SIZE EFFECT INVESTIGATION OF PALLADIUM NANOPARTICLES SUPPORTED INTO SILICA COLLOIDS AS THE CATALYST FOR SUZUKI CROSS COUPLING REACTION

Palladium nanoparticles (Pd NPs) provide high activity in catalyzing Suzuki cross coupling reaction, which is the most versatile reaction for forming carboncarbon bond, due to its high surface to area ratio. Silica colloids are used as the support for Pd NPs to provide heterogeneous catalysis for the reaction. Size factor is very important in the activity of the catalyst. Four different sizes of Pd NPs stabilized by Polyvinylpyrrolidone (PVP) are synthesized using seed-mediated growth method and supported onto silica colloids. Besides that, four different sizes of silica colloids were synthesized as the support of seed Pd NPs. All of the catalysts were used for Suzuki reaction of phenylboronic acid and iodobenzene. The size effect of the PdNPs supported by silica colloids was compared by comparing the activity of each of the catalysts. We found out that the smaller the size of the Pd NPs, the higher the activity of the catalyst. In addition, the smaller the size of the silica colloids, the higher the activity of the catalysts.


Suzuki Reaction and Classic Catalyst used in Suzuki Reaction
First published in 1979, Suzuki reaction is one of the most important carboncarbon bond formation reaction. 1 Scheme 1.1 shows an example of the Suzuki reaction, which is the cross-coupling reaction between arylboronic acids with aryl halides to form biaryls in the presence of a base. The reaction has been used widely to construct complex carbon-carbon bonds as intermediates in the synthesis of polymers, agrochemicals, pharmaceutical intermediates, and advanced materials. 2,3 Scheme 1.1. Generic scheme of Suzuki cross-coupling reaction The popularity of Suzuki reaction is due to its versatility and efficiency in the synthesis of biaryl compounds. 4 A variety of substrates and functional groups can be used under the reaction conditions, which is ideal to synthesize many intermediates in constructing the complex drug molecules. Besides that, boronic acid, which is a starting material needed for the reaction is stable, has high selectivity for crosscoupling reactions, is nontoxic, and also is tolerable of the various functional groups.

Scheme 1.2. General catalytic cycle of Suzuki Reaction
The general mechanism of the Suzuki reaction can be seen on Scheme 1.2. The first step of the catalytic cycle is attachment of palladium (Pd) catalyst to the halides by oxidative addition, which increases the oxidation state of Pd catalyst from 0 to 2. This step is the rate determining step of the reaction. After oxidative addition, the boronic acid is activated by the base present in the solution which enhances the polarization of the ligand and facilitates transmetalation. The base has been suggested to have a role of increasing the nucleophilicity of the organic group of boron atom and forming alkoxy palladate from aryl palladium halide. [5][6][7] The last step of the cycle is reductive elimination, releasing the biaryl product and regenerating Pd catalyst back to its original oxidation state so that it can participate in the catalytic cycle again.
One of the classic catalysts for Suzuki reaction is Pd 0 metal coordinated with ligands as the precursor, mainly phosphine ligands. 8 Early Suzuki reactions used metal to support catalysis. 9 The phosphine ligand was widely used because it is an electron-rich ligand, which could facilitate the oxidative addition step in the catalytic cycle. 10 Besides that, phosphine ligands could bind strongly to Pd 0 intermediate to prevent aggregation and precipitation which is the contributing factor in the stabilization of Pd 0 intermediate by forming π interactions with the aryl ring. 11,12 Phosphine ligand as the precursor of Pd catalyst for Suzuki reaction is one example of homogeneous catalysis. Homogeneous catalysis is a catalysis process where the catalyst is the same phase as the reaction.
Because of the same phase, it is hard to separate the catalyst from the product, which makes this one of the disadvantages of phosphine ligand. The other disadvantage of this type of catalyst is that often the phosphine ligands poisons the product, lowering the yield of the reaction.
Another precursor for Pd catalysts is using chelating ligands, better known as palladacycles. 13 Palladacycles was proven to have better activity than phosphine ligands, therefore it could result in better yields. The catalytic mechanism of palladacycles is still unclear. The proposed mechanism includes different oxidation states of Pd involved in the cycle. The first one is Pd(II) and Pd(IV) system which Another type of catalyst for Suzuki reaction is phosphine-free catalyst. 16 Phosphine free catalysts are most useful in the coupling reaction of aryl iodides. The addition of tertiary ammonium salts make the catalyst more reactive and hence the coupling reaction of aryl bromides could be done. 17,18 The family of phosphine-free catalysts includes carbene complex coordinated with palladium. Carbene has similar electron configuration as trialkylphospine, which has high σ-basicity and π-acidity. 19 The size of substituents' of carbene ligands affects the activity of the catalyst. Compound 1 (Figure 1.2) was shown to be an effective catalyst due to the large size of the substituent and being more electron-donating compared to the classic PCy3 ligand. 20 However, it takes a lot of steps to synthesize larger substituents of carbene complex.
The overall disadvantages of the catalysts above are the high cost to make the metal coordinated with the ligands, and high concentration of catalyst that is needed to produce a good yield of product, which leads to the high cost of cleanup. 21

