesh size) were prepared by a new method, characterized and functionalized with titanium tetrachloride to afford the corresponding polystyrene?titanium tetrachloride complex in one step reaction and characterized by FT-IR, UV, TGA, DSC, XRD, SEM, BET. This polymer metal complex (PS/TiCl₄) was used as a heterogeneous, recoverable, reusable Lewis acid for solvent-free Knoevenagel condensations of 1,3-diketones with aromatic aldehydes under green and mild conditions. The rate of reactions was found to decrease with an increasing percentage of crosslinking and the mesh size of the copolymer beads. This complex showed good stability and catalytic activity in the Knoevenagel reactions.

Full text of DOI:10.1016/j.catcom.2018.11.001

Accepted Manuscript
Cross-linked polystyrene-TiCl4 complex as a reusable Lewis acid
catalyst for solvent-free Knoevenagel condensations of
1,3-dicarbonyl compounds with aldehydes
Ali Rahmatpour, Niloofar Goodarzi
PII:
S1566-7367(18)30398-4
DOI:
Reference:
https://doi.org/10.1016/j.catcom.2018.11.001
CATCOM 5545
To appear in:
Catalysis Communications
Received date:
Revised date:
Accepted date:
28 August 2018
31 October 2018
1 November 2018
Please cite this article as: Ali Rahmatpour, Niloofar Goodarzi , Cross-linked polystyrene-
TiCl4 complex as a reusable Lewis acid catalyst for solvent-free Knoevenagel
condensations of 1,3-dicarbonyl compounds with aldehydes. Catcom (2018),
https://doi.org/10.1016/j.catcom.2018.11.001
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ACCEPTED MANUSCRIPT
Cross-linked polystyrene-TiCl4 complex as a reusable Lewis acid catalyst
for solvent-free Knoevenagel condensations of 1,3-dicarbonyl compounds
with aldehydes
Ali Rahmatpour*, Niloofar Goodarzi
Polymer Research Laboratory, Polymer Chemistry Department, Faculty of Chemistry, Shahid Beheshti
University, P. O. Box: 1983969411, Tehran, Iran
*Corresponding author E-mail: a_rahmatpour@sbu.ac.ir; Fax: +98 21 22431671; Tel: +98 21 29903250
Graphical abstract
Abstract
Cross-linked polystyrene copolymer beads with the average particle size in the range of (50-80 mesh size)
were prepared by a new method, characterized and functionalized with titanium tetrachloride to afford the
corresponding polystyrene-titanium tetrachloride complex in one step reaction and characterized by FT-IR, UV,
TGA, DSC, XRD, SEM, BET. This polymer metal complex (PS/TiCl4) was used as a heterogeneous,
recoverable, reusable Lewis acid for solvent-free Knoevenagel condensations of 1,3-diketones with aromatic
aldehydes under green and mild conditions. The rate of reactions was found to decrease with an increasing
percentage of crosslinking and the mesh size of the copolymer beads. This complex showed good stability and
catalytic activity in the Knoevenagel reactions.
Keywords: Cross-linked polystyrene copolymer bead ; Polymeric catalyst; Heterogeneous catalyst; Solvent-free
condition; Knoevenagel condensation
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1. Introduction
Knoevenagel condensation is a synthetically important reaction both in chemistry and in
material science wherein the end products are generally the trisubstituted alkenes. This
reaction is widely used in the synthesis of natural products, biologically important molecules,
functional polymers, and photonic materials [1,2]. It may be carried out either in
homogeneous or heterogeneous phase. Many homogeneous base and Lewis acid catalysts
have been employed to accomplish this reaction [3-9]. However, using these catalysts have
numerous disadvantages such as waste production, significant problems in handling, disposal
and regeneration due to their toxic and corrosive nature, and no catalyst recovery. For
overcoming these drawbacks one approach is replacing of conventional, toxic, and polluting
homogeneous catalysts with eco-friendly reusable heterogeneous catalysts to combine the
advantages of these catalysts with those of heterogeneous support materials including higher
atom efficiency, stability, operational simplicity, selectivity and recyclability. The
development of polymer-immobilized catalysts is a rapidly growing field, which has great
importance in conventional and combinatorial organic synthesis mainly because of the easy
separation and reusability of polymer-supported catalysts. The polymeric catalysts also
present one of the most powerful tools for”green”sustainable chemistry, in the sense that they
can be easily recovered and reused many times.
Many heterogeneous catalysts, such as Ni-SiO2-supported catalysts [10], nitrogen-doped
carbon materials [11], MCM-41 [12], zeolites [13], enzymes [14], amino groups immobilized
on silica gel [15], Lewis acidic/basic bifunctional organobismuth complex in ionic liquids
[16], and other catalysts based on alumina [17], silica sulfuric acid [18,19], zinc and
magnesium oxides [20], microporous polyurethane [21], zeolite membrane microreactor [22-
24] have been exploited as catalysts for the Knoevenagel condensation.
There has been a long standing desire in preparative chemistry to avoid waste, to
substitute benign chemicals and solvents for toxic ones and to use solvent-less reactions.
Most of the Knoevenagel condensations in literature are reactions of highly reactive
methylene active compounds carrying two electron withdrawing groups such as malononitrile
and ethyl cyanoacetate with aldehydes [25]. However, only few examples of 1,3-diketones as
starting materials in the green known condensations are reported [26]. Very likely, such
compounds are less reactive than the other ones since their attitude to form a stable six-
membered enolate which makes it less reactive [6,7], hence a green procedure for
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Knoevenagel condensations between aldehydes and 1,3-dicarbonyl compounds using highly
efficient and reusable heterogeneous catalysts either solvent-free or in water is always
desirable.
