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Nanosized Catalysis as a Basis for Developing Innovative Technologies
in the Pharmaceutical Industry
ESTHER SULMAN, Department of Biotechnology and Chemistry
Tver State Technical University nab. Afanasiya Nikitina 22, Tver, 170026
RUSSIA
[email protected] Abstract: This investigation of the catalytic properties of noble metal nanoparticles stabilized in hypercrosslinked polystyrene (HPS) matrix shows the prospect for their application in regioselective oxidation and hydrogenation, which represent key stages for the synthesis of the intermediates and final products of pharmaceutical industry. Commercial use of nanosized catalysts allows shortening the synthetic stages, increasing product yields, and improving the environmental safety of the existing industrial processes. In this review, the synthesis, structure and catalytic properties of Pt, Ru, Pd - nanoparticles stabilized in the pores of a polymeric HPS matrix are discussed. Physicochemical investigations have shown that the formation of metal-containing nanoparticles depends on the properties of the porous polymeric structure, the nature of the initial metal precursor, and the synthesis conditions. The use of nanosized catalysts is revealed to be effective in the most important field of fine organic synthesis: preparation of materials for medicine, vitamins, and food additives (e.g., in the food and pharmaceutical industry).
Key-Words: - nanosized catalysts, oxidation, hydrogenation, medicine, vitamins, pharmaceutical industry
1 Introduction The main goal of constructing and maintaining an innovative economic model requires the use and development of nanotechnologies, as they can be used to create new economically competitive goods. On the other hand, the general discussion on the prospective implementation of nanosystems seems to be groundless and unreasonable; however, it is necessary to indicate the industrial branches and directions where the application of nanosystems is of certain value. For chemistry and chemical technology, such a branch is certainly represented by metal complex catalysis. The general applications of this method have been evolving in an explosive manner: while in the period of 1996– 2005, papers on this subject made up approximately 1.7% of the total number of investigations, currently the number of works on catalysis has increased up to 5.4% from 2.9% of all scientific publications. The possibilities of the development and application of nanosized catalysts were proven in numerous papers [1–7]. Special interest appears to be related to their use in such a field of fine organic synthesis, as preparation of materials for pharmaceutical and
food manufacture (active pharmaceutical ingredients (API), vitamins, food additives, etc.).
Taking the above mentioned into consideration the discussion of nanotechnical innovations for vitamin synthesis (including food additives) and medications seems very timely and useful. Moreover, the recently obtained results in this field are very informative for both the technological and environmental aspects of chemical industry, because the implementation of new efficient techniques should diminish the overall time it takes to obtain target materials and reduce the total number of synthesis steps and/or replace them with more efficient ones. The use of safe and environmentally friendly solvents instead of toxic and dangerous media should favor the goals of environmental protection.
Nowadays, at least one catalytic step is included into the modern industrial synthesis sequence to produce such compounds as vitamins A, E, K, C, B6, β-carotene, calcium gluconate, and a number of other next-generation API and BAA that often contain pure optically-active isomers. One of the goals of presented investigation is to improve
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the existing technologies using an integrative innovative approach which includes the replacement of several synthesis steps with catalytic one; optimization of the efficiency of existing catalytic steps via utilization of new, more active, selective and operationally stable nanosized catalysts instead of traditional ones; application of new chiral modifiers immobilized on a polymeric matrix; minimization of side products; and using environmentally friendly solvents.
Heterogeneous catalysts are known to provide a more convenient choice for the needs of industry. Most of inorganic matrices are presented by the classical supports for heterogeneous catalysts (SiO2, Al2O3 and TiO2) [8]; however, they usually contain pores with a rather broad and poorly reproducible size distribution [9, 10]. The most important part of the nanostructured inorganic matrix is made up of nanocarbon materials (nanotubes, nanofibers, mesoporous soot, etc.) and celites which possess various regular structures and pores 0.3–1.0 nm in size that are characterized by quite narrow distributions (more than 150 types of celites). Another option is provided by the use of specially developed nanostructured polymeric matrices [11]. Micelles of amphiphilic block co-polymers immobilized on inorganic supports, polyelectrolytes of both cationic and anionic types, ultrathin nanoporous films (membranes) [11, 12], and dendrimers [7] have been investigated as nanostructured polymers which allow controlling the formation, morphology, sizes, and resulting properties of nanopolymeric composites. The nanoparticles formed in polymer matrix directly control the nanopore surface. Such hybrid materials prevent the agglomeration of nanoparticles and do not require stabilizing ligands, which makes nanoparticles more active in catalytic processes [9, 10]. The selection of hypercrosslinked polymeric matrices is confined by porous membranes on the basis of polyacrylic acid crosslinked by a bifunctional epoxide [13–15] and polystyrene-based materials (HPS) [16, 17].
