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Journal of Advanced Research (2017) 8, 245–270 Cairo University Journal of Advanced Research REVIEW Bis[(L)prolinate-N,O]Zn: A water-soluble and recycle catalyst for various organic transformations Roona Poddar a, Arti Jain b, Mazaahir Kidwai a,* a b Department of Chemistry, University of Delhi, Delhi 110007, India Department of Chemistry, Daulat Ram College, University of Delhi, Delhi 110007, India G R A P H I C A L A B S T R A C T A R T I C L E I N F O Article history: Received 9 September 2016 Received in revised form 28 November 2016 Accepted 20 December 2016 Available online 9 January 2017 A B S T R A C T Under the green chemistry perspective, bis[(L)prolinate-N,O]Zn (also called zinc–proline or Zn [(L)-pro]2) has proven its competence as a promising alternative in a plethora of applications such as catalyst or promoter. Owing to its biodegradable and non-toxic nature of bis[(L) prolinate-N,O]Zn, it is being actively investigated as a water soluble green catalyst for synthetic chemistry. Bis[(L)prolinate-N,O]Zn are readily utilized under mild conditions and have high selectivity and reactivity with broad range of substrate acceptance to make it better reaction * Corresponding author. Fax: +91 1127666235. E-mail address: kidwai.chemistry@gmail.com (M. Kidwai). Peer review under responsibility of Cairo University. Production and hosting by Elsevier http://dx.doi.org/10.1016/j.jare.2016.12.005 2090-1232 Ó 2017 Production and hosting by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 246 R. Poddar et al. Keywords: Bis[(L)prolinate-N,O]Zn Amino-acid complex Zinc Asymmetric catalyst Lewis acid Organometallic chemistry medium for a wide variety of organic transformations. This Review summarizes the till date literature on its synthesis, characterization, and its catalytic role in various organic reactions. Ó 2017 Production and hosting by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/). Roona Poddar is an Assistant Professor of Chemistry and teaches post graduate student in Department of Chemistry, University of Delhi, Delhi, India. She has a Master Degree in Chemistry from Indian Institute of Technology (IIT) Delhi, and a Ph.D. in Chemistry from the University of Delhi (DU). She has worked as Post Doctorate Fellow for three years before joining as faculty in Department of Chemistry, University of Delhi, Delhi, India She has published numerous research papers in peer reviewed journals. Arti Jain obtained her PhD (Organic Chemistry) from University of Delhi, India, in 2013. She is currently an Assistant Professor in Department of Chemistry, Daulat Ram College, University of Delhi, India. Her research area is based on the exploration of newer environmental benign protocol for various traditional reactions, use of agricultural waste material to apply cradle to cradle approach etc. She has 4 years of teaching experience to the undergraduate students. She is still doing research in the college. M. Kidwai is working as Professor at the Department of Chemistry, Delhi University, delhi, India. He has 30 years of teaching experience at the university level. Currently he has 260 papers in the Journal of National and International repute and supervised 40 Ph.D. students and 31 M. Phil students. Pioneer in the field of Green Chemistry, who has started first research work in this field in India in 1990. From Asia among 5 members is inclusive of himself in the international Advisory board make Globally figure in the exclusive field of Green chemistry. Zinc catches eyes of several researchers due to several reasons, as it can show various coordination geometries, is abundant in nature, is redox-inactive [8], and forms stable complexes with nitrogen. Zinc is an essential micronutrient, which is involved in various biological processes such as transcription, cell signaling catalysis, hormone