Amphiphilic Dendrimer as Reverse Micelle: Synthesis, Characterization and Application as Homogeneous Organocatalyst

Journal Pre-proof Amphiphilic dendrimer as reverse micelle: Synthesis, characterization and application as homogeneous organocatalyst P.B. Sherly Mole, Smitha George, A.M. Shebitha, V. Kannan, Suseela Mathew, K.K. Asha, K. Sreekumar PII:

S0040-4020(19)31050-6

DOI:

https://doi.org/10.1016/j.tet.2019.130676

Reference:

TET 130676

To appear in:

Tetrahedron

Received Date: 12 August 2019 Revised Date:

30 September 2019

Accepted Date: 1 October 2019

Please cite this article as: Sherly Mole PB, George S, Shebitha AM, Kannan V, Mathew S, Asha KK, Sreekumar K, Amphiphilic dendrimer as reverse micelle: Synthesis, characterization and application as homogeneous organocatalyst, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130676. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.

Graphical Abstract

Amphiphilic Dendrimer as Reverse Micelle: Synthesis, Characterization and Application as Homogeneous Organocatalyst Sherly mole P. B. †, ‡, *, Smitha George‡, Shebitha A. M. ‡, Kannan. V.II, ‡, Suseela Mathew§, Asha K. K. § and Sreekumar K. ‡,* ‡

Department of Applied Chemistry, Cochin University of Science and Technology, Cochin-682022, Kerala,

India, †Department of Applied Science, Model Engineering College, Thrikkakara, Cochin- 682021, Kerala, India,

II

Department of Chemistry, Government College, Kattappana, Idukki685508, Kerala, India, §The

Central Institute of Fisheries Technology, Cochin-682029, Kerala, India.

The core and surface terminal groups are the two main catalytic sites in a dendrimer. In most of the reported examples, the catalytic sites in dendritic catalysis are the surface terminal functional groups. This perspective article concerned with the dendrimer based catalysis, involving these two catalytic sites and the dendrimer cavities. The interior cavities provide the nanoscale reactor sites, by creating reverse micelle like appearance for catalysis. In exploring the significant achievements in this area, a low generation PAMAM dendrimer with amphiphilic nature, having a polymeric core with large number of pendent amino groups was synthesized and concentrated its catalytic activity. The key features with respect to positive and/or negative catalytic activity was highlighted by synthesizing various aryl and heteroaryl 2-substituted benzimidazoles. The synthesized dendritic organocatalyst was proved to be amazingly reactive and gave high yield of products within a few minutes at room temperature with low catalyst loading. Here, a new stable hemiaminal, the species rarely been detected and much less isolated in bulk, was obtained during the synthesis of benzimidazoles. Moreover, this is the first reported method for the synthesis of benzimidazoles, using the homogeneous PAMAM dendrimer as a basic organocatalyst. Keywords:

organocatalyst, homogeneous catalyst, benzimidazoles, dendritic effect, reverse micelle,

hemiaminal

1 Introduction Dendritic organocatalysis is an emerging area of research due to the green reaction delivery and efficiency of the catalysts [1]. The unique architecture of dendrimers like uniformity, monodispersity, the extraordinary branching and high loading present in a confined space and 1

globular conformation at higher generations has stimulated the development of multivalent dendrimers for catalytic applications [2]. The core and surface terminal groups are the two main catalytic sites in a dendrimer. These two possible catalytic sites and the dendrimer cavities, which provide the nanoscale reactor sites for catalysis, make the faster kinetics of dendritic catalysis [3]. The large size of dendritic catalysts compared to products, allow easy removal from the medium and reuse of the catalyst several times. These catalysts are active under green reaction conditions and reduce the use of organic solvents. Most of the reports have focused on heterogeneous dendritic catalysis [4] that benefit from easy removal of catalyst materials, their reusability and possible use at high temperatures. In the case of homogeneous dendritic catalysts, every single catalytic entity can act as a single active site which makes homogeneous catalysts intrinsically more active and selective compared to heterogeneous catalysts. Another interesting feature of homogeneous catalysis by dendrimers is that, both the catalyst and the reactants are in the same phase which offers improved selectivity, high activity, good reproducibility and avoid mass transfer limitations by virtue of intimate contact between the catalyst and reactant(s) [5]. The soluble catalyst, as its active sites on the surface would always be exposed towards the reaction mixture; are easily accessible to the reactants in the system. The number of reported soluble homogeneous dendritic catalysts is very few. The present work was to synthesize a homogeneous dendritic polyamine having large amount of functionality even at the low generation level and its application as homogeneous organocatalyst. A simple and efficient approach have been followed to synthesize G0 and G1 generations of the dendritic polyamine with a three directional polymeric core, by using glycerol as the core initiator and following the divergent strategy. As the polyamine contains a polymeric core, the G0 generation itself was a macromolecule; with the particle size come within the nano range. Here, in addition to the limited amino groups on the periphery of the dendrimer molecule, a large number of pendant amino groups are introduced to the three flexible polyether chains present in the interior of the synthesized dendrimer. The catalytic activity of a conventional dendrimer takes place either in the dendritic interior or at the surface groups. In the newly synthesized dendrimer, all amino groups present both in the interior and surface regions are collectively participating in catalysis. The loss in activity found in conventional dendrimers, due to steric hindrance by the congestion of the 2

terminal functional groups of higher generation is eliminated here. At the same time, the cooperative interaction developed between the large number of catalyst units present inside and periphery of the molecule enhances the activity and/or selectivity, a positive dendrimer effect in a miraculous way. Above all, there is the possibility of formation of catalytic pocket or cavity equipped with precisely positioned amino groups for catalysis, surrounded by the three directional hydrophobic flexible polyepichlorohydrin chain in the dendrimer interior, because the large number of amino groups present in the flexible polyepichlorohydrin chain forms intramolecular hydrogen bonding and thus becomes a tightly packed ball like appearance, with the amino groups inside and polyepichlorohydrin chain outside, as in reverse micelle and can behave as in enzyme catalysis [6]. As the polyamine dendrimer was a macromolecule, with the particle size come within the nanometer range, can be recovered simply by membrane filtration and can be reused. Thus the novel dendrimer corrects the limitations of both homogeneous and heterogeneous dendritic catalysts. Benzimidazoles, the bicyclic molecules obtained by the fusion of benzene and imidazole moieties, is a promising class of bioactive heterocyclic compounds, with a wide spectrum of activities [7]. Benzimidazole pharmacophore is a privileged structure in medicinal chemistry. Many drugs with benzimidazole ring system having different biological activities are obtained by changing the groups on the core structure. The biological activities include, anticancer and antiHIV [8]; antitumour [9]; antimicrobial and antiprotozoal [10]; antiviral [11]; antifungal [12]; antiasthmatic [13]; antibacterial [14] and antiulcer [15]. In addition, benzimidazoles are present as ligands for transition metals, which have potential applications for the treatment of diseases like ischemia-reperfusion injury [16], hypertension [17] and obesity [18]. Some other applications [19] of benzimidazoles are, as fluorescent whitening agent dyes [20] and functional materials [21]. Considering the high therapeutic value, biological activities and industrial applications of benzimidazole nucleus, an attempt was made to synthesize benzimidazole derivatives by using the newly synthesized homogeneous dendritic polyamine as an organocatalyst. 2 Experimental All the solvents were purified according to the standard procedures prior to use. All other chemicals were purchased from local commercial suppliers and used as received. FTIR spectra 3

were recorded by means of JASCO FTIR 4100 spectrophotometer with KBr pellets. GC/MS analysis was carried out on a 1200 L single quadruple, Varian gas chromatograph model. 1