In this review the data on the influence of HPS structure and conditions of catalyst formation on the properties of noble metal nanoparticles, their sizes and morphology, as well as catalytic properties in the syntheses of intermediates for the production of vitamins and medications were gathered and summarized. The catalysts developed were described by the number of physicochemical methods including X-ray fluorescence analysis (XFA), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), and low-temperature nitrogen physisorption (BET).
2 Synthesis and study of noble metal
nanoparticles in pores of HPS
The representative of a new type of polymeric HPS-based networks, which was synthesized at the Laboratory of Sorption Processes Stereochemistry of INEOS RAS for the first time, has shown a unique topology and, therefore, a number of unusual properties [16, 17]. In order to prepare a hypercrosslinked net, two conditions needed to be fulfilled: (1) the polymer had to have been prepared in the presence of a proper solvent to prevent phase separation and the formation of an open network microstructure and (2) the resulting polymeric lattice should have a rather rigid conformation structure to avoid its collapse due to solvent removal. The HPS material was prepared by the incorporation of a high number of CH2-bridges between the neighboring phenyl rings of linear polystyrene with the formation of porous structure. The high degree of polymeric cross-linking provided its conformational rigidness and high porosity. Rigid hypercrosslinked polymers are known to have huge inner surfaces, usually within the range of 1000–1500 m2/g, and the ability to swell in any liquid medium, including precipitators for the initial polymer [16–18]. The proposed concept for the metal nanoparticles formation in nanoporous HPS matrix was based on the ability of the material itself, which was also characterized by rather narrow size distribution, to control the growth of metal nanoparticles inside it. This thought appeared very prospective for the synthesis of new polymer-based catalytic systems.
Thus, the HPS acted both as the nanostructured matrix for the control of nanoparticle growth and the support for the catalytically active particles formed. Moreover, as soon as the HPS was found to be able to swell in any solvent, good access to catalytic centers should be observed for practically all reaction media, including water.
In our earlier papers [19–21], the nanosized (micro-) pores of HPS (around 2 nm) were proven to be responsible for the controlled formation of cobalt and platinum nanoparticles. Cobalt was introduced into the HPS matrix as a solution of Co2(CO)8 in DMF (a relatively stable complex [Co(DMF)6]
2+[Co(CO)4]2–formed), followed by
thermal treatment at 200°C. Platinum was incorporated into the polymeric matrix by via the sorption of H2PtCl4 from its tetrahydrofurane (THF) solution. In contrast to the synthesis of cobalt nanoparticles, the nanoparticles of platinum were prepared by the reduction of the precursor with gaseous hydrogen at ambient temperature in order to
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restrict the migration of particles inside HPS. According to the TEM data, the average particle diameter was determined to be 2.1 ± 1.0 nm for cobalt and 1.3 ± 0.3 nm for Pt. Most likely, the size distribution of cobalt and platinum particles could arise from the different formation mechanisms for these metal nanoparticles. The initial nucleus of cobalt were formed at 200°C and migrated easily in pores of HPS, resulting in the formation of particles in accordance to pore size. In case of platinum, this reduction was performed at room temperature, and the solid-phase migration of isolated atoms or nucleus of platinum was significantly retarded. Therefore, while the HPS matrix controlled the size of metal nanoparticles directly for the formation of cobalt nanoparticles (restricting physically their sizes by the pore size (2 nm)), for platinum the pores limited the quantity of the compound-precursor which filled each separate pore. During the reduction with hydrogen, the volume of precursor particle was reduced to the size of metal particle due to the increase of metal in density over its precursor compound [11]. The platinum-containing metal polymeric composite based on HPS revealed remarkable catalytic and stability properties in the direct selective oxidation of L-sorbose to 2-keto-L-gulonic acid (which is intermediate in the synthesis of vitamin C) and allowed excluding the acetonation of hydroxyl groups of the starting monosaccharide, followed by polymeric system under investigation appeared to be determined by the completely microporous structure of HPS (pore size ≤2.0 nm), which limited the mass transfer of reagents and therefore reduced catalytic efficiency. Moreover, some micropores were clogged up by platinum compounds, making the area inaccessible for the substrate.