Titanium tetrachloride as a powerful Lewis acid has found many applications in industry.
However, this compund is a liquid and highly aggressive material that creates clouds of HCl
when is exposed to air and moisture. Therefore, its handling needs serious precautions. Our
attempt is to immobilize TiCl4 directly into the polymer matrix for reaching the high loading
catalyst in one step reaction without functionalization of the polymer matrix. In continuation
of our previous experience on the synthesis of cross-linked polymer beads as supports using
conventional synthetic suspension stabilizers and the recent works on the use of polymeric
catalysts in organic transformations [27-29], herein we report the preparation of cross-linked
polystyrene copolymer beads with the given particle size and morphology using guar gum
from bioresource as new alternative synthetic suspension stabilizers by carrying out cross-
linking suspension copolymerization and immobilizing of TiCl4 on them in one step without
functionalization of the copolymer bead matrix, and then investigation of catalytic activity of
the resulting polystyrene-TiCl4 complex as a stable, highly active and reusable heterogeneous
catalyst in the Knoevenagel condensations of 1,3-dicarbonyl compounds with various
aromatic aldehydes in a solvent-free media and mild conditions in absence of any water
absorbing drying agents (Scheme 1). The procedure was environmentally friendly and
efficient, and the water stable PS/TiCl4 catalyst possessed high catalytic activity and could be
easily separated, recycled and reused several times without significant loss of activity. This
PS support with lower crosslinking degree and mesh size prepared using conventional
suspension stabilizer through suspension polymerization has been recently used for the
synthesis of PS/TiCl4 [30].
<Scheme 1>
2. Experimental
2. 1. Preparation of cross-linked polystyrene copolymer beads
In a 250 ml three-necked round-bottomed flask equipped with a mechanical stirrer,
nitrogen gas inlet, and reflux condenser that is placed in a thermostated water bath, a mixture
of distilled water (500 parts) containing guar gum (GG, 2 wt% in relation to the monomers)
and NaCl (1% w/v in relation to water volume) was first introduced and stirred at room
temperature for 30 min. While stirring, nitrogen was purged from the mixture, the suspending
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medium was then heated to the reaction temperature. A mixture of the monomers (St and
several weight ratios of DVB cross-linker, 4, 6, 8, 10%) were first mixed well with the
porogen (toluene-heptane (3:2) mixture ) to form an organic phase in which, the initiator,
AIBN, was added in the amount of 1 mol% of monomers. The organic phase mixture was
then added dropwise to the aqueous phase, through a dropping funnel to the flask for about 30
min (The volume ratio between the two phases (organic/aqueous) was kept constant at 1/5).
The stirring rate was kept at 350-400 rpm and the polymerization was allowed to proceed at
o
80 C for 18 h. After the polymerization, the copolymer beads were filtered out on a Buchner
funnel under vacuum, and treated in 1N HCl at boiling temperature for 15 min, washed twice
with hot water, and then vacuum filtered to remove the stabilizer. The copolymer beads were
extracted thoroughly with acetone for a few hours in a soxhlet apparatus to remove porogen
and residual monomers, and then were washed twice with acetone, two times with methanol
to ensure complete removal of impurities. Finally, the samples were dried in a vacuum oven
o
at 50 C for at least 10 h. The overall conversion of the monomers to solid copolymer was
determined gravimetrically. Of these beads the 50-80 mesh size (or 170-290 μm) beads were
used in the subsequent studies.
2. 2. Preparation of polystyrene-supported titanium tetrachloride (PS/TiCl4)
The above prepared polymer beads (8% DVB, grain size range: (170-290 μm, 50-80 mesh
size) suspended in 6 ml of dry carbon disulfide in a round bottomed flask equipped with an
overhead stirrer and left to swell for 0.5 h at room temperature. A solution of anhydrous TiCl4
(2 g) in dry carbon disulfide (4 ml) was added to the dispersed polystyrene bead solution
under strring. The mixture was kept under refluxing conditions and stirring for 1 h under a
nitrogen atmosphere. The reaction mixture was allowed to cool at room temperature and cold
water (50 mL) was then cautiously added to hydrolyze the uncomplexed TiCl4. The mixture
was stirred until the bright red color disappeared, and the polymer became light yellow. The
polymer beads were collected by filtration through suction and washed thoroughly with water
(100 mL) and then with ether (10 mL) and chloroform (10 mL), respectively. The light
o
yellow colored catalyst sample was further dried in a vacuum oven overnight at 50 C before
use. The chlorine content of PS/TiCl4 was 11.62 % analyzed by the Mohr titration method
[27-31] and the loading capacity of TiCl4 on the polymeric catalyst or the amount of TiCl4
complexed with polystyrene was calculated to be 0.824 mmol/g complex bead.
2. 3. Determination of the quantity of TiCl4 complexed
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The PS-TiCl4 complex samples were decomposed by burning via the sodium fusion method.
The amount of TiCl4 complexed with polystyrene was calculated from the chlorine content. It
was also determined by the atomic absorptiom spectrophotometry technique from the
titanium content.
2. 4. Determination of acidity (pH) of the PS-TiCl4 complex
The catalyst sample was hydrolyzed in a acetone-water solution (60%, 3/2 v/v) at room
temperature. The pH of the resultant solution was determined by using a standard pH meter.