synthesis, and structural integrity of cell membrane [9,10]. From the biological point of view, more than 300 zinc metallo-enzymes covering all six classes of enzymes have been discovered [11,12]. In most cases, the zinc ion is an essential cofactor for the observed biological function of these metalloenzymes. By the virtue of biological activity, thousands of synthetic zinc complexes have been formed either to mimic natural structure or to completely diverge from the natural platform [13–18]. Moreover zinc is present in active site of class II aldolases (an enzyme) witnessing the bis[(L)prolinate-N,O]Zn as a valid candidate for aldolase mimics. Deprotonated amino acid coordination chemistry is dominated by the formation of the nitrogen and oxygen chelating motif producing the geometrically (and energetically) favoured five membered metallocyclic compounds [19]. Stability of the zinc complexes varies with different amino acids [20–23]. Metal ion-ligand affinity increases as the polarizability of the donor atom is increased (O < N < S) [24]. So there is an increase in selectivity for the amino acid having (N, S) linkage followed by (N, O). It has been shown that cysteine and its derivatives are more selective for metal ion-ligand binding as compared to other amino acid having (N, O) linkage [25]. The cumulative energy required for the acid dissociation of carboxylic acid to carboxylate ion and ammonium ion to secondary amine for proline with Zinc (II) is lower than other amino acid which has primary amine group and acid group. In secondary amine, there is more inductive effect which makes it more labile for acid dissociation constant [26,27]. Complex synthesis Introduction The recent past scientific and technological advances have provided a great insight regarding the catalytic properties and mechanism of metal-amino acid complexes. Metal salts with chiral amino acid have been used as promising materials for biological as well as chemical advancement as they tend to exhibit the advantage of the metal salts and the asymmetrical organic amino acids [1,2]. a–Amino acids could act as chelating ligands and form five member ring because they have two types of coordination atoms [3–7] due to the presence of proton acceptor amino group (NH2) and the donor carboxylic acid group (COOH) in them. Originally Darbre and Machuquiero have synthesized this bis [(L)prolinate-N,O]Zn complex. They have synthesized bis[(L) prolinate-N,O]Zn complex by adding small quantity of Et3N COOH + Zn(CH3COO)2 N H (L)Proline Zinc acetate Et3N MeOH O O NH Zn NH O O Bis[(L)prolinato-N,O]Zn Zn(L-Pro)2 Yield=90% Scheme 1 A water-soluble and recycle catalyst for various organic transformations Fig. 1 247 1 H NMR of proline and bis[(L)prolinate-N,O]Zn. as base to the proline in methanol followed by zinc acetate (double ratio of amino acid) (Scheme 1). After stirring a white precipitate was obtained which could be separated from reaction medium by simple filtration with good yield [28]. formation of carboxylate ion; moreover, there is a noticeable shielding in C(5) as compared to proline, which further confirms the synthesis of bis[(L)prolinate-N,O]Zn [28]. FTIR analysis Structure and characterization of the catalyst 1 H NMR analysis In the comparison of 1H NMR of proline and bis[(L)prolinateN,O]Zn complex in Fig. 1, 1H NMR of the bis[(L)prolinate-N, O]Zn showed that there is proton shielding of protons of proline and the splitting pattern resolved in the presence of Zinc metal ion. Shielding is more in C(2), which indicate the In IR spectra of bis[(L)prolinate-N,O]Zn complex shown in Fig. 2, the shift observed confirms the formation of the target compound in comparison with L-proline. There was decrease in broad band at 3422 cm
1 for OH stretching of COOH. The NH stretching band at 3220 cm
1 was very prominent while twisting was observed at 1205 cm
1. The COO
vibration peak appeared comes at 1410 cm