H NMR and

13

C NMR spectra were recorded with a Bruker 400 MHz instrument with TMS

as internal standard and CDCl3 as solvent (SAIF, CUSAT). C-H-N Analyzer used was Elementar Vario EL III (SAIF, CUSAT). MALDI-TOF/MS analysis was performed on Bruker Daltonics Ultrafle Xtreme model equipped with smart beam solid state laser (337 nm) in linear positive ion mode using 19 KV acceleration voltage (RGCB, Thiruvananthapuram), TEM analysis was carried out with JEM 2100 HRTEM (SAIF, CUSAT). Synthesis of Catalyst Preparation of Polyepichlorohydrin (PECH) Epichlorohydrin (10.2 ml, 0.13 mol) was added to a reaction mixture containing dichloromethane (10 ml), glycerol (0.36 g, 4.9 mmol) and BF3-etherate (0.36 ml, 2.8 mmol) with constant stirring. The reaction mixture was stirred for 5 h at room temperature. After completion of the reaction, the reaction mixture was taken in a separating funnel and washed with saturated sodium carbonate solution followed by distilled water. Anhydrous MgSO4 was added and kept overnight and filtered. On removing the solvent under vacuum, PECH was obtained as a colorless viscous liquid. Yield: 8.9 g; IR (cm-1): 3458; 2877, 1422, 1118, 746, MALDI-TOF/MS: M. W. 28,961, -O-H group capacity: 1.9 mmol/ g. O-Methylation of polyepichlorohydrin To a vigorously stirred mixture of PECH (2 g, 21.6 mmol) in THF (50 ml) at 60-65 °C, crushed solid commercial KOH (0.104 mol) was added over a period of 10 minutes and dimethyl sulphate (0.03 mol) was added drop wise over a period of 20 minutes while maintaining the internal temperature mentioned above. The reaction mixture was stirred/ refluxed at 70 °C for 20 h. After completion of the reaction, the reaction mixture was filtered after centrifugation to remove the solid material. Excess of dimethyl sulphate was removed by washing with ammonia solution. The resulting solution was treated with anhydrous MgSO4 and kept overnight and filtered. The excess solvent was removed by rotary vacuum flash evaporator and the polymer was obtained as a honey colored viscous liquid. The product was further purified by column chromatography.

4

Yield: 2.09 g; IR (cm-1): 2923, 2861, 1718, 1453, 1239, 1119, 746; MALDI-TOF/ MS: M. W. 18,970. Conversion of O-methylated PECH to Poly (glycidylazide) (GAP) Stirred slurry of sodium azide (1.52 g, 23.3 mmol) in DMSO (0.5 ml) was added to LiCl (0.011g, 0.25 mmol) taken in an R. B. flask and the reaction mixture was heated to 100 °C. A solution of methoxy PECH (2.01 g, 21.76 mmol) in DMSO (1 ml) was heated to 100 °C in a beaker. This second hot solution was rapidly added to the first reaction mixture with stirring. The resulting mixture was maintained at 100 °C, for 3 days with constant stirring. After completion of the reaction, the excess reagents were removed by washing with hot water in a separating funnel. The organic layer was separated, dried with anhydrous MgSO4 and passed through a column containing silica gel. The solvent, DMSO was removed under vacuum to obtain the polymer as a dark brown colored viscous liquid. Yield: 2.07 g; IR (cm-1): 2923, 2861, 2099, 1656, 1473, 1290, 1106; MALDI-TOF/MS: M. W. 19, 686. Reduction of GAP to Polyamine dendrimer 2 g (0.02 mol) of poly (glycidylazide) was dissolved in anhydrous THF (40 ml) taken in 250 ml double necked round bottomed flask with a magnetic stirring bar, a dropping funnel and a water condenser with attached guard tube containing CaCl2 at the open end of the condenser. The reaction mixture was cooled in an ice bath. A solution of powdered LiAlH4 (0.7659 g, 0.02 mol) in dry THF was added drop wise with constant stirring to the polyazide solution using the dropping funnel. The reaction mixture was stirred at 0 °C for 4 h. The temperature was allowed to rise to room temperature and the reaction mixture was gently refluxed for 1 h. Excess LiAlH4 was decomposed by rapid addition of ethyl acetate (10 ml). The reaction mixture was filtered using methanol. The filtrate and washings were combined and evaporated under vacuum to give the polyamine as a dark brown colored viscous liquid. Yield: 1.45 g; Amine capacity: 2.64 mmol/ g; CHN (%): C-40.02, H-10.13, N-4.17; IR (cm-1): 3369, 1575, 1412, 1106; 1H NMR (CDCl3, 400 MHz): δ 5.15, 3.25-3.70, 3.39, 1.67-2.21; 62.7, 30.0, 26.3, 22.6. Synthesis of G 0.5 PAMAM dendrimer

5

13

C NMR (CDCl3, 400 MHz): δ 80.2,

The polyamine (0.014 mol, 1 g) was added in portions over a period of 1 h to a 100 ml double necked round bottomed flask containing methyl acrylate (6.16 ml, 0.07 mol) and methanol (10 ml) at 0 °C for 30 minutes, with stirring under an atmosphere of N2. The solution was stirred for further 30 min at the same temperature and allowed to come to room temperature and stirred for further 2 days. After the reaction, excess reactants and solvents were removed under vacuum using a rotary vacuum flask evaporator. The product was a dark brown colored viscous liquid. Yield: 3.2 g; IR (cm-1): 2933, 2872, 1656, 1586, 1422, 1106; 1H NMR (DMSO-d6, 400 MHz): δ 3.31-3.57, 3.24, 3.21;

13

C NMR (DMSO-d6, 400 MHz): δ 165.6, 60.7, 57.9, 35.6;

MALDI-TOF/MS: M. W. 18,924. Synthesis of G1 PAMAM dendrimer The above polymer (0.004 mol, 0.98 g) was added in fractions with stirring to a mixture of ethylene diamine (0.2 mol, 12.02 g) and methanol (10 ml) taken in 100 ml double necked round bottomed flask and cooled to 0 °C for 1 h. The temperature was allowed to rise to room temperature and stirred at room temperature for 4 days to ensure complete reaction. After the completion of the reaction, the excess reactants and solvents were removed under vacuum using a rotary vacuum flash evaporator. The product was a dark brown colored semisolid. Yield: 1.94 g; Amine capacity: 5.41 mmol/ g, CHN: C-35.50 %, H-7.48 % N-15.31 %; IR (cm-1): 3468, 2932, 2367, 1628, 1547, 1413, 1090; 1H NMR (CDCl3, 400 MHz): δ 5.84, 3.54, 3.27-3.44, 2.82-3.05; 13

C NMR (CDCl3,400 MHz): δ 163.6, 41.7, 9.6, MALDI-TOF/MS: M. W. 19,092.