2. 5. Typical procedure for the solvent-free Knoevenagel reaction
A mixture of aromatic aldehyde (1 mmol), acetylacetone (6 mmol) was charged into a 25
ml of round-bottomed flask equipped with a magnetic stirrer, followed by adding PS/TiCl4
containing certain amount of TiCl4 (0.12 gr, 0.1 mmol of TiCl4). The resulting mixture was
o
heated at 60 C in a water bath with stirring for an appropriate period of time under solvent-
free conditions (Table 1). The progress of the reaction was indicated by TLC (silica gel,
petroleum ether or hexane/ethyl acetate). After completion of the reaction, the reaction
mixture was allowed to cool to room temperature, and the catalyst was filtered and washed
o
with ethyl acetate several times. The recovered catalyst was dried at 60 C for 2 h. The
washings were collected and combined with the filtrate. The organic solution was
concentrated/evaporated under reduced pressure in a rotary evaporator, or treated by
chromatography on a silica gel column (eluted by a mixture of petroleum ether and ethyl
acetate), leading to the substituted olefin product with satisfactory purity.The structure of
1
which was confirmed by m.p. data and with H NMR, and IR techniques. Characterization of
1
the products was performed by comparison of their FT-IR, H NMR, and physical data with
those of the authentic samples. Conversion was defined as a percentage of the starting
aldehyde converted into products. The products were characterized by comparison of their physical
data with those of the known samples or by comparison of their IR and NMR. The same procedure
was applied for the condensation of β-ketoesters and dimethyl malonate with aromatic aldehydes
(Table 3, entries 10-26). The characteristic data of selected compounds 3dk, 3dj are provided in
supplementary data.
3. Results and discussion
3.1. Synthesis and characterization of crosslinked poly (St-DVB) beads and titanium
tetrachloride complex with them
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The polymeric carrier beads as polymer support were synthesized by carrying out aqueous
cross-linking suspension radical copolymerization of St-DVB monomers. For lightly cross-
linked resins, swelling in common organic solvents is an important factor in the success of
solid-phase reactions. A polymer with high degree of cross-linking has a network consisting
of dense and relatively larger number of inaccessible domains leading to less
functionalization. For this reason, in the present study, the copolymer beads containing (8
wt.%) of DVB as cross-linker were utilized as the polymer carrier. All resins were sieved to a
range of 25-80 mesh. The 50-80 mesh beads were used as carrier in the polymer supported
catalysts.
The PS/TiCl4 complex was prepared by complexation of cross-linked PS with TiCl4 in one
step reaction without functionalization of the polymer matrix. The copolymer beads (DVB, 6-
8%) were combined with TiCl4 in carbon disufide or carbon tetrachloride to form a stable
complex. The DVB-crosslinked PS-TiCl4 complex was prepared by the concise route
outlined in Scheme S1 (see supplementary data). To confirm the immobilization of TiCl4 on
polymer carrier, FT IR spectroscopic studies were firstly carried out with PS/TiCl4 and PS.
Figs. S2 are the IR spectra of PS and PS/TiCl4, respectively (see supplementary data).
-
Comparing the FT IR spectra of PS and PS/TiCl4 catalyst, peak intensity centered at 3025 cm
1
significantly decreases, indicating a reduction in the electron density on the carbon-carbon
(π) double conjugated bond. This is due to the donation of electron density from π bond to the
vacant d orbital of Ti in TiCl4. Further, the obvious difference between the FTIR spectra of
-1
polystyrene-titanium tetrachloride complex and crosslinked polystrene was at 1500-1600 cm
-1
-1
and at 500-800 cm . The FTIR spectrum of PS/TiCl4 showed new peaks at 1500-1590 cm
-1
due to for C-C stretching, 500-800 cm for benzene ring C-H bending, indicating the donor-
acceptor interaction of carbon-carbon (π) bond on the benzene rings with TiCl4 . This
interaction causes weakening carbon-carbon bond and this characteristic absorption band (C-
-1
C stretching) negatively shifts to 1540 cm , indicating coordination of the π bond with the
titanium and further confirming the formation of a titanium complex on the surface of the
polymer and modification of the phenyl rings of the PS/DVB.
The FT-IR spectra of pyridine adsorbed on PS/TiCl4 Lewis acid and PS samples are shown in
-1
Fig. S8. After adsorption of pyridine, the characteristic absorption band at 1450 cm is
originated C-C stretching vibration in pyridine molecules coordinatively chemisorbed on
Lewis sites (Ti), so it was attributed to Lewis acid sites. The other signals for pyridine
-1
molecules coordinatively chemisorbed on Lewis sites are about 1493 and 1600 cm (C-C
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ring vibration). However, no band at the same wavelength was observed for the PS sample.
Therefore, it was proved that the Lewis acids were successfully immobilized on polystyrene.
The UV spectrum of the solution of PS/TiCl4 complex in CS2 showed a new absorption band
at about 262 nm, which is due to the formation of a stable π
p type coordination complex
between the benzene rings in the polystyrene carrier with TiCl4. UV spectra of PS, PS/TiCl4
are shown in Figure 7S. The probable way of complex formation is shown in Scheme S2 (see
supplementary data). As a result of the electron donation from PS moiety to TiCl4, the Lewis
acid is stabilized due to the decreased mobility of the benzene rings hindered by the long
polystyrene chain. These significant changes revealed that TiCl4 is coordinated with benzene
rings through the π bond. The white polystyrene beads becomes pale yellow after the
heterogenation with TiCl4 which gives physical evidence of complex formation taking place
between TiCl4 and polystyrene beads.
The pH monitoring was used to investigate the acidity changes occurred in a acetone-
water solution after adding the PS-TiCl4 complex beads. The pH of PS-supported TiCl4
complex catalyst dispersed in a solution of acetone-water (60%) is shown in Fig. S3 (see
supplementary data). It was observed from Fig. S3 that the acidity of solution containing
catalyst gradually increased with time. This is due to the liberation of HCl into the acetone-
water solution after reaction of TiCl4 incorporated in PS with water. This reveals that there
must be a Lewis acid (TiCl4) in the complex. The same experiment was also performed with
the naked polymer which shows pH= 6.2 (Fig. S3).