1 along with the carbonyl peak of carboxylic group at 1608 cm
1 while the in- 248 R. Poddar et al. 3341.25 1616.00 2686.53 1397.95 2174.31 805.94 969.07 985.93 870.49 899.62 1331.29 1381.57 708.93 1410.93 1273.17 1064.03 784.41 1448.43 1261.48 1077.11 938.50 1608.00 1478.00 1301.02 1090.98 847.56 1205.43 1034.10 774.28 2890.88 2996.53 3220.00 4000.0 3600 2957.65 2866.59 3200 2800 430.91 645.33 609.33 2400 2000 1800 1600 1400 1200 1000 800 480.86 582.46 530.01 600 400.0 cm-1 Fig. 2 FTIR of bis[(L)prolinate-N,O]Zn. Fig. 4 Fig. 3 Zn. Powder XRD of bis[(L)prolinate-N,O]Zn. Single crystal X-ray diffraction of bis[(L)prolinateo-N,O] plane deformation at 774 cm , scissoring at 703 cm and rocking vibrational peak o at 530 cm
1 were also observed. The CH2 stretching, wagging, and rocking were observed at 2800–3216, 1330–1300, and 938–847 cm
1 respectively. The CAN stretching was observed in between 1330 and 1450 cm
1 while the CAN stretches due to absorption were noticed at 1077 and 1064 cm
1 [29]. hexacoordinate. The Zn atom has trigonal bipyramidal geometry with O(4 i), N(1) and N (2) while O(1) and O(3) occupying the axial position and the pyrrolidine rings are transformed from planner to 3-dimension shape. The distance ZnAO and ZnAN and all the bond lengths of the proline unit were comparable and normal for metal-coordinated amino acids [31– 34]. The angle between O(3)AZn(1)AO(1) is nearly linear with value of 173.8 (1)°. Single crystal X-ray diffraction Powder X-ray diffraction Structure of bis[(L)prolinate-N,O]Zn complex was first shown by Chew H-N, and he described trans complex [Zn (C6H7NO2)2] in Fig. 3 [30], as a spiral structure formed along the 21 direction with atoms O4 (2
x, y
1/2,
z), Zn, N(2), C(7) and C(6) constituting a repeating unit. The Zn atom is pentacoordinate, the fifth coordination site being occupied by the symmetry related atom O(4 i) [symmetry code: (i) 2
x, y
i ,
z] of a neighboring proline molecule so that an infinite polymeric chain is generated. The polymer shows a helical structure along the 2 direction. The zinc coordination here is unique, as most zinc-amino acid complexes are Kidwai and his coworkers group have shown for the first time X-ray diffraction of the complex in the range 2h = 0–100 as shown in Fig. 4. The characteristic peak obtained from powder XRD of bis[(L)prolinate-N,O]Zn of specific d value has showed that the complex is orthorhombic in structure since it is in agreement with data card 47-1919JCDPS [35,36].
1
1 TEM image For crystal assessment of bis[(L)prolinate-N,O]Zn, TEM technique was used. Kidwai and his co-workers (2011) had A water-soluble and recycle catalyst for various organic transformations Fig. 5 249 TEM images of fresh bis[(L)prolinate-N,O]Zn. Thermal analysis Fig. 6 TGA/DTA graph of bis[(L)prolinate-N,O]Zn. The thermal stability of bis[(L)prolinate-N,O]Zn complex was evaluated by TG/DTA and DSC experiments as described by kidwai and research group in Figs. 6 and 7 [38]. Briefly the complex was heated at the rate of 10 K min
1 in N2 atmosphere. A blunt endothermic peak due to the release of adhered water molecules was observed at 100.62 °C in the DTA curve. The purity of crystal was further confirmed by the sharpness of endothermic peak at 342.81 °C in the DTA curve which matches the melting point of bis[(L)prolinate-N,O]Zn. TGA curve showed the detailed decomposition of the complex (Fig. 6). Differential scanning calorimetry (DSC) study was carried in the inert atmosphere from the temperature range 20–500 °C with a heating rate of 10 K min