Synthesis of Benzimidazoles A mixture of 1, 2-phenylenediamine (5 mmol), aldehyde (6 mmol) and the dendritic polyamine catalyst (4 mg) in ethanol (5 mL) was stirred at room temperature under air atmosphere in a beaker. After completion of the reaction, the reaction mixture was dissolved in acetone and poured into ice cold water. The product was precipitated as pale-yellow solid which was filtered, washed with hot water and dried. The crude product on recrystallization from hot methanol or ethanol gave the pure benzimidazole products. 3 Results and Discussion PAMAM dendrimer with glycerol initiated polyepichlorohydrin (PECH) as the core was synthesized, using the procedure shown in Scheme 1. The first step used for the development of 6

PAMAM dendrimer was the synthesis of polyepichlorohydrin (PECH), by the cationic ring opening polymerization (ROP) of epichlorohydrin (ECH) [22]. The driving force for the ROP is the high ring strain which is in the order of 110-115 kJ/mole for ethylene oxide [23]. Lewis acids like BF3-etherate, SnCl4, SnCl5 or FeCl3 are usually used for that purpose. In the present study, branched hydroxyl terminated polyepichlorohydrin (PECH) was prepared by ring opening polymerization of epichlorohydrin (ECH), in the presence of glycerol as the co-initiator and BF3-etherate as the initiator [24]. Slow addition of monomer during the synthesis, favor the polymerization by activated monomer mechanism. The polymer product obtained was a colorless viscous liquid. The hydroxyl group capacity of PECH was estimated quantitatively and the value obtained was 1.9 mmol/ g.

7

)n )n )n

)n

( (

Scheme 1 Synthesis of PAMAM dendrimer with glycerol initiated polyepichlorohydrin as core In the IR spectrum of (3), the presence of a broad band at 3458 cm-1 and another band at 1118 cm-1 (s) corresponded to the hydroxyl group and ether linkage respectively. An absorption band at 2877 cm-1 and another at 746 cm-1 were due to C-H stretching of -CH2-group and C-Cl stretching of chloromethyl group respectively. A band at 1422 cm-1 could be attributed to C-H deformation of -CH2-O- moiety (see Fig. S1 of the Supporting Information). By employing MALDI-TOF/MS technique, which can give the average size, shape and size distribution of the 8

polymer, the molecular weight was found to be 28,961. The mass spectrum showed that, the polymer sample spans a wide range of molecular weight. This was due to the polymer fragmentation occurred by absorbing the applied laser beam, used for desorption/ionization [25]. From the molecular weight of the polymer, number of repeating units calculated was 310 (see Fig. S2 of the Supporting Information). The O-H group in the polyepichlorohydrin, prepared was protected by methylation. For that, PECH was heated with dimethyl sulphate in the presence of potassium hydroxide in THF medium. The product (4) was a honey colored viscous liquid. From MALDI-TOF/MS method, the molecular weight of the polymer obtained was 18,970 which was less than the molecular weight of PECH, which may be due to the cleavage of some polymer chain during heating in the presence of alkali, for the methylation of O-H group. By absorbing the applied laser beam, the polymer was fragmented and a number of fragments with low molecular weight were obtained. Here two intense fragmented parts with the molecular weights of 999 and 4,098 were observed (see Fig. S3 of the Supporting Information). O-methylated PECH was converted to the azide functionalized polymer like glycidyl azide polymer (GAP), an important energetic polymer with high energy density and high nitrogen content. In the last few decades, a number of methods have been reported for the synthesis of GAP using suitable catalysts. The substitution reaction of PECH with NaN3 in different solvents (organic or aqueous medium) [26], resulted in the formation of GAP. The azidation of PECH required molar excess of ionic azides like lithium azide, sodium azide or potassium azide, because, it was reported that, the azidation reaction slowed down after reaching about 90% conversion. In the present study, the conversion of O-methylated PECH to GAP was done by heating the PECH with sodium azide and lithium chloride as the phase transfer catalyst, in DMSO at 100 ºC [27]. The product (5) obtained was a dark brown colored viscous liquid. By azidation, chlorine was replaced by azide group. The conversion of polyepichlorohydrin to GAP was also monitored by FTIR spectroscopy. The disappearance of the absorption band at 746 cm-1 (due to -CH2Cl group) and appearance of an intense band at 2099 cm-1 and another at 1290 cm-1, indicated the formation of azide functionality (see Fig. S4 of the Supporting Information). The molecular weight of the polymer obtained by MALDI-TOF/MS was 19,686. From the spectrum it was observed that, the fragmentation of the polymer occurred in laser medium and a number of low molecular weight 9

polymer moieties were produced. Two stable fragmented parts of the polymer with high intensity peaks were observed at the molecular weights of 1,209 and 4,096 (see Fig. S5 of the Supporting Information). GAP was reduced to polyamine, the G0 dendrimer (6) using the strong reducing agent, LiAlH4 which has high capacity in reducing azides to amines with high efficiency and at a faster reaction rate. From the FTIR spectra of the polymer, before and after reduction showed that, within five hours all the azide groups were converted to amino groups. The dark brown colored viscous product, on CHN analysis showed the percentage of carbon, hydrogen and nitrogen as 40.02 %, 10.13 % and 4.17 % respectively. Kaiser ninhydrin test was used to identify the presence of amino groups and conductometric titration was used to determine the amino group capacity of the polymer. From the equivalence point of the titration curve, the calculated amino group capacity of the G0 dendrimer (GLY G0) was 2.64 mmol/ g. The vibrational spectrum showed that, the characteristic bands of azide groups at 1290 cm-1 and 2099 cm-1 had disappeared completely and new bands at 3369 cm-1 (N-H stretching) and 1575 cm-1 (N-H bending) corresponding to amino group appeared. A band at 1412 cm-1, was due to C-N stretching vibration of amine (see Fig. S6 of the Supporting Information). This indicated that, the reduction reaction was successful and the polyamine was formed. 1H NMR spectrum is another important tool for elucidating the structure of polyamine dendrimer. The multiplet present between 1.67-2.21 ppm was originated from the methylene protons present in >CH-CH2-NH2 unit in the periphery of the molecule. A signal at 3.32 ppm was corresponding to -OCH3 protons obtained by the methylation of alcoholic group. The multiplet at 3.25-3.70 ppm was due to the backbone -CH2-O- and >CH-O- protons in the molecule. The presence of a signal at 5.15 ppm was due to the amino group in the polymer (see Fig. S7 of the Supporting Information). In the

