Polydopamine: An Amine Oxidase Mimicking Sustainable Catalyst for

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Polydopamine: An Amine Oxidase Mimicking Sustainable Catalyst for the Synthesis of Nitrogen Heterocycles under Aqueous Conditions Shweta Anil Pawar, Ayushi Naresh Chand, and A. Vijay Kumar ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b06677 • Publication Date (Web): 20 Mar 2019 Downloaded from http://pubs.acs.org on March 20, 2019

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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ACS Sustainable Chemistry & Engineering

Polydopamine: An Amine Oxidase Mimicking Sustainable Catalyst for the Synthesis of Nitrogen Heterocycles under Aqueous Conditions Shweta A. Pawar, Ayushi N. Chand and A.Vijay Kumar* Department of Chemistry, Institute of Chemical Technology, Nathalal Parekh Marg, Matunga, Mumbai, Maharashtra- 400019, India. E-mail of corresponding author: [email protected] ABSTRACT: The catalytic activity of polydopamine (PDA) as an amine oxidase mimic is demonstrated under aqueous conditions for the synthesis of benzimidazoles, quinoxalines, quinazolinones and oxidation of secondary amines. The synthesis occurs through activation of the amines by the catechol-quinone moieties of PDA, followed by transamination and an oxidative cyclization of these benzylic (or) arylethyl imine adducts with o-phenylenediamines and 2-aminobenzamides akin to the amine oxidase enzymes in the presence of benign oxidant molecular oxygen. PDA demonstrated excellent efficiency on par with the existing regime of metal/non-metal based catalysts without any additives under aqueous conditions.The mechanistic studies showed evidence for an oxygen mediated non-radical pathway via a quinone-imine step. Additionally, PDA was found to be easily recoverable and reusable up to three cycles without any loss of catalytic activity. Moreover, the utility of non-toxic and cheap solvent such as water along with a biomimicking recyclable catalyst PDA makes it a benign protocol from the sustainability point of view. Keywords: Amine oxidase mimics, Aerobic oxidative cyclization, Aqueous conditions, Nitrogen heterocycles, Polydopamine, Recyclable, Sustainability.

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INTRODUCTION Mimicking nature’s artistry by employing benign materials as catalysts for organic transformations precluding the existing hazardous solvent regime represents an interesting strategy for fostering environ-friendly and sustainable synthetic protocols. Over the recent years, such biomimetic protocols are gaining popularity due to the growing concern for environment preservation and sustainability. In this context, polydopamine (PDA) - a dopamine based polymer has emerged as a promising material because of its several interesting features such as ease-of-synthesis from readily available inexpensive precursor-dopamine, non-toxic nature, ability to coat any surface, bio-compatibility, etc.1,2 Besides being a marine mussel adhesive protein mimic, owing to several other interesting properties,3 it has been explored for a plethora of applications such as drug delivery,4-6 supporting/capping nanoparticles,7-9 molecular sensing,10,11 immobilizing enzymes,12,13 etc. Our group has recently shown the utility of PDA coated magnetic nanoparticles as a robust support for palladium nanoparticles (magnetically recoverable catalyst) for Suzuki cross-coupling reactions,14 followed by other metal/PDA type systems for catalysis by several groups.15 Prior to these works, Liebscher’s group for the first time demonstrated PDA’s special ability as an organocatalyst for aldol reaction thus revealing the non-innocent behaviour of polydopamine.16 Zhang and co-workers reported a PDA mediated carbon dioxide incorporation for the formation of cyclic carbonates from epoxides.17 Later, Xu and co-workers reported a PDA catalyzed thiol coupling reaction which further endorsed PDA polymer’s organocatalytic activity.18 Moreover, these reports bespeak the innate potential of PDA in catalyzing organic reactions in the absence of metals or additives. The catalytic activity of PDA in these reports was presumed to be by the catechol-quinones as well as the basic amine moieties present in its structure (Figure 1). Interestingly, Copper amine oxidases (CuAOs) and Lysyl oxidases (LAO) are a class of ubiquitous enzymes prevailing in wide range of organisms which are known to utilize quinone based co-factors for the metabolism of various polyamines of endogenous or xenobiotic origin.