1. Bis[(L) prolinate-N,O]Zn undergone through an irreversible endothermic transition at its melting point 342.81 °C. Henceforth it was confirmed that the material is stable up to its melting point making it suitable for various applications, where the complex is utilized at high temperatures. Solubilities of bis[(L)prolinate-N,O]Zn Fig. 7 DSC graph of bis[(L)prolinate-N,O]Zn. acquired various images of complex on carbon coated grid and confirmed the crystalline in nature of the complex as depicted in Fig. 5 [37]. Bis[(L)prolinate-N,O]Zn is highly soluble in water and insoluble in organic solvent due to its ionic nature. The N, O and Zn atoms form H-bond with water molecules and make it hydrated which is not possible in organic solvent. The recyclability of complex depends upon its solubility in the reaction medium. Majority of the reactions with complex are performed in aqueous medium and extracted with organic solvent (Ethyl acetate, ether, chloroform or DCM) from the aqueous layer and reused for further reaction [29,36,37]. In aqueous medium the reactivity of metal complexes is restricted because water molecules can participate as substrate for metal bonding. Criterion for water stable Lewis acids (improbable to hydrolysis) has been investigated based on the relationship between the catalyst activity with two parameters viz water exchange rate constant and hydrolysis constant [26]. Zinc complexes are found to be appropriate for various organic reactions in aqueous medium. 250 R. Poddar et al. Bis[(L)prolinate-N,O]Zn distribution in biological system Bis[(L)prolinate-N,O]Zn in organic synthesis as catalyst Although metal ions and complexing agents occur ubiquitously in biological tissues and fluids, few studies have been done for the distribution of the metal ions among the competing ligands in such systems [39,40]. First time equilibria of complex were understood in Bjerrum’s book ‘‘Metal Ammine Formation in Aqueous Solution” that was published in Denmark in 1941 [42]. It has been confirmed that the equilibrium between a complex forming agent and an ion is usually thermodynamically reversible and occurs instantaneously without significant energy of activation. So equilibria can be written in mass-action equations. Furthermore, Bjerrum has established that complex formation is occurred in stepwise course. Quantitative studies by Albert (1950) for the avidity of Lproline for Zn(II) ion have been reported [41]. It was found that pKa value for L-proline is 10.68 and stability constant of the bis[(L)prolinate-N,O]Zn complex is 10.2, implying that L-proline has the greatest avidity for Zn(II) ion and forms a stable complex with it. The computed distribution of Zn(II) ion among seventeen amino acids present in human blood plasma had been studied and approximately 50% of the Zn(II) is coordinated to cysteine and histidine (as their stability constant is highest among all amino acids), but considerable amino acid complex formation occurs with most of the other amino acids [43]. Recently, metal ions have been used in metallization of biomacromolecules [44]. These processes rely upon the specific metal ion amino acid interaction, which allow an efficient metal deposition and attachment to biological systems. The molecular mechanism of the metallization process was studied by means of chemical quantum calculations of metal ionamino acid interaction [45]. An interesting feature of the zinc (II) ion is its ability to adopt a tetrahedral, a trigonal bipyramidal, or an octahedral geometry depending on the ligands bonded to the ion. On the other hand the Zn2+ aqua ion, as well as Zn2+ complexed to two N donors, is six-coordinated [46,47]. Zinc(II) ion coordinated by at least three N or S donor forms either tetrahedral or trigonal bipyramidal complexes [48]. A theoretical study of Zn(II) interaction with L-proline was carried out using density functional theory method with Becke’s three parameter, hybrid exchange functional and the Lee-Yang-Parr correlation functional (B3LYP). A moderately high affinity (
13.4 kJ mol