13

C NMR spectrum of GLY G0, the signals at 80.2 ppm and 62.7 ppm

confirmed the presence methine groups and methylene groups in the backbone. The signals at 30.0 ppm and 26.3 ppm were due to the presence of branched methylene group in the molecule (see Fig. S8 of the Supporting Information). From the MALDI-TOF/MS analysis, the molecular weight of the polymer was observed at 16,802 and the fragmented moiety with high intensity was obtained at 4,246. A number of peaks were formed by the fragmentation of the polymer (Fig. 1).

10

Fig. 1 MALDI-TOF/MS of GLY G0 Transmission electron microscopy (TEM) has the unique feature and advantage of the ability to visualize individual molecules and have been used to determine the diameter and shape of dendrimers. In the case of dendrimers, it is difficult to get their images; due to their small size (2-15 nm) which makes difficulty in the resolution by electron beam techniques. In high-resolution electron microscopy, the visualization of isolated molecules is rare, because most often they are observed in crystalline arrays or assemblies of many molecules. The images of dendritic polymers showed excessive clumping, which makes size measurements difficult. The clumping of dendrimers may be due to the method adopted for the preparation of samples for taking the images [28]. TEM images on analysis showed that, the particles have the size below 50 nm and possess the hexagonal shape. In some regions, the molecules are clumped and overlapped (Fig. 2a). The selected area electron diffraction (SAED) pattern showed the slight crystalline nature of the polymer (Fig. 2b).

11

Fig. 2 TEM image of GLY G0 G0 dendrimer, was converted to the 0.5 generation dendrimer (GLY G0.5) (7), by the double Michael addition of methyl acrylate to the primary amino group. Excess amount of methyl acrylate was taken to ensure complete reaction and to avoid the formation of defected dendrimer. The polymer obtained was a dark brown colored viscous liquid. FTIR spectroscopy and negative Kaiser ninhydrin test results, confirmed the complete conversion of primary amino groups to the ester groups (see Fig. S9 of the Supporting Information). The presence of a band at 1106 cm-1 and another strong band at 1656 cm-1 were due to the presence of C-N stretching of tertiary amino group and >C=O stretching (s) of carbonyl group respectively. In the 1H NMR spectrum (DMSO-d6), the signal at 1.88-2.79 ppm was due to the methylene protons in the -CH2-CH2-CO- moiety in the periphery. The singlets at 3.21 ppm and 3.24 ppm showed the presence of methyl protons in the CH3-COO- moiety and -OCH3 respectively. The multiplet between 3.31-3.57 ppm resulted from the backbone -CH2-O- and >CH-O- protons in the molecule. The signal at 5.15 ppm corresponding to the amino group in the G0 dendrimer has disappeared here. These results showed that the amino group was completely converted to ester group (see Fig. S10 of the Supporting Information). In the 13C NMR spectrum of GLY G0.5 in DMSO-d6, the signal at 165.6 ppm indicated the presence of carbonyl group. The signals at 71.6, 69.8 and 69.6 ppm indicated the presence of -OCH3 and -OCH2- unit in the molecule. The signals at 60.7, 57.9, 57.7 and 56.9 ppm were attributed to the presence of methyl carbon of CH3-COO- group. The signals at 35.6, 29.1 and 25.8 ppm have originated from >CH2 carbon adjacent to carbonyl group of the ester and adjacent to the nitrogen atom of –N(CH2-CH2COOCH3)2 moiety. These results proved the formation of GLY G0.5 (see Fig. S11 of the Supporting Information). MALDI-TOF/MS showed that, the molecular weight of GLY

12

G0.5 as 18,924. From the spectrum, it was observed that, by absorbing the applied laser beam polymer fragmentation occurred continuously. The high intensity fragmented moiety carried the molecular weight of 6,813 (Fig. 3).

Fig.3 MALDI-TOF/MS of GLY G0.5 First generation PAMAM dendrimer (GLY G1) (8) was synthesized by transamination of the ester groups of the G 0.5 dendrimer in methanol kept at 0 ºC. For that, excess amount of ethylene diamine was taken to ensure complete reaction and prevent cyclization. After the slow addition of dendrimer to a solution of excess of ethylene diamine in methanol at 0 ºC, the reaction mixture was stirred for one hour and the stirring was continued at room temperature for four days for the completion of the reaction and a dark brown colored semisolid was obtained. Kaiser test proved the formation of primary amino group in the polymer. On CHN analysis, the percentage of carbon, hydrogen and nitrogen were found as 35.50 %, 7.48 % and 15.31 % respectively. Conductometric titration was used to determine the amino group capacity of the dendrimer. From the equivalence point of the titration curve, the calculated amino group capacity of the GLY G1 was 5.41 mmol/g. FTIR spectrum, showed bands at 1545 cm-1, 3398 cm-1 and 3106 cm-1 which indicated the presence of amine moiety. The band at 1656 cm-1 was due to >C=O stretching vibration. The weak bands at 1442 cm-1 and at 1126 cm-1 were due to C-N stretching vibrations of primary amine (see Fig. S12 of the Supporting Information). In the 1H NMR spectrum, the 13

multiplet between 2.82-3.05 ppm was due to methylene protons in the -CH2-CH2-CO- and -CH2-CH2-NH2 units in the periphery of the molecule. Another multiplet at 3.27-3.44 ppm was observed due to -CH2-O- and >CH-O- protons in the backbone of the molecule. The presence of a singlet at 3.54 ppm confirmed the presence of -OCH3 moiety in the molecule. The signal at 5.84 ppm proved the conversion of ester to amino group (see Fig. S13 of the Supporting Information). In the 13C NMR spectrum of GLY G1, signal at 163.6 ppm was due to the carbonyl stretching and at 41.7 ppm due to the methylene carbon of -CH2-NH2 unit (see Fig. S14 of the Supporting Information). MALDI-TOF/MS of GLY G1 showed that, the molecular weight of the dendrimer was 19,092. A number of peaks with low molecular weight were present in the spectrum and the high intensity peak observed was at 6,672 (Fig. 4).