Fig. S4 shows the XRD diffraction pattern of the PS carrier and the synthesized PS/TiCl4
catalyst (see supplementary data). The virgin PS exhibited a broad diffraction peak at (2θ)
ranging from 15o-30o suggesting the amorphous structure of the polymeric scaffold (see
supplementary information). But in case of PS/TiCl4 after incorporation of TiCl4 into the
polymer matrix, the intensity of characteristic reflection peak at 2θ=15o-30o has been
considerably diminished without altering the peak position. The reason for the decrease in
peak intensity is probably due to the accommodation of TiCl4 molecules onto the PS matrix
which combine the polymer chain and it forms complexes with polystyrene. This
phenomenon confirms the presence of TiCl4 in the polystyrene matrix.
The incorporating of TiCl4 in PS carrier was also confirmed by using TGA technique. Fig. S5
presents the thermal behavior of the PS and the as-synthesized PS-supported catalyst (see
supplementary data). The PS bead showed single step degradation. The initial decomposition
o
temperature of the PS was occurred at about 334 C. The major degradation of the polymer
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o
o
chain occurs in the range of 380-440 C (midpoint 422.38 C) and the loss is related to
breaking the main chain and side group of PS. But in case of TiCl4 incorporated PS catalyst,
o
the weight loss starts at about 50 C. This weight loss could be assigned to the release of
residual solvent and adsorbed water. Except the slightly initial weight loss, the synthesized
PS/TiCl4 showed one step degradation. The major degradation of the polymer chain occurs in
o
o
the range of 310-450 C (50 % weight loss at about 417 C and (80% weight loss at about 450
oC ). The degradation temperature (2nd) slightly decreases with the incorporation of TiCl4
into the polymer matrix. The lower second degradation temperture of catalyst relative to that
of the pristine polystyrene is mainly due to loss of crystallinity of PS by incorporation of
TiCl4 and to an outlet of TiCl4 from the polystyrene matrix. The TGA data reveals that
o
PS/TiCl4 catalyst is thermally stable up to 210-270 C (depending on percent of TiCl4
loading), and so it may be inferred that this synthesized catalyst is sufficiently thermally
stable to be applied for a variety of chemical transformations which is carried out in that
temperature range including the Knoevenagel condensation.
The DSC analysis provide analogous information (Fig. 1). The maximum decomposition
o
temperature (50 wt.% weight loss) for the copolymer bead prepared is about 417 C. No
o
exothermic peak in the range 200-250 C was observed. For this peak, polymer cross-linking
is responsible. Absence of such peaks in the case of copolymer beads prepared indicates that
all double bonds of monomers were consumed during copolymerization.
<Figure 1>
To obtain a visual image of the polymer support and the distribution of the titanium
species on the polymer support, the SEM micrographs of the beads and the synthesized
PS/TiCl4 were prepared. A clear change in morphology was observed after incorporating
TiCl4 onto the polymer support. Fig. S6 shows the SEM images of the PS carrier and the
sample after immobilization (see supplementary data). From the Figure S6, it can be seen that
the PS carrier exhibits randomly regular shape particles and almost non uniform in their sizes
with an average diameter of 100 μm. In the case of catalyst after incorporation of TiCl4 on the
polymer matrix, randomly irregular aggreagated particles were observed. Moreover, it was
observed that the particle size becomes considerably larger than the pristine one and the
surface becomes slender smooth. The observed increase in particle diameter of the catalyst
particle could be a further evidence of an effective incorporating of TiCl4 with the polymer.
The above result is a clear indication of the chemical immobilization of the active catalyst on
the support of PS.
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The loading capacity of the polymeric catalyst based on its chloride content obtained by
gravimetric method and checked by atomic absorption technique was 0.673 mmol TiCl4/g of
complex catalyst beads [31]. The data obtained by these two techniques showed, within
experimental error, that the catalyzing species are in the form of TiCl4 supported on the
polymeric support.
To verify the incorporation of TiCl4 Lewis acid onto polystyrene, BET surface area and
pore volume of PS and PS/TiCl4 were measured. In Table S1, porous structure parameters of
the studied PS and PS/TiCl4, and catalyst loading of PS/TiCl4 are presented. As surface area
of PS carrier bead is almost totally contributed by its open pore system, the catalytic
functional group prepared via this scheme should have been evenly confined in the pores.
After immobilization, the BET surface area of PS decreased from 42 to 12.24 m2/g and pore
volume decreased from 0.14 to 0.035 ml/g due to the loading of TiCl4 in the pores. The
reduction of both surface area and pore volume of the catalyst compared to the original PS
support confirms the presence of Lewis acid moieties within the pores of the support. The
structure of the parent material (polymer chain) was unaffected after this step; however, a
decrease in the PS surface area, as well as some blockage of pores and a slight decrease in the
mean pore size are observed, as expected (Table S1, supplementary data).
3.2. Catalytic activity of the PS/TiCl4 catalyst on Knoevenagel condensation
It is well known that titanium chloride as a strong Lewis acid shows unique reactivity in
various organic and polymerization reactions [32]. However, it is found to be highly toxic,
corrosive, and moisture sensitive, and so its usage, storage, and separation from the reaction
mixture were invariably difficult; the strictly anhydrous conditions and stoichiometric
amounts or more are required in order to achieve good yields. Moreover, several molar
equivalents of triethylamine to titanium tetrachloride are also needed to improve the reaction
yields. Therefore, we thought to develop reagent by incorporation of TiCl4 on the organic PS
support. The resulting polymer protected reagent, a stable tightly bound complex between
anhydrous TiCl4 and PS-DVB copolymer beads was used for the condensation of aromatic
aldehydes with 1,3-dicarbonyl compound.