1) was predicted for the proline residue complexing a zinc ion via the nitrogen atom of the five membered ring [49]. In plant, there is increase in concentration of proline to get rid of heavy metals which are toxic in nature. To check the importance of proline in plant reactions to heavy metal stress, Sharma et al. have studied the effect of proline on Zn-induced inhibition of glucose-6-phosphate dehydrogenase and nitrate reductase in vitro. Proline appeared to protect both enzymes against Zinc. There were no indications of any significant role for proline-water or proline-protein interactions. The significance of these findings with regard to heavy metal-induced proline accumulation in vivo has been discussed [50]. A synergistic immunological adjuvant formulation having bis[(L) prolinate-N,O]Zn complex as synergist has been patented which showed the pharmaceutical properties associated with the complex [51]. Bis[(L)prolinate-N,O]Zn has received immense attention over the last eight years which provided intriguing opportunities in organic synthesis because of its ability to act as Lewis acid and ease of preparation. The following section illustrates various synthetic approaches exploiting bis[(L)prolinate-N,O]Zn as a catalyst. In most cases, water had been used as a part of the reaction media. Henceforth, in each synthetic approach, examples related to the use of this organometallic complex in biphasic systems, water saturated organic solvents and even water as a sole reaction media have been described. This section examines the growing opportunities and applications of bis[(L)prolinate-N,O]Zn catalyzed reactions. Originally Darbre et al. (2003) have shown bis[(L)prolinate-N,O]Zn as a selective catalyst for the direct aldol reaction in aqueous media. They have investigated that 5 mol% of the Zn complexes of lysine, arginine and proline are catalysts for the aldol addition of acetone (1) and p-nitrobenzaldehyde (2) in aqueous medium, giving considerable yields and enantiomeric excess up to 56% at room temperature (Scheme 2) [28]. The catalytic ability of other with 5 mol% Zn-(L)-amino acid complexes had been studied in water-acetone medium. The complexes were prepared and isolated as described for Zn-proline [52–57]. In the absence of zinc, product (3) was obtained in 74% yield and 6% ee with the R-1 enantiomer in excess. The higher ee values were observed with different amino acids requiring chiral Lewis acid as catalyst. Moreover in 2004, Darbre and Reymond et al. together explored the bis [(L)prolinate-N,O]Zn complex catalyzed pathway for the formation of sugars [58]. Bis[(L)prolinate-N,O]Zn complex catalyzed the aldolization of unprotected glycolaldehyde (4) in water to give tetroses (5,6) in 51 % yield which further aldolization gave hexoses (9) with 10% enantiomeric excess of the D-isomer (Scheme 3). A mixture of pentoses (8) was produced by the reaction of glycolaldehyde with glyceraldehyde (7) in the presence of bis[(L)prolinate-N,O]Zn complex in water. The aldol reaction of 4-nitrobenzaldehyde catalyzed with three different ketones (2-butanone, cyclopentanone and cyclohexanone) in three different combinations with aqueous media, has been studied to explore selectivity of environmentally benign reaction. The combination included conditions are bis[(L)prolinate-N,O]Zn complex, NaHCO3/bis[(L) prolinate-N,O]Zn complex and L-proline/bis[(L)prolinate-N, O]Zn complex. For the synthesis of b-hydroxy ketones NaHCO3 was surprisingly found to be a proficient catalyst, showing high-quality diastereo- and regioselectivity within 9 h. Cyclopentanone (17) were mainly found to give syn diastereoisomers while cyclohexanone (19) produced anti isomers being the major product which was an exceptional result (Scheme 4) [59]. O O + (1) O OH Zn(L-Pro)2 (5 mol%) (2) H2O NO2 (3) NO2 S Yield = 100% ee= 56% Scheme 2 A water-soluble and recycle catalyst for various organic transformations O O OH glycolaldehyde (4) O OH Zn(L-Pro)2 H H2O, 7 days (7) OH glyceraldehyde H2O, 7 days OH HO HO OH OH β-erythrose α/β-threose (5) (6) Yield= 