To avoid this disadvantage, we investigated the formation of noble metal nanoparticles in the matrix of the commercially available HPS MN 270 (Purolite Int., (UK)), which contained all types of pores: micro- (≤2 nm), meso- (2.1–5.0 nm), and macropores (>50 nm). The occurrence of unclogged meso- and macropores in the polymeric matrix would favor the mass transfer of reagents; however, the presence of macropores made control over the size of the metal nanoparticles formed non-evident. The monograph [22] summarized data on the synthesis and investigation of platinum nanoparticles in the matrix of mixed micro-macroporous HPS. The insertion of platinum was performed in a manner identical to that described elsewhere [20] by the sorption of tetrachloroplatinic acid from its solution in THF. It is noteworthy that the presence of macropores in the polymeric HPS
matrix had almost no effect on the size and structure of platinum nanoparticles formed. According to the TEM data, the average size of particles was calculated to be 1.6 ± 0.6 nm (with rather narrow size distribution), the XPS investigation demonstrated the presence of Pt(0), Pt(II), and Pt(IV) species, which was also detected for nanoparticles in the microporous HPS matrix. The reduction of platinum and formation of nanoparticles were proven to proceed due to the oxidation of THF to tetrahydrofurane-2-one, the removal of the isopropylidene protection with oleum (this is rather usual for the non-catalytic oxidation of L-sorbose) [11]. The only drawback of the platinum-containing metal tetrahydrofurane-2-ol, and 4-hydroxybutyral species [20]. To study the influence of the pore size on the catalytic properties of the respective samples, the behavior of the platinum-containing catalysts in the selective oxidation of L-sorbose was investigated.
As expected, the presence of macropores significantly improved the mass transfer and catalytic properties of platinum nanoparticles based on micro-macroporous HPS; namely, catalytic efficiency increased by a factor of 4.6 while the induction period of the reaction (the time required for the formation of catalytically active sites) reduced from 100 up to 60 min [12, 22].
The optimization of the synthesis conditions and nanoparticle composition has become the next step of the research (see below). According to the literature [23, 24], Pt(IV) catalyses the reactions of catalytic oxidation effectively in the states of hydrated oxide and hydroxide, as well as in the form of free ions; therefore, the conditions for the formation of platinum-containing nanoparticles were changed.
Considering all the above mentioned, the synthesis and structure of mono- (Pt, Ru, Pd), bi- (Pt–Pd, Pt–Ru, Pd–Ru), and trimetallic nanoparticles (Pt–Pd–Ru) formed in pores of polymeric HPS matrix were investigated. The metals chosen demonstrate the maximal activity in reactions of regio- and enantioselective hydrogenation [24–28], as well as toward the catalytic oxidation of monosaccharides [23, 29–31], which are widely used in the API synthesis. The impregnation of metals into the polymeric matrix was performed by the sorption of respective precursors and led to catalytic systems containing 0.1–5 wt. % of active metal. Because of the complex nature of sorption interaction and the participation of various starting components of catalytic systems (the organic matrix of hypercrosslinked polystyrene and inorganic compound of target metal), the
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Fig. 1. TEM images of (a) HPS-Pt (3% Pt), (b) HPS-Pd (3% Pd), and (c) HPS-Ru (3% Ru).
mixture of tetrahydrofurane–methanol–water (THF–MeOH– H2O) was chosen as optimal for dissolution of precursors (as a result of the numerous preliminary experiments). In Table 1, the data in the conditions of the formation and structure of noble metal nanoparticles immobilized on HPS are also reported.
2.1 Platinum-containing nanosized catalysts The platinum-containing nanosized
catalysts (Table 1, 1–6) were synthesized by the sorption of H2PtCl6 · 6H2O from the complex solvent THF–MeOH–H2O in the HPS matrix, followed by sodium bicarbonate treatment for the precipitation of platinum(IV) oxide [32–34]. The TEM investigation (Fig. 1a) revealed no influence of platinum quantity (Table 1, 1–6) on the resulting nanoparticle size; moreover, the average particle size was found (2.1–2.3 nm) to not differ significantly from those of the earlier described sample [22]. The data repeatedly showed that the possible size of the nanoparticles was determined by the polymeric HPS matrix as a direct function of the inner micropores size. The investigation of porosity distribution was performed by BET, and it demonstrated the presence of micropores (≤2 nm) and mesopores, the most abundant of which were approximately 4 nm in size. A fraction of bigger mesopores was also detected (15–30 nm). As it was already mentioned above, the occurrence of rather wide meso- or macropores is highly desirable, as far as they favor the mass transfer to the active catalytic sites. The average size of mesopores during the formation of Pt-nanoparticles was shown to stay unchanged, in contrast to their specific inner volume, which decreased proportionally to the increase in platinum content (Table 1, 1–6). Platinum nanoparticles likely stayed in 4 nm mesopores in the openings of bigger micropores (~2 nm). It is noteworthy that immobilization did not influences the size of the mesopores and did not
clog them up (the size of the nanoparticles was approximately 40% less than the pore’s inner section).