Palladium Nanoparticles as Catalyst for Suzuki Reaction
Nanoparticles as catalyst has increased in popularity due to its high surface to volume ratio and high activity of surface atoms compared to bulk catalysts. 22 Due to its high activity as catalyst, no ligands are needed as the precatalyst. Low concentration of metal nanoparticles in solution could produce high Turnover Number (TON) of the product. Therefore, the use of palladium nanoparticles as catalysts of Suzuki reaction provides simpler synthesis methods that leads to reduced production cost. 23 Metal nanoparticles have been synthesized since 1980s. Bonnemann's method is the one that is generally used in synthesizing metal nanoparticles in the presence of stabilizer. [24][25][26] The reaction of nanoparticles synthesis is: precursors in the presence of stabilizer. 30 Stabilizers are used to prevent agglomeration of Pd atoms in the solution so that Pd black precipitate can be avoided. Many organic and inorganic stabilizers in the form of micelles, microemulsions, surfactants, polymers, and dendrimers have been used to synthesize Pd nanoparticles. The function of stabilizers are not only preventing the agglomeration but also making access to the nanoparticle surface for substrate activation and transformation. [31][32][33][34][35][36][37][38][39][40][41][42] Inverse micelles containing palladium nanoparticles is synthesized using KBH 4 as the reducing agent. 31 The nanoparticles is synthesized with the help of surfactants.
One common surfactant used is fluoro surfactant. It assists the stabilization for palladium nanoparticles in water-in-supercritical CO2 microemulsions in the form of micelles. 35 Polymers are widely used as stabilizers. hyperbranched aromatic polyamides (aramids), 55 and common surfactants such as sodium dodecylsulfate. 56 nanoparticles with single dendrimer or it can also surround the nanoparticles with several dendrimers. PAMAM is the most common type of dendrimer that is used as stabilizer. Nanoparticles are encapsulated inside the dendrimer and stabilized.
PAMAM G4-OH-terminated dendrimers had been used as catalyst for Suzuki reaction. 43 The stability and activity of the dendrimer stabilized nanoparticles was compared to PVP stabilized nanoparticles. The nanoparticles encapsulated inside the dendrimer are more stable but also had lower activity compared to PVP stabilized nanoparticles.
Scientists have not reached an agreement yet about the mechanism of Suzuki reaction catalyzed by palladium nanoparticles. 23 Some authors reported that Pd nanoparticles underwent homogeneus catalysis, the soluble Pd species is the one that To confirm the nature of the Suzuki reaction mechanism by Pd nanoparticles, metal leaching test was done. The test confirms that the dissolved molecular palladium is catalytically active. [57][58][59] This finding indicates that the Suzuki reaction catalyzed by palladium nanoparticles occurs via homogeneous catalysis. The study using X-ray absorption spectroscopy (XAS), which was used to quantitatively monitor the structure of palladium nanoparticles during the reaction, indicates that Pd-Pd coordination number stays constant during the reaction (Figure 1.4). The stability of the atoms indicate the stability of the surface during catalysis, which points to the heterogeneous nature catalysis of Suzuki reaction by palladium nanoparticles. 60,61 The two contradicting pieces of evidence of the catalysis nature by nanoparticles Scheme 1.4. Proposed mechanism of Palladium nanoparticles as a catalyst for Suzuki Reaction.
lead to the catalysis mechanism described in Scheme 1.4. Many have proposed that the nanoparticles catalyze the Suzuki reaction both homogeneously and heterogeneously. Pd(0) atom will leach into the solution and catalyze the reaction homogeneously. It can also be deposited back to the Pd cluster and catalyze the reaction heterogeneously. However, depending on the reaction conditions, the leached Pd could also agglomerate and Pd black could be formed.