51% out of 51% =threose 65% and erythrose 35% O H Zn(L-Pro)2 H2O, 7 days OH (4) glycolaldehyde O HO O OH + Zn(L-Pro)2 H 251 O HO OH HO OH HO OH OH OH (8) (9) A mixture of hexoses A mixture of pentoses Yield= 27% Yield=45% out of 45% ribose (34%), lyxose (32%), arabinose (21%) and xylose (13%) Scheme 3 O H O OH OH + OH (13) OH O O + OH Ar Ar syn O Ar (R)- and (S) (15) anti (14) O Ar (12) (11) Zn(L-Pro)2 H2O, RT O Ar Ar (21) NO2 (10) OH O (16) (11+14)/(12+15): 84/16 syn/anti: 48 / 52 O HO (17) (10) O + Ar Zn(L-Pro)2 H2O,RT Ar (18) O OH O HO syn/anti: 81/19 Yield= 81% OH O O (19) Ar + (10) Zn(L-Pro)2 H2O, RT Ar (20) syn/anti:15/85 Yield =78% Scheme 4 Sivamurugan and his research group have performed the reaction of o-phenylene diamine (21) and a-hydrogen carbonyl (22) with 0.2 mmol of bis[(L)prolinate-N,O]Zn as catalyst to produce 1,5-benzodiazepine derivatives a one pot reaction under solvent-free conditions [60]. The effectiveness of the catalyst has been checked by microwave irradiation technique as 252 R. Poddar et al. R2 NH2 +2 R NH2 1 O 2 R1 R H N 0.2mM [(L)-Proline]2Zn R2 or MW (21) (23) N (22) R1 Yield= 90-93% b: R1 = -CH3 ; R2=CH3 a: R1 = -CH3 ; R2=H 1 d: R1 =-CH2CH2CH3;R2=-CH2CH3 2 c: R = -CH2CH3; R = CH3 1 f: R1 = R2 = -(CH2)4- 2 e: R = CH3;R =-CH2CH3 g: R1 = R2 = -(CH2)5i: R1 = 4-ClC6H4; R2 = H 2 k: R1 = 4-OHC6H4 ; R = H h: R1 = C6H5 ; R2 = H j: R1 = 4-BrC6H4 ; R2 = H Scheme 5 well as conventional method. 1,5-Benzodiazepine (23) was obtained in moderate to good yield (90–93%) in all the reactions within a shorter reaction time (2–3 mins) under microwave irradiation while in conventional the yield (80–88%) was lower and had in longer reaction time (2 h). The catalyst was recycled up to five times with marginal loss of its catalytic reactivity (Scheme 5). To explore the wide applicability of bis[(L)prolinate-N,O] Zn, the aldolization of different hydroxyl aldehydes and ketones was studied by Darbre group using the complex [61]. Glycolaldehyde (4) gave mainly tetroses whereas in the crossaldolization of glycolaldehyde and rac glyceraldehydes (7), pentoses accounted for 60% of the sugars formed with 20% of ribose. They suggested that generally, unprotected ahydroxy aldehydes and ketones could undergo aldol additions in the presence of bis[(L)prolinate-N,O]Zn as catalyst in water. Depending on the starting aldehyde, the products formed may include tetroses, pentonse, hexoses, keto-pentoses, ketohexoses with smaller yields of higher sugars. For the simplicity of analysis, the sugars were also reduced to polyols using NaBH4 (Schemes 6 and 7) [62]. An appropriate mechanism was proposed by darbre for bis [(L)prolinate-N,O]Zn to catalyze the aldol reaction shown in Fig. 8. The chelating enolate formation took place by bonding of glycolaldehyde (4) to the zinc. This is similar step which O R 1 H HO (24) R1 = H R1 = CH2OH occurs in class II aldolase enzyme having zinc (II) in active site as cofactor. The electron deficient carbonyl reacted with the enolate which does not require to coordinating with zinc. The main difficulty to use pentoses as probable prebiotic reagents was the lack of stabilities in earlier days. Previously, the self condensation of formaldehyde in basic medium was used to synthesize pentoses to yield less than 1% of riboses [63]. So the investigations were carried out to escalate the amount and stability of pentoses. The results showed that synthesis of pentoses should be done using Lewis acid and maximum stability of products could be achieved at room temperature in aqueous. In another publication by Lopez et al. [64], bis[(L)prolinateN,O]Zn complex was depicted to catalyze the very famous aldol reaction of acetone (1) and broad range of aromatic aldehydes (32) in aqueous media, and even less reactive aromatic aldehydes such as methoxybenzaldehyde gave good yields. The reaction was also comprehensive to hydroxyacetone