To check the potency of polystyrene-supported TiCl4 catalyst as a heterogeneous catalyst,
it was used in the Knoevenagel condensation (which is a versatile and most suited method for
generation of C-C bond in organic synthesis). To test the reactivity of β-diketones, a
condensation between benzaldehyde and 1,3-diketone (acetylacetone) was initially chosen as
a model reaction and was investigated under various experimental conditions to optimize the
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reaction efficiency. The reaction conditions were optimized, and the results are presented in
Table 1. It was found that the best system for this reaction was solvent-free in combination
o
with the reaction temperature 60 C, which yielded a 100% conversion of benzaldehyde
within 2 h using 10 mol% of the PS-TiCl4 complex (with respect to the TiCl4 content in
1
PS/TiCl4) (entry1) relative to benzaldehyde. We checked the conversion by H NMR at
maximum after 2 h and the reactions were monitored by TLC, and the consumption of
aldehyde was measured. Also, we examined the effect of catalyst loading and reaction
temperature on the model reaction. The loading of the catalyst was reduced down to 5 mol%
by prolonging the reaction time in order to get full conversion. Increasing the amount of
catalyst loading from 74 mg to 222 mg significantly increased the yield and decreased the
reaction time (Table 1, entries 9,15,17). However, it was found that the reaction was not
completed without an efficient and required amount of the catalyst, 5 mol% PS/TiCl4 gave a
conversion of 80% after 6 h while 10 mol% PS/TiCl4 was sufficient to get full conversion
after 2 h (Table 1, entries 15,17). A further increase in the amount of catalyst did not exhibit
any advantage on the product yield. Therefore, using 120 mg (0.1 mmol) of PS/TiCl4 under
sovent-free conditions was deemed ideal for reaction (Table 1, entry 15). Whereas decreasing
the amount of catalyst leads to a decrease in the product yield. The optimal conditions for the
Knoevenagel condensation with a broad range of aromatic aldehydes and yield (conversion)
of the adduct products are listed in the Table 2.
In order to confirm that the catalytic activity arises from the Lewis acid TiCl4 moiety of
the polystyrene-supported catalyst, a control experiment or the matrix influence for the
condensation reaction was performed by taking benzaldehyde and acetylacetone in the
absence of any catalyst and solvent or using PS carrier alone at room temperature; no
reactions occurs, and the starting components remain unreacted (Table 1, entries 1,4). In
order to improve the experimental results, the reaction was also performed under solvent-free
o
o
conditions without any catalyst or in the presence of PS carrier alone at 60 C and 70 C, no
conversions were observed, respectively (Table 1, entries 2,3). It is found that the initial
reaction (convert to its enolic form) starts merely in the presence of an efficient amount of the
catalyst and that on a cross-linked PS surface, acetylacetone is unreactive in the condensation
reaction. Also, PS/TiCl4 was found to be a more effective catalyst than PS/AlCl3 for
Knoevenagel reaction under identical conditions (Table 1, entry 18).
The reaction temperature played a crucial role in determining the activity of the
heterogeneous polystyrene-supported TiCl4 for the synthesis of the Knoevenagel adducts.
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The effect of reaction temperature on the catalyst was investigated by performing the
condensation of benzaldehyde and acetylacetone under solvent-free conditions at different
o
temperatures. When the reaction was performed at room temperature (25 C) under solvent-
free conditions, only a conversion 35% was achieved. As the temperature of the reaction was
o
increased to 40 C, the reaction conversion increased to 53%. As the product yield increases
with increase of temperature, we further performed the reaction at three other higher
temperatures like 50, 60 and 70 oC. From the data in Table 1 , it is clear that the temperature
o
of 60 C is the optimal temperature for completion of this reaction (Table 1, entry 15) and at
lower temperatures, even if the time was prolonged to 6 h, only low yields were observed
o
(Table 1, entries 13-15). Beyond 60 C, no remarkable improvement in the product yield was
observed. The reason why a higher temperature was necessary seems to due to the acidity of
PS/TiCl4 was weaker than that of anhydrous TiCl4. In addition, this may be explained to be a
result of the difficulty associated with the diffusion of the reactants or molecular mass
transfer process due to the unfavorable polystyrene micropores and channels. Therefore, the
generation of active sites requires temperature pretreatment. In order to compare the catalytic
activity of the homogeneous phase and heterogeneous phase at the same reaction temperature
and to clarify the role of the PS carrier, we have performed the catalytic reaction of
benzaldehyde and acetylacetone in the presence of TiCl4 as the homogeneous phase at 60oC
under solvent-free conditions. This data clearly suggests that the microporous polystyrene as
support plays a crucial role in this condensation reaction. On complexation of PS support
with TiCl4, it is stabilized due to the decreased mobility of the benzene rings hindered by the
long polystyrene chain and no need the several equivalents of organic base such as,
triethylamine to stabilize TiCl4 and the improve of reaction yields [33,34]. These
functionalities, as well as the surface area are absent in the homogeneous catalyst of TiCl4.
Thus, the yield of the condensation product over our reusable and heterogeneous polystyrene-
supported TiCl4 is much higher than the homogeneous TiCl4 form and also could be avoid
tedious extra wok up after completion of the reaction and reduce the amount of acidic waste
water generated.