The presence of oxygen, carbon, platinum, chlorine, and sodium was detected in all the samples by HPS. Thus, the platinum-containing nanoparticles were likely surrounded by NaHCO3 and/or organic ligands, e.g. products of THF oxidation [20]. Nanoparticles were found to contain a mixture of Pt(IV), Pt(II), and Pt(0) species, which is in accordance with to earlier reported results [20, 22]. It is noteworthy that the optimization of preparation conditions (i.e., the use of sodium bicarbonate and complex solvent), resulted in change of the ratio of platinum species in mixed nanoparticles regardless of the metal loading. More than 90% of species were represented by Pt(IV) and Pt(II) and only a few by Pt(0). If neither the complex solvent for the impregnation nor the treatment with NaHCO3 was used, the platinum nanoparticles were found to contain 26% Pt(0), 48% Pt(II) and 26% Pt(IV). The most significant decrease of Pt(0) content indicated the influence of NaHCO3 treatment on the formation of insoluble oxides of a mixed nature, most likely PtO2 · 2PtO and PtO2 · H2O [32, 34]. This effect might be responsible for the high stability of both nanoparticles and catalysts.
The catalytic properties of platinum-containing nanoparticles (Table 1, 1–6) were tested in the reaction of the selective oxidation of monosaccharides (see below).
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Table 1. N
anosi
zed c
atal
yti
c sy
stem
s on t
he
bas
is o
f nob
le m
etal
s im
mob
iliz
ed i
n t
he
HP
S m
atri
x [
35 -
38]
Expt.
num-
ber
Catalyst
Content
of metal,
%
(XPA)
Metal
precursor
Extra
chem
ical
treatm
ent
Mean
diameter
of
nanopar-
ticles, nm
(TEM)
Specific
surface
SBET,
m2/g
Metal state (XPS)
H
PS
(M
N 2
70)
1484
1.
HP
S -
Pt
(5%
Pt)
4.8
5
H2P
tCl 6
· 6
H2O
N
aНC
O3
2.2
968
Pt(
0),
Pt(
II),
Pt(
IV)
2.
HP
S -
Pt
(3%
Pt)
2.9
1
2.1
1015
Pt(
0),
Pt(
II),
Pt(
IV)
3.
HP
S -
Pt
(1%
Pt)
0.9
5
2.3
1156
Pt(
0),
Pt(
II),
Pt(
IV)
4.
HP
S -
Pt
(0.3
% P
t)
0.2
7
2.2
1347
Pt(
0),
Pt(
II),
Pt(
IV)
5.
HP
S -
Pt
(0.1
% P
t)
0.1
1
2.3
1400
Pt(
0),
Pt(
II),
Pt(
IV)
6.
HP
S -
Pt
(6%
Pt)
5.8
1
2.1
782
Pt(
0),
Pt(
II),
Pt(
IV)
7.
HP
S -
Pd (
5%
Pd)
4.8
3
Na 2
PdC
l 4
NaН
CO
3
7.6
, 25.0
649
Pd(I
I)
8.
HP
S -
Pd (
3%
Pd)
2.8
9
35.6
705
Pd(I
I)
9.
HP
S -
Pd (
1%
Pd)
0.9
4
32.1
890
Pd(I
I)
10.
HP
S -
Pd (
0.3
% P
d)
0.2
8
22.3
1106
Pd(I
I)
11.
HP
S -
Pd (
0.1
% P
d)
0.0
9
6.7
1118
Pd(I
I)
12.
HP
S -
Ru (
5%
Ru)
4.8
3
Ru(O
H)C
l 3
NaO
H,
H2O
2
1.2
1172
Ru(0
), R
u(I
V)
13.
HP
S -
Ru (
3%
Ru)
2.8
9
1.1
1225
Ru(0
), R
u(I
V)
14.
HP
S -
Ru (
1%
Ru)
0.9
4
1.3
1264
Ru(0
), R
u(I
V)
15.
HP
S -
Ru (
0.3
% R
u)
0.2
8
1.2
1285
Ru(0
), R
u(I
V)
16.