Fig. 4 MALDI-TOF/MS of GLY G1 From the TEM analysis of GLY G1 in the Fig. 5 (a), the shape of a single particle can be seen, where there is a dense interior part and in the peripheral region, the hydrophilic terminal groups are aligned outward beautifully. In the Fig.5 (b), the particles are clumped and overlapped, which makes size measurement difficult. The selected area electron diffraction (SAED) pattern of the polymer [Fig. 5 (c)], showed the presence of well-ordered arrangement of particles in the lattice sites, which indicates the polymer, is partially crystalline in nature.

14

Fig 5 TEM image of GLY G1 Synthesis of Benzimidazoles A number of methods have been reported for the synthesis of 2-substituted benzimidazole derivatives. Even though, there are many procedures reported for the synthesis of 2-substitited benzimidazole derivatives [29], many of them are associated with many practical difficulties such as tedious workup procedures, drastic reaction conditions, co-occurrence of several side reactions, low yields etc. Here, a simple, convenient and highly efficient method for the synthesis of benzimidazole and its derivatives was introduced by the application of PAMAM dendrimer as a homogeneous organocatalyst. A variety of 2-substituted benzimidazole derivatives have been synthesized in excellent yields by the condensation of 1, 2-diamines and different aldehydes by applying the general preparation method depicted in Scheme 2. Optimization of various reaction parameters like the nature of solvent, temperature, time and the nature and amount of catalyst were evaluated by using 4-bromobenzaldehyde and 1, 2-phenylenediamine as the model reactants. First, the importance of the amount of catalyst for the catalytic activity was investigated by studying the model reaction with different amounts of GLY G1 in ethanol as solvent at room temperature (30 °C). The 100 % yield of the product was given by 4 mg GLY G1. In the case of dendrimers, the catalytic activity largely depends on its conformational state, which in turn depends on the solvation power of the solvent. Thus, the model reaction was studied with different polar solvents at room temperature, under identical reaction conditions as shown in Table 1. The reactions were very fast and gave good yield of products in all solvents, except water. In water, as the solubility of 1, 2-phenylenediamine is low; the yield of product was also low. Whereas the

15

other solvents used were organic solvents, in which the substrates were soluble and hence gave high yield of products. As the reaction was found to occur best in ethanol, further studies were conducted in ethanol. Table 1 Optimization of solvent for the synthesis of benzimidazoles Yield (%)a

Entry

Solvent

1

C2H5OH

100

2

CH3OH

95

3

THF

94

4

CH3CN

92

5

DMF

94

6

CH2Cl2

94

7

H2O

74

a

Reaction conditions: 1,2-phenylenediamine (5 mmol), 4-bromobenzaldehyde

(6 mmol), GLY G1 (4 mg), R. T., solvent (5 mL), 2 min.

The effect of generation of the dendrimer for catalysis was investigated by monitoring the model reaction with GLY G0/G1 as given in Table 2. Normally, the number of amino groups increases with generation and the co-operative effect of these sites enhances the catalytic activity; a positive dendrimer effect, which was demonstrated in the present case. Thus, the optimized condition for the transformation was by stirring 1, 2-diamine (5 mmol) with the aldehyde (6 mmol) in the presence of G1 GLY (4 mg) in ethanol medium at 30 °C. Table 2 Effect of generation on the synthesis of benzimidazole derivatives Entry Generation number Yield (%)a 1 0 97 2 1 100 a Reaction conditions: 1,2-phenylenediamine (5 mmol), 4-bromobenzaldehyde (6 mmol), dendrimer catalyst (4 mg), R. T, solvent (5 mL), 2 min.

After optimizing the reaction conditions, the feasibility of the strategy was explored with a variety of substrates under the optimized reaction conditions and the results are depicted in Scheme 2. The synthesis strategy worked well affording the desired product within a short time, irrespective of whether an electron-withdrawing or an electron donating group was present in the aromatic aldehyde. 2-Nitrobenzaldehyde easily provided excellent yield of the product whereas, the reaction of 4-nitrobenzaldehyde was slow and yield was poor which showed that, the product yield 16

depended on the position of the substituent in the aromatic aldehyde. Heteroaromatic aldehydes also gave high yield of products within a few minutes. The catalytic activity of the dendrimer was studied in detail by the reaction between bulky naphthaldehyde and 1, 2- diamines having electron donating and electron withdrawing substituents with respect to o-phenylenediamine under the same optimum reaction conditions. Expected products were obtained in good yield by o-phenylenediamine and 4-chloro o-phenylenediamine. But 3, 4-diaminotoluene, the amine with electron donating methyl group, was unable to complete the reaction pathway and it gave the tetrahedral addition intermediate product, formerly referred to as carbinol amine and presently termed as ‘hemiaminal’ by IUPAC. It did not undergo further reaction. The superficially simple reaction of o-phenylenediamine and its derivatives with carbonyl compounds is a complex sequence of competing reactions. In the first part of the mechanism, the nucleophilic addition of amine to the carbonyl group of aldehyde or ketone occurs, leading to imine formation. The imine formation is believed to be occurring in a stepwise fashion. In the first step, for the condensation of amine with carbonyl compound, the thermodynamically unstable or a labile species called ‘hemiaminal’ is formed and is generally not isolated or detected. The tetrahedral intermediate subsequently eliminates a water molecule and the C=N linkage is generated to get the imine. The reason for the extra stability of hemiaminal formed by 3, 4-diaminotoluene is the +I effect and hyperconjugative effect, developed by the methyl group present in the benzene ring, which leads to a high electron density to the nitrogen atom of secondary amino group and resists the attack of catalyst to the >NH proton, adjacent to the hydroxyl group containing carbon as shown in the Scheme 3 (case 1). In the case of 4-chlorophenyl-1,2- diamine, an opposite effect occurs due to the presence of electronegative chlorine, which leads to the formation of highly unstable and nonisolable hemiaminal, Scheme 3 (case 2). The newly synthesized hemiaminal, ((2-amino-5methylphenyl)amino)(naphthalen-1-yl)methanol was characterized by melting point, GC/MS, 1

H NMR and 13C NMR spectroscopic techniques. The model experiment was performed in the absence of a catalyst at room temperature, but the

reaction was not proceeding much even after prolonged time and gave very low yield of the product. Moreover, the model reaction was repeated at room temperature, in the absence of air under N2 atmosphere in the presence of the catalyst, but the reaction proceeded slowly and gave very low yield of the product even after 6 h, which proved the importance of oxygen in the reaction. When the model experiment was conducted in the presence of pure O2 gas instead of air, no additional 17

increase in yield was observed. The reported products obtained were characterized by melting point, GC/MS, 1H NMR and 13C NMR spectroscopic methods. The general preparation method and the benzimidazole derivatives synthesized were depicted in Scheme 2.