To survey the generality of the catalytic protocol using the heterogeneous catalyst, we
investigated the reaction using a variety of aldehydes, including aromatic/heterocyclic/α,β-
unsaturated aldehydes with acetylacetone under the optimized condition (Scheme 1). The
results are shown in Table 2 (entries 1-9). The electron-neutral, electron-rich and electron-
poor aromatic aldehydes reacted with acetylacetone very well. The catalytic performance was
11

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excellent for the substrate with electron-withdrawing groups (Table 2, entries 3,4,5,6), which
exhibited higher reactivity. Nevertheless the efficiencies were only slightly lower for the
substrates with electron-donating groups, because of the decreased activity (Table 2, entries
2,3,7). The reaction conditions were mild enough not to induce any damage to moieties, like
the methoxy group (Table 2, entry 3), which often undergo cleavage in the presence of strong
acids or certain Lewis acids. Moreover, the protocol could also work equally well with the
acid and base sensitive heterocyclic aldehydes, and excellent yields were obtained (Table 2,
entry 8). We tried to extend the procedure to α,β-unsaturated aldehydes and the satisfactory
results were obtained. In fact the reaction of acetylacetone with cinnamaldehyde gave only
the desired condensation product in high yield, which retained the double bond geometry, and
no 1,4-addition product was detected (Table 2, entry 9).
Based on these results, we decided to investigate the behavior and catalytic activity of the
heterogeneous catalyst PS/TiCl4 in the Knoevenagel condensation reactions between β-
ketoesters (ethyl/methyl acetoacetate) and various aldehydes, including aromatic
o
/heterocyclic/α,β-unsaturated aldehydes using 10 mol% of catalyst at 60 C in a solvent-free
conditions. The results are summarized in (Table 2, entries 10-21). Compared to the
Knoevenagel reactions of acetylacetone with aromatic/heteroaromatic aldehydes, the
reactions of ethyl/methyl acetoacetate with the same aldehydes needed more time because of
the decreased activity. On the other hand, asymmetric systems like (Table 2, entries 10-21)
took longer times to give the corresponding Knoevenagel adducts in good yields even if two
isomeric products are formed, the Z-isomer usually being predominant. The adduct products
of ethyl/methyl acetoacetate were a mixture of Z- and E-geometical isomeric alkenes and the
assignment of stereochemistry of different configurations was made on the basis of the
1
chemical shifts of CH=C, which migrated to lower field for the E-isomers as confirmed by H
NMR. For example, the reaction between ethyl acetoacetate and pNO2-benzaldehyde gave
adduct 3cj containing a mixture of E/Z geometrical isomers in the ratio 5:1. However, oNO2-
benzaldehyde and oCl-benzaldehyde gave adduct products 3cf , 3ce containing E/Z isomers
in the ratio 5:5. Compound which shows lower δ value for COCH3 protons were assigned as
E-isomer, where COOEt is trans to the aromatic ring and the other compound as Z-isomer.
The lower δ value for COCH3 protons could be attributed to the effective shielding by
benzene ring which is positioned cis to COCH3 group. Moreover, the performance of the PS-
TiCl4 complex catalyst was examined in the Knoevenagel reactions of dimethyl malonate
12

ACCEPTED MANUSCRIPT
with aromatic aldehydes under optimized conditions and the Knoevenagel adducts were
obtained in good yields (Table 2, entries 24-26).
<Table 1>
<Table 2>
The effect of crosslinking on the reactivity of the polymeric catalyst in the Knoevenagel
reaction was studied. It was found that as the proportion of the crosslinking agent increases
the penetration of the solvent and reactants to the active sites of the polymer becomes more
difficult because of the highly crosslinked network structure. With higher extents of
crosslinking the polymer matrix becomes more rigid and the penetration of the solvent and
reactant molecules to the active sites of the catalyst is more difficult. Access to the reactive
groups on highly crosslinked networks is considerably diminished as they are flanked by a
large frequency of crosslinks leading to a decreased reactivity. Highly crosslinked resins were
mechanically stable and rigid, but lacked reactivity.
3.3. Heterogeneity test and catalyst reuse
Next, in order to establish the recyclability and reusability of the catalyst (PS/TiCl4), the
condensation reaction under similar conditions, between benzaldehyde and acetylacetone,
was taken as the representative case. After the reaction was over, the PS/TiCl4 was separated
from the reaction mixture, washed with ethyl acetate thoroughly. Then the recovered catalyst
was dried and used for a further five additional reaction cycles. It was used for 5 cycles and
almost retained its catalytic activity in these repeating cycles, but consecutive cycles required
more time to complete. In all cases, the catalyst exhibited consistent catalytic activity,
establishing the recycling and reusability of the catalyst without any significant loss of
catalytic activity. Only a very small drop in the reaction conversion in each catalytic cycle is
observed and 93% conversion was achieved for 3 h at the fifth cycle (Table 3, Run 5). The
result of recycling is shown in Table 3. The supported catalyst is stable under the reaction
conditions, but stirring provokes some etching in the beads of the immobilized catalyst
leading to a decrease in the effective catalyst loading as the series of experiments progresses.
Moreover, a small drop in the 4rd and 5rd cycles may be explained by a considerable
decrease in the catalyst mass during the recycling procedure. Nonetheless, the typical IR
bands of the immobilised TiCl4 and crosslinked polystyrene backbone after the catalytic
cycles remained unchanged, indicating the stability of the catalytic active species and support
itself under the catalysis experimental conditions. Hence, the loss of catalytic activity with
13

ACCEPTED MANUSCRIPT
the reuse of the catalyst may be due to slight leaching of active species, promoted by some
degradation of the bond between the support and Lewis acid.