Effect of Nanoparticles Size in Catalysis
One reason for the popularity of nanoparticles as catalyst for various reactions is due to its high surface area to volume ratio, which makes it catalyze the reaction faster than the other ligand bound catalysts. The ratio of surface area to volume determines the activity of nanoparticle catalyst. As a result, the size of nanoparticles itself determines the activity of the catalyst. Size dependence of nanocatalysts has been proven on different type of nanoparticles and different reactions.

Nanoparticle Size Effect on Tsuji-Trost Reaction
The first example of the size effect of the nanoparticles was observed in the Tsuji Trost reaction, an allylic substitution reaction catalyzed by palladium nanoparticles.

Nanoparticles Size Effect on Hydrogenation Reaction
Wilson  occurs preferentially at the surface atom at the particles size between 1.5 nm and 1.9 nm (geometric effect). However, at the particle size below 1.5 nm, the catalytic activity is dominated by the electronic effect.

Nanoparticle Size Effect on Suzuki Reaction
Li, et al., 2000 studied the effect of different sizes of nanoparticles on Suzuki reaction between phenyl boronic acid and iodobenzene (Scheme 1.6). 65 The reaction was monitored using HPLC with L4500A diode array detector (254 nm wavelength).
A reverse-phase packed column (Rainin Microsorb-MV C18, 300Å, diameter 4.6 x 250 mm) was used with acetonitrile-water mixture as the solvent for the separation.
They used the stepwise growth reaction to prepare palladium nanoparticles with PVP as the stabilizer. Palladium seeds had a size of 3 nm. The three larger nanoparticles had the size of 3.9 nm, 5.2 nm, and 6.6 nm, respectively. The plot on Figure 1.8b shows that the TOF does not depend on the particle size except for the smallest particle size when only the vertex and edge are considered.
That happens because the particle surface is poisoned by strongly bound species. The reaction intermediates adsorb strongly to the particle surface, and then cover the surface of the catalyst, which leads to catalyst poisoning. On From all of the examples above, it could be seen that as the particles size decrease, the total surface area increases; therefore the activity will also increase. However if the size of the nanoparticles is too small, catalyst poisoning could occur. As a result, the activity of very small catalyst will decrease. For the Suzuki reaction, the catalysis site is located on the vertex and edge of the nanoparticles.