and dihydroxyacetone as donors (Schemes 8 and 9). Heterocyclic aldehydes with acetone were also established to be appropriate substrate for the aldol reaction. Variation in molar concentration acetone was also done and good to better yields were achieved with even cyclopentanone. Moreover e 2-butanone and cyclohexanone underwent aldol reaction with 4-nitrobenzaldehyde. They also extended bis[(L)prolinate-N,O] OH O + R2 OH (25) Zn(L-Pro)2 H2O R2 = H R2 = CH2OH R O 1 R2 OH OH (26) R1 = R2 = H R1 = CH2OH, R2 = H R1 = CHOHCH2OH, R2 = H R1 = H, R2 = CH2OH R1 = R2 = CH2OH The product consisted of tetroses (51%), hexoses (27%) and unidentified compounds (22%). The tetroses consisted of 65% threose and 35% erythrose.The hexose mixture contained mainly glucose, galactose (together 40% of the hexose mixture) and talose (10% of the hexose mixture) Scheme 6 A water-soluble and recycle catalyst for various organic transformations O OH O H + OH OH O H + OH O Zn(L-Pro)2 H2O OH (4) OH (28) Ribitol 13% Xylitol 15% Hexoses 12%% + OH OH HO (27) OH HO (29) OH Peracetylated keto-tetroses Peracetylated Keto-pentoses Glycerine 39% Reactant Erythritol 8% Threitol 16% Xylitol 11% Ribitol 7%% OH O O O Zn(L-Pro)2 HO H OH + H2O OH OH (28) OH (30) HO OH OH (31) Dihydroxyacetone 42% Fructose 26% Sorbose 13% Tagatose 3% Unidentified 16% Scheme 7 O OH R O O H OH OH OH NH O 2+ Zn NH O O O R O OH H O N O 2+ Zn OH O H O NH HO H O H O O NH 2+ Zn NH O O O HO H O O R H OH N 2+ Zn H O NH (1) X (32) OH Zn(L-Pro)2 (5 mol%) H2O O R X (33) X = 4-NO2, 2-NO2,2-Br, 4-F, H, 2-CH3, 2-Cl, 4-Cl, 2-OCH3, 3-OCH3, 4-OCH3, 4-CF3, naphthyl Erythritol 9% Threitol 11% Arabitola 34% O OH H + OH HO (27) OH (8) Peracetylated aldoses Peracetylated alditol Erythrose 7% Threose 13% Arabinose 14% Lyxose 21% Ribose 19% Xylose 9 % Hexosesb 14% O O HO (7) O OH OH HO + H 2O H (4) O O Zn(L-Pro)2 253 O O Fig. 8 Plausible mechanism for the bis[(L)prolinate-N,O]Zn catalyzed the formation of ribose and other pentoses. Scheme 8 Zn complex catalyzed reaction with Hydroxyacetone and Dihydroxyacetone. Encouraging results were obtained with ketones too. They postulated a mechanism linking a formation zinc-assisted enamine, where zinc complexation stabilized the enamine intermediate [65]. Coordination to zinc stabilized the enamine in aqueous, possibility of the condensation with the aldehyde shown in Fig. 9. In 2006, Kofoed et al. have explored the dual mechanism of bis[(L)prolinate-N,O]Zn complex catalyzed aldol reactions in water. They found that the aldol condensation of aldehydes with acetone in water medium under numerous catalyst e.g. proline, bis[(L)prolinate-N,O]Zn complex, (S)-(+)-1-(2-pyrroli dinomethyl)pyrrolidine and (2S,4R)-4-hydroxyproline progressed via an enamine mechanism, while the aldol reaction of dihydroxyacetone catalyzed by bis[(L)prolinate-N,O]Zn complex and by organic bases such as N-methylmorpholine occured under rate-limiting deprotonation of the a-carbon and formation of an enolate intermediate [66]. Bis[(L) prolinate-N,O]Zn complex appeared to be a particularly efficient catalyst for both enamine and enolate type catalyses. Addition of a base to bis[(L)prolinate-N,O]Zn complex induced precipitation of Zn(OH)2 above pH 9, implying that the conjugate base [(OH)((L)prolinate-N,O)2]Zn was not available as a general base for deprotonating dihydroxyacetone, while the pH curve showed that proline could easily disintegrate from zinc upon protonation from pH 8 to pH 6 (Scheme 10). Bis[(L)prolinate-N,O]Zn complex was shown to be an capable catalyst for the Hantzsch synthetic route for the synthesis of 1,4-Dihydropyridine (DHP) (41) derivatives using a broad variety of aromatic aldehydes (39) and dicarbonyl compounds (40) in aqueous medium under microwave irradiation. The Bis [(L)prolinate-N,O]Zn exhibited greater catalytic activity even with low MW power (200 W) and gave excellent yield (90– 98%) in