HP
S -
Ru (
0.1
% R
u)
0.0
9
1.1
1295
Ru(0
), R
u(I
V)
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2.2 Palladium-containing nanosized catalysts The palladium-containing catalysts based on
HPS (Table 1, 7–11) were prepared in a way similar to that described above for platinum materials: by the sorption of Na2PdCl4 from the complex solvent, followed by treatment with sodium bicarbonate. In contrast to platinum nanoparticles, palladium ones quite differ and have an alternative mechanism of formation. The TEM investigation revealed that the size distribution for the palladium nanoparticles is rather complex (Table 1, 7–11). For example, the sample HPS-Pd (5% Pd) no. 7 contained two fractions: particles with average diameters of 7.6 nm and bigger aggregates with diameter of 25.0 nm (Table 1, 7). The samples HPS-Pd (3% Pd) (Fig. 1b) and HPS-Pd (1% Pd) contained no small fraction, and the average diameter of rather bulky particles was found to be 35.6 and 32.1 nm, respectively (Table 1, 8, 9). The following decrease of Pd content in samples up to 0.3 and 0.1% led to the decrease of the average diameter of palladium nanoparticles up to 22.3 and 6.7 nm, respectively (Table 1, 10, 11). The formation of bigger palladium nanoparticles is in accordance with the data of the specific surface area (BET method) (Table 1, 7–11). In comparison to platinum samples, the surface area of palladium ones was found to decreased approximately in 1.5 times for the samples with the same metal content. Moreover, the partial volume of smaller mesopores (about 4 nm) stayed practically unchanged, while the volume of bigger mesopores (15–30 nm) decreased with the increase of palladium content, which is due to the formation of palladium nanoparticles in bigger mesopores of HPS. On the basis of the data presented, the formation of 20–30 nm palladium nanoparticles was likely caused by the low compatibility of the inorganic precursor with HPS. Nevertheless, in contrast to platinum, palladium does not coordinate THF and does not form the products of its oxidation [32]. Thus, the palladium nanoparticles were not homogeneously distributed in the 4 nm mesopores (as it was observed in the case of platinum) but aggregated in bigger mesopores, resulting in much bulkier nanoparticles characterized by the high degree of poly dispersity. According to the XPS data (Table 1, 7–11), the calculated binding energy for palladium-containing nanoparticles corresponded to Pd2+ for all samples, irrespective of the active metal loading; e.g. the oxidation level of palladium did not change during the incorporation into the pores, which was also confirmed by the absence of any signs of THF oxidation. As the process of nanoparticles formation included the treatment with sodium bicarbonate, the hydrated
palladium oxide PdO · xH2O was most likely precipitated [32, 34].
The catalytic properties of palladium-containing nanoparticles were tested in the reactions of the selective oxidation of monosaccharides and the selective hydrogenation of acetylene alcohols (see section 3.2, Fig. 4).
2.3 Ruthenium-containing nanosized
catalysts For the synthesis of ruthenium nanoparticles
stabilized into the HPS matrix, several specific features of ruthenium inorganic compounds and their behavior in solutions should be taken into account [32, 34]. Unlike other noble metals, ruthenium has the unique ability to take various valence states (from 0 to 8). The versatility of the transitions from one valence state to another results in the enormous complexity and originality of the chemistry of ruthenium compounds [32, 34]. As a starting material for the synthesis of ruthenium nanoparticles in HPS matrix, ruthenium (IV) hydroxychloride (Ru(OH)Cl3) was used as a solution in the complex solvent THF–MeOH–H2O. The ruthenium-containing HPS was treated with the alkaline solution of hydrogen peroxide to ensure the precipitation of hydrated ruthenium (IV) oxide. The TEM data showed that the ruthenium-containing nanoparticles in the HPS matrix had diameters of 1.1–1.3 nm and rather narrow size distribution regarding to the metal loading (Table 1, 12–16; Fig. 1c).
According to the low-temperature nitrogen physisorption (Table 1, 12–16), a minor decrease of HPS surface was observed proportional to the total amount of adsorbed ruthenium salt. At the same time, the increase of ruthenium loading in the HPS matrix from 0.1 up to 5% caused the decrease of the specific volume for 4-nm mesopores (Fig. 2), which revealed the formation of Ru-containing nanoparticles in these nanopores or in the places of their openings into micropores, which is similar to the platinum nanoparticles.