Types of Intermediate Nanocatalysts
Homogeneous palladium nanoparticles provide excellent methods for catalyzing C-C coupling reaction, especially Suzuki reaction because of the high activity and selectivity. However, it is hard to separate the catalyst from the product and recycle it because it has the same phase as the product. The disadvantage of homogeneous catalyst includes the loss of expensive metal and product contamination.
In with MgO and followed by reduction. 67 Suzuki reaction of aryl bromides and iododides with arylboronic acids was done with this catalyst. The catalyst was found to be an effective one for Suzuki reaction, and 0.5 mol% of the catalyst could lead the reaction to completion in 5-6 hours. Recycling the catalyst is also proven to be simple.
It is recovered by simple filtration and it could be reused for four cycles with comparable activity to the first cycle. The high activity of this catalyst is due to the high surface area and strong basicity.
Copper oxides can also be used as the support for Palladium nanoparticles. It could be prepared by reacting Cu(NO) 3 and Pd(OAc) 2 in polyethylene glycol (PEF-6000). 68 In this case, the amount of PEG determines the shape of the composite. For Suzuki reaction, oval Cuo/Pd is the best catalyst among other shapes. The catalyst could be recycled up to five times without notable loss of activity.
Another example of metal oxide is zirconium oxide (ZrO 2 ). It was used to catalyze Suzuki reaction between aryl bromides and iodides with phenylboronic acid using tetrabutylammonium hydroxide. 69 (TBAOH) as the base. TBAOH was proven to catalyze the reaction better than inorganic bases such as KOH, NaHCO 3 , and K 2 CO 3 .
This occurs because TBAOH could serve as a base and a phase transfer agent. It is also an efficient catalyst, which could be recycled up to ten times while maintaining its activity.
Alumina based oxides (Al2O3, Al2O3-ZrO2 and Al2O3-ZrO2-Eu2O3) could be synthesized using sol-gel method and used as support for palladium nanoparticles and then used as the catalyst for the Suzuki reaction. 66 This catalyst has been proven to be effective in catalyzing Suzuki reaction of 2-bromotoluene with phenylboronic acid.
Very high yield was observed when the Pd 2+ was not reduced before supporting it to the oxides.
Beside metal oxides, layered double hydroxides (LDH) could also be used as nanoparticle support. LDH is also referred to as anionic clays or hydrotalcite-like materials. It is a class of ionic lamellar solids with positively charged layers with two kinds of metallic cations and exchangeable hydrated gallery anions. It gains interest because of its potential as the support for carbon-carbon coupling reactions. 70 It has been reported that Pd supported by LDH could effectively catalyze Suzuki reaction of activated aryl chlorides with arylboronic acids (Scheme 1.7). The catalyst could be recycled up to five times without notable loss of activity.

Nanocatalysts Supported on Carbon Nanotubes
Carbon nanotubes are popular support materials for nanoparticles because of its small size so that it can be dispersed uniformly into solution. One simple way to attach metal to carbon nanotubes is by depositing metal nanoparticles onto the surface of multiwalled carbon nanotubes (MWCNT) by hydrogen reduction of Pd(II)-βdiketone precursor in a supercritical carbon dioxide medium. 71 The method resulted well dispersed and spherical Palladium nanoparticles attached to the outside wall of MWCNT (Figure 1.9). The size of Palladium nanoparticles is between 5-10 nm.
Palladium nanoparticles supported onto MWCNTs was then used as a catalyst for the Suzuki reaction of phenylboronic acid and 1-iodo-4-nitrobenzene in methanol. 72   Attaching palladium nanoparticles onto single-walled carbon nanotubes (SWNT) had also been studied. A three step method to deposit palladium nanoparticles to the SWNT involved the electrochemical activation of SWNT by Na2SO4 for 10 minutes followed by the formation of Pd(IV) complex on the activated site of SWNT and then palladium nanoparticles attached to SWNT were formed by the reduction of Pd(IV) complex. 73 Pd/SWNT was then used as the catalyst for Suzuki reaction of 4-iodoacetophene and phenylboronic acid. The conversion of the product reached 98% in 40 minutes, suggesting that this catalyst has much higher activity compared to hollow palladium spheres under the same reaction conditions. 74 This catalyst could also be recycled up to five times without notable loss of activity.

Nanocatalysts supported on Silica
Silica is widely used as solid support of nanoparticles because it is widely accessible, stable, and provides an inert environment for the immobilization of the nanoparticles. Some methods to deposit palladium nanoparticles to mesoporous silica include ion exchange, wetness impregnation, chemical vapor infiltration, and in situ reduction.
There are many types of mesoporous silica. One example is SBA-15, which is Santa Barbara amorphous type silica. It has a highly ordered pore structure and has pore size between 5-10 nm, which makes it have a large surface area. Palladium nanoparticles could be loaded to SBA-15 and the loading amount is adjusted using different amount of palladium salts. 75 The catalyst was proven to have good activity in catalyzing the Suzuki reaction of activated aryl bromides. It can be recycled for five times without notable loss of activity.