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The human vascular adhesion protein-1 (VAP-1) is a CuAO enzyme which is a known regulator of leucocyte trafficking and glucose transport mechanism. Also it is upregulated at the sites of inflammation, owing to which several potential therapeutic agents are designed that are selective CuAO inhibitors. Moreover, the CuAO enzymes are known to oxidize primary amines to aldehydes synergistically through the quinone based co-factor topaquinone TPQ19-24 (Figure 1). It has been established that TPQ in these enzymes converts primary amines into aldehydes via a transamination mechanism involving two redox processes wherein the quinone functionality is converted to a reduced amino-quinol initially in the first step and later gets reoxidized to quinone in a second step mediated by molecular oxygen.25 Lysyl oxidases (LAO) enzymes which belong to the family of multifunctional amine oxidases also use a quinone based co-factor lysine tyrosylquinone (LTQ) (Figure 1). These enzymes play a pivotal role in development of extracellular matrix, cross-linking of collagen and elastin in birds and mammals.26 They do so by deaminating the lysine and hydroxylysine side chains of collagen to yield reactive aldehyde groups which further form covalent bonds thus leading to cross-linking.27 Both CuAO and LAO enzymes make use of catechol-quinone based motifs as co-factors for oxidising amines.



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RESULTS AND DISCUSSION Intrigued by these common molecular features of the enzyme machinery and PDA, we envisaged the catechol-quinone moieties of PDA could be explored for mimicking the functioning of the aforementioned amine oxidase enzymes.

HO

OH

O

O

n HN

HO

o

m HN

p HN

H2N

HN

O

OH O

OH HO

Polydopamine (PDA) O

O

HN

HN

O

O

HO

O

TPQ

N H

O

LTQ

H N 4

O

Figure 1. Catechol-quinone sites in polydopamine, CuAO oxidase enzymes co-factor topaquinone (TPQ) and Lysyl Oxidase enzymes co-factor lysinetyrosylquinone (LTQ). Also recently, quinone moiety based catalysts for oxygen mediated transformations have seen limelight and are booming owing to the importance of metal-free protocols.28-30 Metal-free protocols are highly advantageous as they are devoid of metal contaminations and henceforth avoid the unnecessary extra steps to make the products free of metal impurities. Such methods are significant especially for the synthesis of bioactive molecules, pharmaceuticals and drugs. In this connection, recently, several groups have showcased quinone based catalysts for amine oxidations (primary as well as secondary) and for the synthesis of various nitrogen heterocycles under aerobic conditions (Scheme 1),31-43 also quinone catalysts under electrocatalytic conditions.44-46 Unfortunately, these methods are less benign from a sustainable point of view as


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they use organic solvents along with metal catalysts (or) salts/additives. Moreover, several of these quinone catalysts preparations are time consuming and cumbersome as they involve multiple steps. Additionally, several of these are not demonstrated to be reusable, therefore their recovery would require extra steps for separation and purification from the reaction mixtures thus making them less suitable for scalable usage. From the perspective of green and sustainable chemistry,47,48 water is a highly preferred solvent on account of its abundance, non-toxicity, non-flammability and cost-effectiveness. Besides these, it also is a promising alternative to the conventional organic solvents, owing to which numerous research groups over the past decades have explored the prodigious potential of water as the reaction medium.49,50 Thus, the development of water-compatible catalysts for the establishment of eco-friendly sustainable protocols are the need of the hour. Therefore, taking into account of the aforementioned advantages of metal-free protocols under aqueous conditions and the drawbacks of existing regime of catalysts, in continuation to our efforts to develop sustainable protocols using benign catalysts,51-57 we, herein report a biomimicking process wherein polydopamine is used as an organocatalyst for the oxidation of benzylic primary amines, alkyl amines and secondary amines aerobically. The formed intermediate imines are trapped by diamines (or) amides and aerobically oxidized to afford nitrogen heterocycles such as benzimidazoles, quinoxalines, quinazolinones, as well as other heterocycles such as quinolines and indole via a domino/cascade process (Scheme 2). This simple methodology depicts the use of benign polydopamine as a promising enzyme mimicking recyclable catalyst devoid of transition metals, organic solvents, and additives. To the best of our knowledge, this is the first report showcasing a benign metal-free, recyclable, heterogeneous catalyst that replicates the function of amine oxidase enzymes for the biomimetic synthesis of nitrogen heterocycles.



Langeron et al31

Primary Amine Oxidation: 2 R

A)

Conditions

NH2

R1

or R2

R

R

Oh et al37 Ph

O

O O

Homo imines: Cu(OAc)2, MeCN, 23 0C, O2, 18-48 h

imines formed

O

carbonyls formed

CH3COOH, 3A MS MeCN, 23 0C, air, 16-24 h

Cross imines: TFA, MeCN, 23 0C, O2, 24 h

HO AuONT H2O or MeOH, rt, air, 24 h

CuMeSal MeOH, rt, air,10 h

O

Clift et al35 O tBu tBu

Doris et al OH O HO

O

R2

Ph

MeCN, rt, O2, 48 h

33

N

O

MeO

HN

Oh et al36 O

OH O MeCN, rt, O2, 20-48 h

OH O

R R1

Luo et al34

Stahl et al32 O

N

Conditions

NH2

R

NH2

Page 6 of 43

MeCN, 80 0C, air, 36 h

PhMe, 80 0C, O2

Secondary Amine Oxidation: R B)