By XPS investigation of the binding energy of 3p sublevel of ruthenium (Table 1, 12–16), the As it was shown before for platinum nanoparticles, in the case of ruthenium, the XPS data revealed the presence of oxygen, carbon, chlorine, and sodium, along with metal in all the samples tested; however, the ruthenium nanoparticle size was revealed to be significantly smaller than is the case of platinum samples. This difference is likely caused by the formation of various species of hydrated ruthenium oxide RuO2 · xH2O in the presence of water, which is reported [39] to favor the formation of smaller
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Fig. 2. Dependence of pore volume vs. pore diameter for ruthenium-containing catalysts of different metal
loading. Data for mesopores are presented in the insertion.
Fig. 3. Direct catalytic oxidation of D-glucose to D-gluconic acid.
nanoparticles. For platinum, the used conditions allowed the formation of both hydrated and water-free oxides and salts.
The data obtained from a physicochemical study of the metal-containing nanoparticles immobilized in HPS clearly demonstrated the strong influence of a variety of factors on the formation and growth of nanoparticles in the solid polymeric matrix, namely, the nature of the polymer itself (i.e. its chemical structure and porosity) and the nature of metal precursor, as well as synthesis conditions (solvent, the use of alkaline agent (and the certain pH of the medium), temperature, etc). In the following sections, the catalytic properties of the
nanosized systems on the basis of noble metals (Pt, Pd, Ru) and HPS in the reactions of selective oxidation, regioselective hydrogenation are described.
3 Nanosized catalysts based on HPS in
the processes of oxidation and
hydrogenation
3.1 The Catalytic Properties of Noble-Metal-
Based Nanoparticles for Monosaccharides
Oxidation (the Synthesis of Intermediates of
Vitamin C and Calcium Gluconate)
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Nowadays, many techniques for the production of vitamins and medications involves reactions of monosaccharides oxidation [23, 40–42].
The catalytic oxidation of D-glucose to D-gluconic acid, which is further extracted in the form of calcium D-gluconate, is used for the synthesis of D-arabinose, a pivotal intermediate in the synthesis of vitamin B2 [41, 46]. Moreover, calcium D-gluconate is used as a drug itself. Because of its polyfunctional nature, D-glucose undergoes oxidation in different directions under the influence of various oxidizing agents (Fig. 3). There are three types of selective oxidizing agents used in the chemistry of carbohydrates [44, 47]: oxidizers for the selective conversion of the semi-acetal group, reagents for the selective oxidation of hydroxyl groups, and those which are used for the cleavage of α-glycol fragment. The semi-acetal group is the easiest to undergo oxidation. The action of mild oxidizers leads to the consumption of one equivalent of oxygen and the respective formation of D-gluconic acid.
For the selective oxidation of monosaccharides (D-glucose), the series of nanosized catalysts on the base of HPS and noble metals (Pt, Pd, Ru) was developed (see above) [22, 48]. The kinetics of monosaccharides oxidation was investigated varying the initial substrate concentration (C0 mol/l), the catalyst concentration Ccat mol/l), and the temperature. On the basis of experimental data, the values of the apparent activation energy for all the catalytic systems were calculated and mathematical models to describe the kinetics of the process properly were constructed; possible oxidation mechanisms were discussed [21, 22, 48].
For all the nanosized catalysts, the optimal process conditions (substrate concentration, catalyst concentration, temperature, concentration of alkalinizing reagent, pH of the reaction medium, rate of oxygen supply, and intensity of stirring) provided both the maximal catalytic activity and regioselectivity were determined.
Table 2 shows the data on the activity and selectivity of the catalytic systems under investigation (for details, see Table 1) in comparison with the industrial catalysts for the oxidation of D-glucose to D-gluconic acid. The catalytic activity was defined as the substrate-to-catalyst (catalytically active metal) molar ratio per second (TOF).
The data presented clearly showed that the HPS-Ru (1% Ru) is the best for the D-glucose oxidation. In comparison with the industrial samples for both processes, the nanosized catalysts revealed
substantially higher activity. We suppose that the higher activity of the catalysts presented could be explained by the nanoeffect [49, 50]. Besides, the certain metal loading caused the achievement of optimal ratio of metal : support : substrate : solvent during the formation of catalytically active sites.
In addition, the stability of HPS-Ru (1% Ru) samples during their multiple use in selective oxidation of D-glucose was investigated. The selectivity of monosaccharides oxidation remained constant up to tenth repeated use, while the activity was slightly reduced (by 1.2%), which corresponded to the minor loss of catalyst. The existing industrial analogues demonstrated the drops of selectivity and activity by 12 and 42%, respectively, under the same conditions. The results obtained showed the high potential of nanosized catalysts for the industrial scale synthesis of vitamin C, calcium gluconate, and corresponding API on their base.