short reaction times (<5 min) [67] (Scheme 11). Quinoxaline derivatives show broad spectrum of biological activities. They have been used in dyes [68,69], pharmaceuticals [70,71] and building blocks for the synthesis of organic semiconductors [72]. An ecofriendly straightforward, proficient method for the preparation of quinoxalines (44) by the condensation of 1,2-diamines (43) with various 1,2-diketones (42) using bis[(L)prolinate-N,O]Zn as a catalyst has been reported by Heravi et al. in 2007 [73]. In his reaction acetic acid was used as a solvent which was unable to precede the reaction (Scheme 12). Direct nitroaldol reaction by bis[(L)prolinate-N,O]Zn complex was performed in 2007 by Reddy et al. [74]. The Henry reaction or nitroaldol is one of the influential CarbonCarbon bond formation reactions in organic chemistry to 254 R. Poddar et al. + R OH O O Zn(L-Pro)2 (5 mol%) H2O/THF H (34) X X OH X Yield% syn/anti 4-NO2 25 2:1 2-NO2 6 3:2 2-Br 35 5:1 4-NO2 80 1:1 2-NO2 88 1:1 2-Br 90 3:1 R H H H OH OH OH syn (35) (32) O OH R OH OH OH O OH O O OH R OH X R X R X anti Scheme 9 O H O O H O NH O 2+Zn O O HN H O NH O Zn2+ O O H O Fig. 9 Proposed intermediates for the zinc-supported enamine mechanism of the bis[(L)prolinate-N,O]Zn complex-catalyzed aldol reaction. NH4OAc + 2 CH3 (40) (38) (37) R O O N H O H O NH R 2+Zn N (36) O O H R2 = OC2H5 OCH3 CH3 Zn(L-Pro)2 O 1 R H (39) H2O/Ethanol 2-5 min. 200W microwave R1 = 4-NO2-C6H4 4-NO2-C6H4 4-CH3O-C6H4 4-OH-3-CH3O-C6H3 3,4-(CH3O)2-C6H4 2-furyl 3-indolyl R1 O 2 R2 R H3C N H CH3 (41) Yield 90-95% Scheme 11 O + Zn(OH)2 2 N H O At pH > 8 O O NH NH O At pH = 2 2+Zn + Zn2+(aq) 2 O N H OH H O At pH = 8 At pH = 6 O + Zn2+(aq) 2 N H O H Scheme 10 produce important functionalized skeletons such as a-hydroxy carboxylic acids and 1,2-amino alcohols [75,76]. The standard nitroaldol reaction is carried out in the presence of inorganic (alkali metal hydroxides, calcium hydroxide, alkoxides, aluminum ethoxides, carbonates, bicarbonates) or organic base (primary, secondary, and tertiary amines) in an organic solvent [77]. To conquer some of the inconveniences associated, the selective, homogeneous and reusable catalysts are highly recommended. Hence, bis[(L)prolinate-N,O]Zn complex was used as a catalyst for this reaction (Scheme 13). Bis[(L)prolinate-N,O]Zn complex also acted as a watersoluble and recyclable Lewis acid catalyst for the selective synthesis of 1,2-disubstituted benzimidazoles via the reaction of substituted o-phenylenediamines (48) and aldehydes (49) in moderate to excellent isolated yields (42–92%) using water as solvent at ambient temperature [78]. Under the optimized reaction conditions, in all cases the yields were high and 1,2disubstituted product (50) was formed selectively rather than 2-substituted product (51). This selectivity could be useful in synthesizing a mini library of biologically relevant 1,2disubstituted benzimidazoles in moderate to excellent yields (Scheme 14). Shah and co-worker have revealed [79] that the bis[(L) prolinato-N,O]Zn, a Lewis acid catalyst under microwave irradiation could afford 3-methyl-1-substituted-phenyl-1Hchromeno[4,3-c]pyrazol-4-ones (54) by cyclization of hydrazones of 3-acetyl-4-hydroxycoumarin. The range of yields of various products was obtained to be 82–93%. In the absence of the catalyst, no reaction occurred. There was no remarkable increase in the yields of product at high temperatures and at high microwave power (Scheme 15). Itoh et al. have utilized the concept that that stereospecific aldol reactions are catalyzed by aldolase enzymes in a reversible manner. Aldolases enzymes are subdivided into two classes aldolase I (on catalyzing stereospecific aldol reaction through the enamine intermediates) and aldolase II (in which Zn2+ enolates of substrates react with acceptor aldehydes) [80] in Fig. 10. Mechanistic studies suggested that the amino acid part