NH

Conditions

or

N H

R

R

N

or N

R Doris et al

Kobayashi et al

Stahl et al O

38

Pt/Ir nanocluster@ polymer, K2CO3 CHCl3:H2O (9:1) OH 35 0C, O , 16 h 2

O

OH

N N

ZnI2, PPTS39 MeCN, rt, O2, 24-48 h

OH

or

OH 2+ 40

[Ru(phd)3] Co (salophen) MeCN, rt, O2, 5-48 h

Nitrogen Heterocycles Synthesis:

C)

+

R

Ag2CO3 MeCN, 23 0C, O2, 36 h

Ph N

O

XH

Largeron et al42

R

CuBr2 MeOH, 45 0C, air, 18 h

[R = Ph, alkyl]

O O

OH O

NH2

NH2

Oh et al36 Ph

RhCNT CHCl3:H2O (3:1) rt, air, 10-23 h

NH

Ph NH

41

N

X

O

R

Luo et al43

N NH2

MeO

+ R

NH2

or

R1

NH2

[where X = NH, O; R = Ph]

O

TsOH or Na2HPO4 MeCN or PhCl 60-100 0C, O2, 24-36 h

+ N N

R1

Scheme 1. Comparative of existing methods for oxidation of amines using quinone catalyst


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This work: Biomimetic oxidative transformations in water: NH2 NH2

PDA H2O, 80 0C, O2

H N Ph N

+ NH2 NH2

PDA

N

H2O:EtOH, 80 0C, O2

N

O

Ph

O NH2 +

NH2

PDA H2O, 100 0C, O2

NH2

NH N

Ph

PDA N H

or

N H

H2O, 80 0C, O2

or N

N H

Scheme 2. Our approach for synthesis of nitrogen heterocycles using PDA Benzimidazole Synthesis: Initially, for the optimisation of benzimidazole synthesis, o-phenylenediamine and benzylamine were chosen as model substrates. We performed the reaction in water with 100 wt% of PDA at 100 0C wherein the starting materials were completely consumed within 6 hours to afford the benzimidazole product in excellent yield of 91% (Table 1, entry 1). Encouraged by this result, we proceeded further to establish the optimisation conditions by screening parameters such as the catalyst amount and temperature. Inferior catalytic activity was observed when the catalyst amount was lowered from 80 wt% to 10 wt% (Table 1, entries 2-5). The reactions with lower amounts of catalyst were sluggish and did not go for completion. The reaction with 100 wt% catalyst at 80 0C furnished an excellent yield of 91% of the benzimidazole product (Table 1, entry 6). Further the reaction was carried out at 60 0C and at room temperature; however product yields were lowered even though the reaction mixture was allowed to continue for 24 hours (Table 1, entries 7 and 8).



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Table 1. Optimisation of Benzimidazole Synthesisa NH2

PDA (wt%)

H N

H2O, O2, temp., time

N

NH2

NH2 1

2

3

entry

PDA amount (wt%)

temp. (0C)

time (h)

yieldb(%)

1

100

100

6

91

2

80

100

6

82

3

60

100

7

75

4

40

100

8

69

5

10

100

24

45

6

100

80

7

91

7

100

60

24

64

8

100

rt

24

42

aReaction

conditions: 1 (0.30 mmol), 2 (1.2 equiv., 0.36 mmol), H2O (2.0 mL), under O2 atmosphere. bIsolated yield

Under the optimised conditions, the scope of this catalyst was explored for a wide range of ophenylenediamines and benzylamines (Scheme 3). The o-phenylenediamine derivatives furnished excellent yields of the product irrespective of the substitutions on the phenyl ring (Scheme 3, 3a-f) and also required shorter reaction times; with the exception of the substrate 4nitro-o-phenylenediamine (Scheme 3, 3f). Though it afforded good yield of 82%, it required 48 hours for the reaction completion. Alkyl groups and halogen groups at the ortho and para position of benzylamines worked well and afforded the products in good to moderate yields regardless of the electronic character of the substituents (Scheme 3, 3g-k). The substrates (Scheme 3, 3h-m) required slightly longer time durations for complete conversions as compared to the substrates (Scheme 3, 3a-e).