Another type of silica is MCM-41 (Mobil Composition of Matter). It can be
used as a support to synthesize highly dispersed palladium nanoparticles with narrow size distributions inside the pores. 76 The pores are used as the template to synthesize nanoparticles, and produced controlled size of the nanoparticles. This catalyst was found to have good activity to catalyze Suzuki reaction of aryl bromides and iodides with phenylboronic acid. It could be recycled for three times without notable loss of activity.
Silica could also be modified using organic compounds such as mercaptopropyl and aminopropyl. 77 Palladium nanoparticles were loaded into the functionalized silica by treating the surface with Palladium acetate as the precursor and then reducing the precursor to form Palladium nanoparticles. The choice of organic modifiers has an important role for the activity and recyclability of the catalyst.
The catalyst had a good activity for Suzuki reaction of phenylboronic acid and 4bromoanisole when chelators such as diamines or triamines were used as the modifiers.
Nanoreactors could be synthesized using palladium nanoparticles that are anchored to the surface of hollow spheres of mesoporous silica by hydroxyl group. 78 A thin layer of mesoporous silica is coated onto the Pd/C spheres using tetraethyoxysilane as silica source and CTAB as the stabilizer (Figure 1.10). C and CTAB are then removed by calcination, producing only nanoparticles inside the hollow spheres. This catalyst has been proven to have a good activity in catalyzing Suzuki reaction between aryl iodides and phenylboronic acids.
Another way to support Palladium nanoparticles into silica is capping by dodecanethiol (DT) and 3-mercaptopropyltrimetoxysilane (MPMS). 79 First, palladium nanoparticles are made by reducing PdCl 2 with hydrazine in an inverse micelle microemulsion. The compound then stabilized with DT and MPMS, which cocondensed with TEOS (Figure 1.11). This catalyst has been proven to actively catalyze the Suzuki reaction between 4-bromoanisole and phenylboronic acid.
Unfortunately, this catalyst could not be recycled efficiently because of the leaching of palladium into the solution, which reduced the activity significantly.  In conclusion, there are many ways to synthesize the support materials for nanoparticles, from organic to inorganic materials. The research nowadays are focusing on the most effective and easy way to synthesize the support materials for the nanoparticles so it could be used as an efficient and highly active catalyst with high recycling capacity.

Introduction
Published in 1979, Suzuki reaction is a cross coupling reaction between arylboronic acid with aryl halides to form biaryls in the presence of base and catalyst. 1 This versatile and efficient reaction is used to construct complex carbon-carbon bonds as the intermediates in many types of industries. The common catalyst that is used for this reaction is palladium metal.
Nanoparticles are often used as catalyst due to its high surface to volume ratio and high activity of surface atoms compared to bulk catalysts. 2 It means that low concentration of metal nanoparticles in solution could produce high TON of the product. 3 Palladium nanoparticles provide a good catalyst for Suzuki reaction because of its high activity and selectivity.
The ratio of surface area to volume determines the activity of nanoparticle catalyst.
As a result, the size of nanoparticles itself determines the activity of the catalyst. Size dependence of homogeneous nanocatalysts has been proven on Suzuki reaction. In The problem with homogeneous nanoparticles lies in its recyclability. [5][6][7][8] It has the same phase as the product, which makes it hard to separate the catalyst and the product. Therefore, heterogeneous nanoparticles are often used as the catalyst for the reaction. In this experiment, silica colloids are used as the support for palladium nanoparticles to catalyze Suzuki reaction. Silica is used because it is widely accessible, stable, easy to synthesize, and provides an inert environment for the immobilization of the nanoparticles. 9,10 The size of silica colloids can also be modified.
In this experiment, the effect of different sizes of nanoparticles and different sizes of silica colloids was investigated. Different sizes of nanoparticles were synthesized and loaded into the silica colloids. Different sizes of silica colloids were also synthesized and the smallest size of palladium nanoparticles was loaded into the silica colloids. The activity was measured by measuring the amount of product formed over time using HPLC.