3.2 The Catalytic Properties of Noble Metal
Nanoparticles in the Selective Hydrogenation
of Acetylene Alcohols Selectivity is the most complicated problem
for the partial catalytic hydrogenation of acetylene alcohols to olefin ones, which have wide application in the production of vitamins A, E, and K [12]. Figure 4 shows the integrated hydrogenation scheme of long-chained acetylene alcohols: 3,7-dimethyl-6-octen-1-yn-3-ol (dehydrolinalool, DHL, C10), 2-methyl-3-butyn-2-ol (dimethylethynyl carbinol, DMEC, C5), and 3,7,11,15-tetramethyl-1-hexadecyn-3-ol (dehydroisophytol, DHIP, C20) to respective olefinic alcohols: 3,7-dimethyl-1,6-octadien-3-ol (linalool, LN), 2-methyl-3-buten-2-ol (dimethylvinylcarbinol, DMVC), and 3,7,11,15-tetramethyl-1-hexadecen-3-ol (isophytol, IP). The synthetic vitamin E is usually produced via condensation of trimethylhydroquinone and isophytol (IP) [51]. IP in turn can be synthesized by various methods, one of which is a combination of elongation reactions using C3 and C2 fragments. Acetone, ethyne and molecular hydrogen serve as starting compounds. The elongation reactions are often followed by reactions of catalytic hydrogenation [25], and LN is an intermediate of IP synthesis.
The selective hydrogenation of the triple bond of acetylene alcohols (DMEC, DHL, DHIP) to the double one is the main goal of the synthesis of the synthesis ethylene alcohols
(DMVC, LN, and IP) [52].
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Table 2. Catalytic properties of metal-containing nanosized catalysts on the basis of HPS (MN 270) toward the oxidation of D-glucosea
Expt.
number Catalyst (for composition see
Table 1)
Oxidation of D-glucose
Activity,
×103 mol/(mol s)
Selectivity
toward target
product
(conversion), %
1. HPS-Pt (5% Pt) 0.7 98(92)
2. HPS -Pt (3% Pt) 0.4 99(90)
3. HPS -Pt (1% Pt) 0.1 99(91)
4. HPS -Pt (0.3% Pt) 0.2 98(90)
5. HPS -Pt (0.1% Pt) 0.1 99(85)
6. HPS -Pd (5% Pd) 0.5 99(88)
7. HPS -Pd (3% Pd) 0.2 99(87)
8. HPS -Pd (1% Pd) 0.1 99(85)
9. HPS -Pd (0.3% Pd) 0.2 99(84)
10. HPS -Pd (0.1% Pd) 0.1 99(81)
11. HPS -Ru (5% Ru) 0.8 98(92)
12. HPS -Ru (3% Ru) 1.0 99(94)
13. HPS -Ru (1% Ru) 1.2 ~99(100)
14. HPS -Ru (0.3% Ru) 0.7 99(92)
15. HPS -Ru (0.1% Ru) 0.6 99(92)
Pd(5%)Bi(0/5%)/C 0.9 99(100) a The reaction was performed in water (25 ml) at 60°C at the atmospheric pressure of oxygen; the rate of oxygen flow was 14 × 10–6 m3/s, stirring rate was 1000 rpm; the reaction time was 8.4 × 103 s. Ccat = 1.2 × 10–3 mol/l, C0 = 0.44 mol/l, and C = 0.44 mol/l
The non-selective carrying out of the reactions leads to a variety of undesirable side products (pentanol-3, dihydrolinalool, and dihydroisophytol) (Fig. 4).
Nowadays, the modified Pd- and Ni-based catalysts immobilized on inorganic supports are the most widely used for the selective hydrogenation of the triple bond to a double one [53, 54]. The existing industrial method for the hydrogenation of acetylene alcohols is based on the use of Lindlar catalyst (Pd/CaCO3 modified with lead acetate and quinoline), which provides the selectivity of 95% at 100% conversion [54]. However, the use of modifiers results in the contamination of the final products and negatively affects the environment. The use of new nanosized metal polymeric catalysts allows one to avoid the above-mentioned drawbacks; therefore, the quality of target products and environmental safety of the processes can be significantly improved, along with the substantial reduction of noble-metal leaching.
Palladium-containing catalysts based on HPS (Table 1, 7–11) were tested in selective hydrogenation of acetylene alcohols C10, C20, and C5. The optimal conditions of triple bond selective hydrogenation were found varying the initial substrate concentration (C0 mol/l), the catalyst concentration (Ccat mol/l), the temperature, the intensity of stirring, and the hydrogen pressure. The results are presented in Table 3.