Scheme 2 Synthesis of benzimidazole derivativesa

a

Reaction conditions: 1, 2-phenylenediamine (5 mmol), aldehyde (6 mmol), GLYG1 (4 mg), R. T.,

ethanol (5 mL)

Recyclability of the catalyst After completion of the reaction, the catalyst was separated by membrane filtration and the recovered catalyst was reused without loss of significant catalytic activity. The reaction proceeded smoothly for four consecutive cycles without any loss of activity shown in Table 3. Table 3 Recycling of polyamine catalyst Cycle number

Catalyst recovered (%)

Product yield (%)

1

97

100

2

95

99

18

3

94

98

4

92

96

a

Reaction conditions: 1,2-phenylenediamine (5 mmol), 4-bromobenzaldehyde (6 mmol), GLY G1 (4 mg), R. T, solvent (5 mL), 2 min

A comparative study of the present catalyst, with other reported catalysts and the conditions used, for the synthesis of benzimidazole by using 1, 2-phenylenediamine and benzaldehyde as the substrates, from literature is presented in Table 4. Table 4

Comparison of different catalysts in the synthesis of benzimidazole derivatives Entry Catalyst

Conditions

Time

Yield (%)Ref

1

Without catalyst

Solvent-free/Grinding, 140 °C 1 h

88 [30]

2

Without catalys

PEG 400/110 °C

1h

90 [31]

3

Without catalyst

C2H5OH/Grinding, R. T

30 min

84 [32]

4

β-Cyclodextrin

H2O/60-65 °C

5h

80 [33]

5

Visible-Light

MeOH (0.1 M) /R. T.

2h

95 [34]

6

K10Ti

Solvent-free/120 °C

2h

79 [35]

7

GLR-G2-Cu polymer C2H5OH/R. T

1h

94 [36]

8

Present work

4 min

94

C2H5OH/R. T

Reactants: 1, 2-phenylenediamine and benzaldehyde

A possible mechanism to afford 2-substituted benzimidazoles, by the condensation of 1, 2-phenylenediamine with aldehyde using the catalyst has been outlined in the Scheme 3. Here, the reaction proceeded via the activation of aldehyde by the dendritic polyamine through hydrogen bond followed by imine formation, which was converted to dihydroimidazole by the reaction of the second -NH2 group present in 1, 2-phenylenediamine. Finally, the dihydroimidazole underwent oxidation in the presence of air to get benzimidazole.

19

ɗ+ ɗ+

ɗ-

ɗɗ-

ɗ+

Scheme 3

Possible mechanism for the formation of benzimidazoles

Here both GLY G0 and GLY G1 dendrimers act in an excellent way for catalysis. By knowing the molecular weight of GLY G0 dendrimer as 16802, the calculated number of repeating monomer units in the polyepichlorohydrin chain was 225. Again, as the molecule is three directional, three PECH chains are present and the average number of pendant amino groups present in each flexible backbone chain was 75. Similarly from the molecular weight of GLY G1 dendrimer, the average number of pendant amidoamine groups calculated in each

20

backbone chain was 40. In the glycerol initiated polyamine molecule, the three long flexible polyepichlorohydrin chains having a number of pendent amino groups are present in the core. In solution, they exist like tightly folded coils or tightly packed ball like appearance, due to intramolecular hydrogen bonding formed by a large number of pendant amino/amido groups present in the PECH chain. The peripheral amino groups help the solubility of the catalyst in polar solvents. Presence of the peripheral multiple amino and hydrophobic glycerol initiated polyepichlorohydrin core helps the dendrimer to behave as an amphiphilic molecule. The intramolecular hydrogen bonding creates a number of cavities in the core part of the dendrimer, containing a number of amino/ amido groups in it. Thus the presence of hydrophilic amino groups and relatively hydrophobic exterior PECH chain helps to behave the cavity as reverse micelle [37] as shown in Fig 6.

Fig 6 Reverse Micelle Formation In normal dendritic catalysis, in protic solvent media outside the dendrimer, the chemical reactions occur. In the present case, due to conformational restrictions, the polar pendant amino groups in the interior of the dendrimer are unable to move to the surface [38]. As the dendrimer is soluble, the lipophilic organic substrate molecules diffuse easily into the interior of dendrimer from bulk, and are entrapped in the cavities/ dendritic boxes where pendant amino groups are present, which function as catalyst. As in the interior cavities, the distance between the catalytic moieties is small; an efficient encapsulation is possible leading to the accumulation of substrates in close proximity to the catalytically active centers and fast reaction occurs there (Fig 7). Thus in the present case, chemical reaction occurs both in the interior cavities and in the bulk solution outside of the dendrimer. Inside the cavity, the energy barrier for the reaction is low, because the negative charge of the transition state is more delocalized due to the presence of a number of 21

pendant amino/ amidoamine groups and a catalytic effect is developed. Thus higher rate constant and a more favorable equilibrium constant are developed which leads to an enhanced reactivity of the encapsulated reagent compared to the bulk solution. In other words, in the cavity region the rate of reaction is several hundred times that of the rate in the bulk solution, as in reverse micellar catalysis. The overall rate of the reaction is the sum of the rates of reaction in the solvent phase and in the inner cavity phase [39]. Again, the equilibrium concentrations of lipophilic organic substrates are much higher in the polymer phase (cavity) than in solvent phase. Thus the dendrimer showed a spectacular catalytic activity in the inner cavity phase [40]. As the dendrimer is a soluble one, the product formed in the cavity can easily pump out and the catalytic reaction can continue easily. Thus the catalytic effect becomes similar to what is observed in enzyme catalysis, where the hydrophobic pockets furnish to control of substrate selectivity and provide optimized conditions for the catalyzed reaction [41].