Experimental
Synthesis of Different Sizes Palladium Nanoparticles. The different sizes of nanoparticles were synthesized using seed mediated growth method. 4 The palladium 30 nanoparticle seeds was synthesized using 0.0667 g of PVP as the stabilizer which was dissolved in 15 mL of 2 mM H 2 PdCl 4 added to 21 mL of deionized water and 14 mL of ethanol. 11,12 The solution was then refluxed for 3 hours at 100 o C. The seed was aged for at least a day. The second growth was synthesized by adding 25 mL of the seed to

Synthesis of Colloidal-Supported Palladium Nanoparticles. Palladium
nanoparticles was added to the silica colloid suspension in 2:1 ratio of nanoparticles:silica colloid and stirred for 24 hours. After that, the solution was centrifuged at 13,500 rpm for 3 minutes. After the first centrifugation, silica colloids were dispersed in ethanol for two times and deionized water for another two times for a total of four times of centrifugation. For the last centrifugation, the supernatant was poured off and the pellet was air-dried overnight.

Characterization by Transmission Electron Microscopy (TEM) and
Energy Dispersive Spectroscopy (EDS). The pellet from the step above was dispersed in deionized water and diluted 10-fold. One drop of the solution was spotted on copper grids and air-dried overnight. TEM images and EDS spectra were obtained using JEOL 2100EX TEM. Zorbax Eclipse Plus C18 (4.6 x 150 mm, 5 micron) and the solvent used for the separation was 70% acetonitrile and 30% water. The flow rate was set at 1 mL/min, isocratic elution, and the wavelength of the detector used was 230 nm.

Synthesis of Different Sizes of Palladium Nanoparticles and Silica
Colloids. The size distributions that were determined by using ImageTool software were plotted into a size distribution histogram. Gaussian fit of the histogram showed an average size of (2.03±0.46) nm. The small standard deviation showed that the nanoparticles were monodisperse in the solution.     The representative images and size distribution histograms above showed that the same size silica colloids had been synthesized. Furthermore, different size of nanoparticles had also been successfully loaded into the silica colloids as the nanoparticles could be seen attached to the silica colloid.     ensured that most of the silica colloids used for the catalysis had similar size. The Pd nanoparticles could also be seen in the picture, which ensured that the Pd nanoparticles is loaded into the silica colloids.
Beside TEM images and size distribution histograms, Energy Dispersive X-Ray Spectroscopy (EDS) spectra were also obtained to ensure that the metal nanoparticles formed were Palladium.      nm silica colloids showed significantly higher activity compared to the 120 nm silica colloids. However, the 265 nm and 437 nm silica colloids showed similar catalytic activity. This trend could also be observed up to 12 hours of reaction (Figure 2.18). The smaller size of silica colloids has larger surface area to volume ratio, therefore many nanoparticles are more readily available to the substrate. Therefore, it could produce higher concentration of product in shorter time. As for the larger size of the silica colloids, similar activity could happen because of saturation of nanoparticles that could be loaded into the silica colloids. Because the volume was too big compared to the available surface area, the silica colloids touched each other and therefore reducing the surface area of the sphere for Pd nanoparticles to attach themselves.

Conclusions
Different sizes of Palladium nanoparticles were successfully synthesized using seed-mediated growth method. The sizes of nanoparticles obtained from this method were 2.0 nm, 4.8 nm, 5.0 nm, and 6 nm from the seed to the fourth growth, respectively. TEM images and size distribution histogram showed that the different sizes of Pd nanoparticles loaded into the silica colloids were relatively uniform in size.
These different sizes of nanoparticles were loaded into 120 nm silica colloids that were then used as the catalyst for Suzuki reaction. Overall, the result showed that smaller size of nanoparticles produced higher catalytic activity of the reaction.
Different sizes of silica colloids were also successfully synthesized using different amount of ammonium hydroxide. Lower amount of ammonium hydroxide produced smaller size of silica colloids. The sizes of silica colloids produced were 76 nm, 120 nm, 265 nm, and 437 nm. TEM images and size distribution histogram showed that the Pd nanoparticles loaded into the different sizes of silica colloids were relatively uniform in size. Palladium nanoparticles with the size of 2.0 nm (seed) were loaded into these different sizes of silica colloids. The smaller size of silica colloids produced higher catalytic activity than the larger ones. However, the two largest of silica colloids showed similar catalytic activity.