<Table 3>
In order to ascertain whether the catalyst was behaving in a truly heterogeneous manner, or
whether it is merely a reservoir for free form of TiCl4 released into the acetylacetone, hot
filtration test was performed. In a typical experiment, crosslinked polystyrene-TiCl4 complex
o
and acetylacetone were taken in a round-bottomed flask and stirred at 60 C for 30 min. At
this stage, the catalyst was filtered off and the experiment was continued, after adding
benzaldehyde to the filtrate, for another 5 h at the same conditions, no reaction took place
(Table 1, entry 20), as is evident from the GC analysis. It is confirmed the heterogeneous
character of the catalytically active species and that release of TiCl4 is negligible. We also
o
carried out a heterogeneity test for the Knovenagel model reaction, which was done at 60 C
in order to check whether the catalyst was truly behaving heterogeneously or not. The
catalyst was separated from the reaction mixture by filtration after 30 min of the reaction, and
the “catalyst-free” filtrate obtained was continuously stirred under the same reaction
conditions for another 1h. Analysis of the filtrate showed no further progress of reaction even
after 1 h and no increment in the % conversion was noticed. Catalyst was filtered off at the
o
reaction temperature (60 C) in order to avoid readsorption of leached titanium chloride on
the catalyst surface on cooling. This again suggest that there is no loss catalyst components
during the course of the reaction, which confirmed the heterogeneity of the catalyst.
According to the results above and based on the literature [33,34], the possible mechanistic
pathway, which is shown in Scheme 2, was proposed for the clarification of the catalytic role
of PS/TiCl4 in the reported method. The reactivity pattern of aromatic aldehyde indicates that
the Lewis acid catalyst, PS/TiCl4 forms a complex with the carbonyl group of 1,3-dicarbonyl
compounds first. The complexation increases the acidity of the α-hydrogen atoms because of
the electron-withdrawing effect of the electron-poor titanium (IV). Thus the dicarbonyl can
be easily deprotonated and converted into the titanium enolate ion. Second, while the
activation of aldehyde by titanium center and the formation of strong Ti-O bond, the reactive
titanium species undergoes nucleophilic attack to the carbonyl carbon atom and generates the
requested Knoevenagel adduct. Therefore, the formation of a strong Ti-O seems to be
involved in the water elimination step. According to this mechanism, titanium species would
not only help the formation of the corresponding enolate but could also promote the
14

ACCEPTED MANUSCRIPT
nuclophilic attack reaction of titanium enolate to the polarized carbonyl group of the aromatic
aldehyde.
<Scheme 2>
In order to establish the catalytic activity of PS/TiCl4 complex and greenness of this method,
we compared our results on the synthesis of Knoevenagel adduct with data from the literature
(Table S2, supplementary data). As shown, the most of the former catalytic systems have
been performed in the organic solvents at higher reaction times than the PS/TiCl4 catalyst.
4. Conclusion
In summary, we have synthesized the first DVB-crosslinked PS-TiCl4 complex for
the use as a heterogeneous Lewis acid catalyst. Cross-linked polystyrene copolymer porous
beads with the average particle size in the range of (50-80 mesh) were synthesized via cross-
linking suspension copolymerization using guar gum as a new biopolymer suspension
stabilizer and functionalized with TiCl4 via complex formation to create surface active acidic
sites. PS/TiCl4 was shown to be an efficient and recyclable catalyst for the solvent-free
Knoevenagel condensation reaction of less reactive 1,3-diketones with various aldehydes.
Acknowledgement
The authors are thankful to TPC for providing the required chemicals and the Shahid Beheshti
University Research Council for partial support of this work.
Scheme 1. Knoevenagel condensations of less reactive methylene compounds (β-diketone and β-
ketoesters) and dimethyl malonate with aromatic aldehydes catalyzed by PS/TiCl4
15

ACCEPTED MANUSCRIPT
Figure 1. DSC thermograph of the copolymer beads (PS/DVB) at 6 and 10 wt.% DVB (up and down,
respectively)
16

ACCEPTED MANUSCRIPT
Cl4
O
O
Ti
H2O
O
O
R
R'
R'
R
R"
R"
Cl4Ti
Cl4
Ti
O
O
H
O
O
R
R'
H
R'
R
H
Cl
Ti
4
R"
HO
O
O
R'
R
H
Cl
Ti
H
4
Ti
H
Cl4
O
O
"R
"R
H
Scheme 2. Proposed mechanism of the Knoevenagel condensation catalyzed by PS/TiCl4
17

ACCEPTED MANUSCRIPT
Tables
Table 1
Optimization of reaction conditions for Knoevenagel condensation of benzaldehyde
with acetylacetonea
O
O
CHO
Ps/TiCl4
O
O
Solvent-free
1a
2a
Ph
3aa
Entry Catalyst
amount
T ( oC)
Time (h) Conversion (%)b
f
1
-
-
-
-
-
-
rtg
10
6
6
10
6h
6h
6h
1.4
1.5
3
3
6
6
6
2
2
6
3
c
f
2
d3
d4
5
60oC
c
PSt
PSt
60oC , 70oC
c
rt
c
Toluene/TiCl4
PSt/TiCl4
PSt/TiCl4
PSt/TiCl4
PSt/TiCl4
PSt/TiCl4
PSt/TiCl4
PSt/TiCl4
PSt/TiCl4
PSt/TiCl4
PSt/TiCl4
PSt/TiCl4
PSt/TiCl4
PSt/AlCl3
TiCl4
60oC
rt
34
39
30
100
100
88
66
35
53
84
100
100
80
80
64
26
6
7
8
9
15 mol%
10 mol%
15 mol%
15 mol%
15 mol%
15 mol%
10 mol%
10 mol%
10 mol%
10 mol%
10 mol%
5 mol%
rt
70
60
50
40
rt
40 oC
50 oC
60 oC
70 oC
10
11
12
13
14
15
16
17
18
19
e20
o
60 C
o
10 mol%
10 mol%
10 mol%
60 C
60 oC
60 oC
2.5
30 min
PSt/TiCl4
a Reaction conditions:benzaldehyde (1 mmol), β-diketone (acetylacetone) (6 mmol), solvent-free;
b Referred to the reacted benzaldehyde, conversion determined by GC and H NMR. Products were
1
c
not found.d Reaction carried out according to footnotea,using unfunctionalized cross-linked PSt as a
catalyst.e The catalyst was filtered after 30 min. Without PSt/TiCl4. g r.t. refers here to 25 oC.