Fig 7 G1 PAMAM Dendrimer with inner cavity Conclusions In the present work, a new type of homogeneous PAMAM dendrimer, having a large number of amino groups in low generation itself was developed. The catalytic activity was studied in the synthesis of various benzimidazole derivatives containing sterically hindered and substituted aromatic and heteroaromatic groups, under open air atmosphere at room temperature. The strategy of including long flexible hydrophobic PECH chain with a large number of pendant active sites, which can form cavities and can act similar to reverse micelles in the interior part of

22

the dendrimer molecule, and the soluble nature due to the presence of peripheral amino groups, helped the dendrimer to act as a highly competent organocatalyst. Thus the novel dendrimer molecule becomes an enzyme mimicking dendrimer and the catalytic effect becomes similar to what is observed in enzyme catalysis. Furthermore, as the particle size of the dendrimer molecules come within the nanometer range, they can be removed easily from the reaction medium by membrane filtration. The salient features of the present method include, high yield of products within a few minutes at room temperature with a substoichiometric amount of the catalyst. The catalyst has the advantages like: ecobenign in terms of stability, recyclability, avoiding transition metals, elimination of toxic organic solvents, water as the only by-product and was also energy saving, because all the reactions were completed at room temperature. Benzimidazole synthesis is basically an acid catalyzed reaction and in the present case, polyamine as a Lewis base catalyst was reported. This is for the first time, that the application of PAMAM dendrimer with reverse micelle property in the interior polymeric core part, acts as a homogeneous organocatalyst for the synthesis of benzimidazoles was reported. To the best of our knowledge, there has been no report available on the synthesis of benzimidazoles, which was completed within such a short period of time at room temperature. A new hemiaminal, ((2-amino-5-methylphenyl)amino)(naphthalen-1yl)methanol was synthesized and characterized by spectroscopic methods. Besides the application as organocatalyst, various new biomedical or industrial applications of the present PAMAM could be explored and extended in accordance with specific requirements based on the unique structure and properties of the new dendrimer. Characterization of Synthesized Products 3a. 2-Phenyl-1H-benzimidazole: Mp: 291-292 °C; 1H NMR (400 MHz, CDCl3): δ 8.04-8.06 (d, 2H, Ar-H), 7.65-7.67 (d, 2H, Ar-H), 7.47-7.52 (m, 3H, Ar-H), 7.27-.29 (m, 2H, Ar-H), 3.49 (s, 1H, N-H); 13C NMR (CDCl3, 100 MHz): δ 151.0, 140.8, 130.2, 129.1, 126.5, 123.0; GC/MS m/z: 194.1 3b 2-(4-Bromophenyl)-1H-benzimidazole Mp: 298-299 °C; 1H NMR (400 MHz, CDCl3): δ 10.06 (s, 1H, N-H), 8.83 (s, 1H, Ar-H), 8.48-8.50 (d, IH, Ar-H), 8.29-8.31(d, IH, Ar-H), 7.85 (s, 1H, Ar-H), 7.67-7.71 (t, 1H, Ar-H), 7.55 (s, 1H, Ar-H), 7.33-7.35 (m, 2H, Ar-H);

23

13

C NMR (CDCl3, 100 MHz): δ 153.3, 142.8, 135.9, 132.3, 132.2, 132.1, 130.6, 127.9,

127.5, 123.5, 120.1, 110.3; GC/MS m/z: 272.0 3c 2-(4-Bromophenyl)-5-methyl-1H-benzimidazole: Mp: 216-217 °C; 1H NMR (400 MHz, CDCl3): δ 7.93-7.95 (d, 2H, Ar-H), 7.51-7.53 (d, 1H, Ar-H), 7.46-7.48 (d, 2H, Ar-H), 7.40 (s, 1H, Ar-H), 7.10-7.12 (d, 1H, Ar-H), 4.37 (s, 1H, N-H), 2.44 (s, 3H, -CH3); 13

C NMR (CDCl3, 100 MHz): δ 149.4, 136.9, 134.2, 132.3, 128.2, 125.6, 125.3, 114.9,

114.2, 101.7, 21.7; GC/MS m/z: 286.0 3d 2-(3-Nitrophenyl)-1H-benzimidazole: Mp: 205-206 °C; 1H NMR (400 MHz, CDCl3): δ 7.90-7.92 (d, IH, Ar-H), 7.58-7.63 (m, 1H, Ar-H), 7.45-7.50 (m, 1H, Ar-H), 7.32-7.35 (m, 1H, Ar-H), 7.27-7.30 (m, 1H, Ar-H), 6.95-6.97 (d, IH, Ar-H), 5.32 (s, 1H, N-H); 13

C NMR (CDCl3, 100 MHz): δ 148.6, 132.5, 131.6, 130.3, 124.5, 120.9; GC/MS

m/z: 239.1 3e 2-(4-Methoxyphenyl)-1H-benzimidazole: Mp: 227-229 °C; 1H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H, N-H), 7.84-7.86 (d, 2H, Ar-H), 7.01-7.06 (m, 2H, Ar-H), 6.96-6.98 (m, 2H, Ar-H), 6.72-6.77 (m, 2H, Ar-H), 3.87 (s, 3H, -CH3);

13

C NMR (CDCl3, 100 MHz):

δ 162.1,157.0, 142.0, 137.6, 130.3, 129.6, 127.1, 118.4, 117.1, 115.2, 114.1, 55.4; GC/MS m/z: 224.1 3f 2-(4-Methoxyphenyl)-5-methyl-1H benzimidazole: Mp: 164-166 °C; 1H NMR (400 MHz, CDCl3): δ 8.04-8.06 (d, 2H, Ar-H), 7.42-7.44 (d, 1H, Ar-H), 7.28 (s, 1H, Ar-H), 6.97-6.99 (m, 1H, Ar-H), 6.78-6.81 (d, 2H, Ar-H), 5.34 (s, 1H, N-H), 3.73 (s, 3H, -CH3);

13

C NMR

(CDCl3, 100 MHz): δ 160.9, 152.1, 132.2, 130.6, 128.3,127.2, 127.1, 123.9, 122.7, 114.3, 55.2, 21.6; GC/MS m/z: 238.1 3g 2-(3, 4-Dimethoxyphenyl)-1H-benzimidazole: Mp: 231-233 °C; 1H NMR (400 MHz, CDCl3): δ 11.57 (s, 1H, N-H), 7.75 (m, 1H, Ar-H), 7.64-7.66 (m, 1H, Ar-H), 7.60-7.64 (m, 2H, Ar-H), 7.22-7.26 (m, 2H, Ar-H), 6.8-6.9 (d, 1H, Ar-H);

13

C NMR (CDCl3,

100 MHz): δ 152.1, 150.8, 149.4, 122.8, 122.7, 119.2, 111.2, 109.8, 55.9, 55.7; GC/MS m/z: 254.1 3h 2-(Naphthalen-1-yl)-1H-benzimidazole: Mp: 273-275 °C; 1H NMR (400 MHz, CDCl3): δ 8.69-8.71 (m, 1H, Ar-H), 7.95-7.97 (d, 1H, Ar-H), 7.91-7.94 (m, 1H, Ar-H), 7.81-7.88 24

(m, 1H, Ar-H), 7.73-7.75 (d, 1H, Ar-H), 7.56-7.57 (m, 2H, Ar-H), 7.50-7.55 (m, 2H, Ar-H), 7.32-7.34 (m, 2H, Ar-H), 5.72 (s, 1H, N-H); 13C NMR (CDCl3, 100 MHz): δ 133.9, 131.1, 130.5, 130.3, 128.4, 127.9, 127.4, 126.4, 125.7, 125.0, 123.1, 120.2; GC/MS m/z: 243.1 3i ((2-Amino-5-methylphenyl)amino)(naphthalen-1-yl)methanol: Mp: 81 °C;