The presented data revealed the HPS_Pd (0.1% Pd) system as the most efficient one which provides the maximal activity and selectivity of DMEC, DHL, and DHIP hydrogenation. It is noteworthy that the elongation of the substrate chain length resulted in the decrease of both activity and selectivity which is likely due to the increase of the steric factor contribution. In comparison to traditional catalysts (17, 18), nanosized catalysts on the basis of HPS show considerably higher activity (two- to fourfold growth) and selectivity, and they make a prospective alternative for use in the industrial schemes of regioselective hydrogenation.
4 Conclusions The developed preparation methods of Pt,
Ru, Pd-nanoparticles in the pores of HPS allowed synthesizing the active, stable, and selective nanocatalysts for the number of important processes widely used in the synthesis of API. According to the physicochemical investigation using XPA, XPS, TEM, and low-temperature nitrogen physisorption (BET), the size of metal-containing nanoparticles formed was proven to depend on (1) the porous structure of the matrix which controlled the nanoparticle growth; (2) the nature of metal precursor, which influences the affinity to the polymeric matrix; and (3) the conditions of the synthesis themselves.
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Table 3. Catalytic properties of palladium-containing nanocatalysts on the basis of HPS (MN 270) and industrial catalysts toward the hydrogenation of acetylene alcoholsa
Expt.
number Catalyst (for composition see
Table 1) Substrate Selectivity toward
target product, % Activity,
b
mol/mol Pd s
1 HPS -Pd (5% Pd) DHL 96.5 12.5
2 HPS -Pd (3% Pd) 97.6 16.9
3 HPS -Pd (1% Pd) 97.8 14.4
4 HPS -Pd (0.3% Pd) 98.0 19.2
5 HPS -Pd (0.1% Pd) 98.5 21.0
7 HPS -Pd (5% Pd) DHIP 97.5 2.3
8 HPS -Pd (3% Pd) 95.2 2.5
9 HPS -Pd (1% Pd) 96.0 5.6
10 HPS -Pd (0.3% Pd) 97.2 7.8
11 HPS -Pd (0.1% Pd) 97.5 10.3
12 HPS -Pd (5% Pd) DMEC 97.5 9.8
13 HPS -Pd (3% Pd) 96.3 10.4
14 HPS -Pd (1% Pd) 97.2 12.9
15 HPS -Pd (0.3% Pd) 98.4 19.0
16 HPS -Pd (0.1% Pd) 98.5 27.0
17 Pd/Al2O3 (0.5% Pd) 94.4 5.8
18 Pd/CaCO3 (2.0% Pd) 95.3 4.7 a The reaction was performed in toluene (30 ml) under an atmospheric pressure of 90°C using an oscillating machine, the rate of oscillation was 960 min–1; Ccat = 2.3 × 10–5 mol Pd/l and C0 = 0.44 mol/l. b The activity value was calculated as the number of moles of the product formed per mole of Pd in a second.
Fig. 4. Hydrogenation of long-chained acetylene alcohols DHL, DHIP, and DMEC (Table 3).
The investigation of the catalytic properties of noble-metal nanoparticles immobilized in the pores of HPS revealed the high potential for their use in the reactions of the selective oxidation of monosaccharides (D-glucose); the hydrogenation of acetylene alcohols C5, C10, and C20; to obtain valuable intermediates for the synthesis of vitamins C, A, E, and K, as well as some other medications.
Thus, the nanosized catalysts developed were not only of obvious scientific interest but were also of practical value due to the number of useful features: the rather modest requirements for the purity of raw materials and reagents, the simplicity
of the equipment and performance procedure, the high yields of target products, environmental safety, stability, etc. (properties which are highly important for industrial use).
The industrial use of nanosized catalysts on the base of the HPS matrix seems quite realistic, because HPS is being manufactured by Purolite Int. (UK) and offered at the reasonable cost of $10/kg.
The development of highly active nanocatalysts for oxidation process can likely meet other pharmaceutical needs. For example, the nanocatalysts suggested could provide some advantages in the industrial preparation of injection
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forms of insulin using phenol and its derivatives such as stabilizers and preservatives. In addition, metal-containing nanosized systems proved their efficiency in processes of the catalytic purification of phenol-containing waste water.
5 Acknowledgments This research was performed with the
support of programs by the Ministry of Education and Science of the Russian Federation.
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