f
Table 2. Knoevenagel condensations of aromatic aldehydes with β-diketone
(acetylacetone)a and β-ketoester (ethyl/methyl acetoacetate)
18

ACCEPTED MANUSCRIPT
Entry
R
R'
R''
Time (h)
Yield (%)b,c,d
(E/Z ratio)
98
Product
1
Me
Me
Me
Ph
2
2.5
3
3aa
3ab
3ac
3ad
3ae
3af
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OMe
OMe
OMe
pMeC6H4-
pOMeC6H4-
pClC6H4-
oClC6H4-
oNO2C6H4-
pOHC6H4-
2-Furyl
97
3
Me
96
4
Me
2
98
5
Me
2.5
2
96
6
Me
97
7
Me
3
94
3ag
3ah
3ai
8
Me
2
98
9
Me
PhCH=CH-(E)
Ph
3
93
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OMe
OMe
2.5
3.2
3.5
2.5
2.5
2.5
97 (44:56)
95 (36:64)
96 (48:52)
96 (49:51)
95 (0:1)
97 (46:54)
92
3ba
3bb
3bc
3bd
3be
3bf
3bi
pMeC6H4-
pOMeC6H4-
pClMeC6H4-
oNO2C6H4-
2-Furyl
PhCH=CH-(E) 3.5
Ph
3.5
3.5
3.5
2.5
2.5
2.5
2.5
4
93 (25:85)
93 (42:58)
95 (44:56)
95 (43:57)
93 (5:5)
94 (5:1)
95 (51:49)
94
3ca
3cb
3cc
3cd
3ce
3cj
pMeC6H4-
pOMeC6H4-
pClC6H4-
oNO2C6H4-
pNO2C6H4-
2-Furyl
3ch
3dk
3dj
3dd
pCNC6H4-
pNO2C6H4-
pClC6H4-
4
95
4
94
a Reaction conditions: aromatic aldehydes (1 mmol), β-diketone (acetylacetone,6 mmol),
β-ketoester (ethyl/methyl acetoacetate) and dimethyl malonate, 6 mmol), PSt/TiCl4 (150 mg,
10 mol%, 0.1 mmol TiCl4), Reaction temperature of 60oC, solvent-free. b Isolated yield of
product or from the weight of the recovered reaction mixture, on the basis of the conversion.
c
1
The E:Z geometry was determined by H NMR. d The IR spectrumof condensation products
-1
showed no stretching band of carbonyl group at 1680-1698 cm .
Table 3
19

ACCEPTED MANUSCRIPT
Recycling potential of the PS/TiCl4 for the Knoevenagel condensationa
No of cycles Fresh Run 1 Run 2 Run 3 Run 4 Run 5
Yieldb(%)
Time (h)
98
2
97
2
96
95
95
93
3
2.2
2.4
2.5
a Reaction conditions: benzaldehyde (1 mmol), acetyl acetone (6 mmol),
solvent-free, reaction temperature: 60 oC, catalyst (10 mol%).
b Isolated yield of pure product.
Table 4
Comparison of the polymeric catalyst PS/TiCl4 with various homogeneous or heterogeneous
catalysts in Knoevenagel condensations forthe synthesis of 3aa.
Entry
Catalyst
Solvent
T (oC)
Time (h) Yield (%) Ref.
1
2
3
4
5
6
L-Tryptophan
Mg(ClO4)2
Yb(OPf)3
Organobismuth complex
Piperidine AcOH
Amino groups immobilized
on silica gel (SiO2-NH2)
USY zeolite
DMSO
Neat
FBS
[Bmim]BF4
Benzene
r.t.
r.t.
80
r.t.
18
70
8
6
18
60
55
80
95
60
[8]
[6]
[9]
[16]
Reflux
[11]
Toluene
Benzene
Neat
25
Reflux
r.t.
41
89
85
91.1
[15]
[13]
[7]
7
8
9
6
1
9
NbCl5
Magnetic Fe2O3 functionalized water
80
[36]
with ionic liquids
10
11
12
13
14
Silica sulfuric acid
Neat
Neat
n -Octane
Solvent-free
Solvent-free
r.t.
140
80
60
60
10
6
8
3
2
66
32.2
82
80
[18]
[14]
[35]
This work,[37]
This work
Zn2+ ion-exchanged β zeolite
Perfluoroalkylated pyridine
PSt/AlCl3 (10 mol%)
PSt/TiCl4 (10 mol%)
98
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22

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Scheme and Figure captions:
Scheme 1. Knoevenagel condensations of less reactive methylene compounds (β-diketone
and β-ketoesters) and dimethyl malonate with aldehydes catalyzed by PS/TiCl4.
Figure 1. DSC thermograph of the copolymer beads (PS/DVB) at 6 and 10 wt.% DVB (up
and down, respectively).
Scheme 2. Proposed mechanism of the Knoevenagel condensation catalyzed by PS/TiCl4
23

ACCEPTED MANUSCRIPT
Highlights
• Polystyrene copolymer beads were prepared by cross-linking suspension copolymerization.
•Polystyrene-TiCl4 coordination complex was prepared through finctionalization of
polystyrene.
•Polystyrene-TiCl4 complex was efficient for the solvent-free Knoevenagel reaction.
•The polymeric catalyst was recovered and reused several times.
24