1

H NMR

(400 MHz, CDCl3): δ 7.60-7.64 (m, 1H, Ar-H), 7.54 (s, 1H, Ar-H), 7.30-7.36 (m, 2H, Ar-H), 7.25-7.26 (m, 1H, Ar-H), 7.16-7.19 (m, 1H, Ar-H), 7.08-7.11 (d, 1H, Ar-H), 6.56-6.57 (m, 1H, Ar-H), 6.26-6.27 (m, 1H, Ar-H), 6.20-6.21 (m, 1H, Ar-H), 5.57 (s, 2H, -NH2), 3.46 (s, 1H, -C-H), 3.24 (s, IH, -OH), 2.48 (s, 3H, -CH3), 2.40 (s, 1H, -NH-); 13

C NMR (CDCl3, 100 MHz): δ 149.6, 145.3, 143.9, 143.8, 143.5, 142.6, 140.9, 135.6,

133.4, 132.7, 124.8, 119.4, 119,2, 112.8, 112.6, 112.0, 110.5, 109.8, 109.5, 108.3, 108.2, 41.6, 21.9; GC/MS m/z: 278.1; Elemental Anal. Calcd (%) for C18H18N2O: C- 77.67; H- 6.52; N- 10.06; O- 5.75. Found: C- 77.66; H- 6.53; N- 10.07; O- 5.75. 3j 5-Chloro-2-(naphthalen-1-yl)-1H-benzimidazole: Mp: 139-180 °C; 1H NMR (400 MHz, CDCl3): δ 8.61-8.64 (m, 1H, Ar-H), 7.94-7.96 (d, 1H, Ar-H), 7.86-7.91 (m, 2H, Ar-H), 7.76-7.77 (m, 2H, Ar-H), 7.53-7.55 (m, 3H, Ar-H), 7.48-7.50 (m, 2H, Ar-H), 5.69 (s, 1H, N-H); 13C NMR (CDCl3, 100 MHz): δ 152.7, 133.7, 133.6, 130.9, 130.8, 130.6, 129.0, 128.5, 128.4, 128.2, 128.1, 127.9, 127.3, 127.2, 126.6, 126.5, 126.1, 125.5, 125.0, 124.8, 123.1; GC/MS m/z: 277.1 3k 2-Methoxy-4-(5-methyl-1H-benzimidazol-2-yl)phenol: Mp: 226-228 °C; 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H, Ar-H), 7.49-7.51 (d, 1H, Ar-H), 7.36-7.38 (m, 2H, Ar-H), 7.05-7.07 (d, 1H, Ar-H), 6.96-6.98 (d, 1H, Ar-H), 6.5 (s, 1H, -OH), 5.34 (s, 1H, N-H), 3.93 (s, 3H, -OCH3);

13

C NMR (CDCl3, 100 MHz): δ 191.9, 185.3, 171.7, 165.0, 147.1, 127.1, 124.3,

119.9, 114.6, 109.5, 56.0, 21.6; GC/MS m/z: 254.0 3l 5-Chloro-2-(pyridin-2-yl)-1H-benzimidazole: Mp: 140-142 °C; 1H NMR (400 MHz, CDCl3): δ 11.52 (s, 1H, N-H), 7.81-7.82 (d, 1H, A-H), 7.37-7.39 (m, 1H, Ar–H), 7.34-7.36 (m, 1H, Ar-H), 7.29-7.31 (m, 1H, Ar-H), 7.16-7.24 (m, 1H, Ar-H), 7.13-71.4 (m, 1H, Ar-H), 6.24-6.26 (d, 1H, Ar-H);

13

C NMR (CDCl3, 100 MHz): δ 149.0, 137.4, 136.9, 128.1, 124.8,

124.4, 122.4, 121.9, 121.1, 119.7, 111.7; GC/MS m/z: 229.0

25

3m 5-Methyl-2-(pyridin-2-yl)-1H-benzimidazole: Mp: 140-141 °C;

1

H NMR (400 MHz,

CDCl3): δ 11.05 (s, 1H, N-H), 8.42-8.46 (m, 1H, Ar-H), 7.82-7.86 (m, 1H, Ar-H), 7.33-7.35 (m, 1H, Ar-H), 7.25-7.34 (m, 1H, Ar-H), 7.09-7.24 (m, 2H, Ar-H), 6.26 (s, 1H, Ar-H), 2.47 (s, 3H, -CH3);

13

C NMR (CDCl3, 100 MHz): δ 148.9, 137.3, 136.8, 128.1, 127.6, 125.3,

124.3, 123.7, 122.2, 121.6, 119.8, 110.4; 209.1; GC/MS m/z: 209.1 3n 5-Chloro-2-(thiophen-2-yl)-1H-benzimidazole: Mp: 222-224 °C; 1H NMR (400 MHz, CDCl3): δ 8.57 (s, 1H, N-H), 7.48 (s, 1H, Ar-H), 7.41-7.43 (d, 1H, Ar-H), 7.34-7.35 (d, 1H, Ar-H), .24-7.26 (d, 1H, Ar-H), 7.13-7.16 (m, 1H, Ar-H), 6.99-7.01 (m, 1H, Ar-H); 13

C NMR (CDCl3, 100 MHz): δ 148.8, 132.7, 128.6, 128.5, 128.2, 127.4, 125.8, 123.5,

119.5, 115.0; GC/MS m/z: 234.0 ASSOCIATED CONTENT

SUPPORTING INFORMATION Estimation of functional groups in Catalysts, FTIR spectra of synthesized dendrimers, GC/MS, 1

H NMR and

13

C NMR spectra of all synthesized benzimidazoles and the newly synthesized

hemiaminal. AUTHOR INFORMATION Corresponding Author *

Email: [email protected], [email protected]

Conflicts of interest There are no conflicts to declare ACKNOWLEDGMENTS The authors thank STIC, CUSAT for assistance with various analysis and RGCB, Thiruvananthapuram for MALDI analysis. References [1]

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Highlights 1. Large number of pendant amino groups in the interior part of dendrimer without any steric crowding 2. Low generation dendrimer but the particle size comes within the nanometer range 3. The dendrimer to behaves as an amphiphilic molecule 4. Reverse micellar catalysis in the interior cavities 5. The process of 2-substituted benzimidazoles synthesis was ecobenign and energy saving 6. The first reported method for the synthesis of benzimidazoles, using the homogeneous PAMAM dendrimer as an exquisite basic organocatalyst 7. Fast reactions 8. New hemiaminal, ((2-amino-5-methylphenyl)amino)(naphthalen-1-yl)methanol