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Scheme 3. Substrate scope for Benzimidazoles Synthesisa,b R

NH2

1

NH2

NH2

PDA (100 wt%) 0

R1

H2O, O2, 80 C

R2

1

H N N

2

3

H N

H N

H N

N

N

3a, 92%, 6 h

3b, 86%, 8 h

Br

H N

Cl

H N

N

Cl

N

H N

H N

N

N

Cl N

H N

N O

N

N 3m, 78%, 24 h

H N N

3i, 84%, 12 h

H N

3k, 85%, 14 h N

3f, 82%, 48 h H N

Br

3j, 83%, 16 h

N

O 2N

H N

H N

3c, 90%, 10 h H N

3h, 76%, 15 h

3g, 85%, 7 h

N

Cl

3e, 88%, 7 h

3d, 85%, 7 h

R2

CF3

N 3l, 80%, 16 h H N

C5H11

3nc, 57%, 24 h

N

C 2H 5

3oc,d, 52%, 24 h

aReaction

conditions: 1 (0.30 mmol), 2 (1.2 equiv., 0.36 mmol), PDA (100 wt%), H2O (2.0 mL), 80 0C, under O2 atmosphere. bIsolated yield. cReactions performed at 90 0C for 24 h with 1.5 equiv., 0.45 mmol amine. dan additional 1.5 equivalent of alkylamine was added after 12 h due to its volatile nature.

The heterocyclic amine, picolylamine formed the corresponding benzimidazole (Scheme 3, 3m) in moderate yield of 78% within 24 hours. When un-activated aliphatic amines such as hexylamine and propylamine were taken as the substrates, we were delighted to observe the



corresponding benzimidazole products in 57% and 52% yields respectively (Scheme 3, 3n, o). The ability of PDA in activating the aliphatic amines for the heterocycles clearly demonstrates PDA as a CuAO enzyme mimicking catalyst. Quinoxaline Synthesis: Next, we attempted to explore the organocatalytic activity of polydopamine for the synthesis of quinoxalines. When 2-phenylethylamine was reacted with o-phenylenediamine, quinoxalines were obtained as the major products along with the expected benzimidazole as a minor product. Optimisation was carried out by screening parameters such as the amount of 2-phenylethylamine, amount of PDA catalyst, solvent and temperature. Initially 100 wt% of PDA was studied along with 1.2 equiv. (0.36 mmol) of 2-phenylethylamine and the reaction was performed at 100 0C for 24 hours in water which afforded the quinoxaline product in moderate yield of 63% (Table 2, entry 1). Under the same conditions, the amount of 2-phenylethylamine was increased to 1.5 equiv. (0.45 mmol) which slightly increased the yield to 68% (Table 2, entry 2). Further the reaction was carried out in ethanol for 24 hours using 1.5 and 2 equivalents (0.60 mmol) of 2phenylethylamine and the yields increased to 77% and 81% respectively (Table 2, entries 3 and 4). Next, the reaction was screened in ethanol:water mixtures (1:1) with varying equivalents of 2phenylethylamine at 100 0C with 100 wt% PDA forming quinoxaline product with good yields.


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Table 2. Optimisation of Quinoxaline Synthesisa NH2

N

NH2

PDA (wt%) N

solvent, O2, temp., time

NH2 1

4

5

PDA amount (wt%) 100

solvent

temp. (0C)

time (h)

yieldb (%)

1

4 (mmol) 0.36

H2O

100

24

63

2

0.45

100

H2O

100

24

68

3

0.45

100

EtOH

100

24

77

4

0.60

100

EtOH

100

24

81

5

0.60

100

EtOH: H2O

100

15

77

76

0.45

100

EtOH: H2O

100

24

82

7

0.45

100

EtOH:H2O

80

18

85

8

0.45

80

EtOH: H2O

80

24

72

9

0.45

50

EtOH: H2O

80

24

68

entry

aReaction

conditions: 1 (0.30 mmol), solvent (2.0 mL), EtOH:H2O = 1:1, under O2 atmosphere. bIsolated yield.

(Table 2, entries 5 and 6). Delightfully, 1.5 equiv. of 2-phenylethylamine with 100 wt% PDA at 80 0C formed the desired product in 85% yield within 18 hours (Table 2, entry 7). Lastly, the amount of PDA catalyst was varied to 80 wt% and 50 wt% which decreased the yield to 72% and 68% respectively (Table 2, entries 8 and 9). Under the optimised conditions, the substrate scope of quinoxalines synthesis was next investigated (Scheme 4). 2-Phenylethylamines proved to be suitable substrates; irrespective of electron-withdrawing or electron-donating substituents on the phenyl ring. The products were obtained in good to moderate yields within 12 to 24 hours (Scheme 4, 5a−f). Next, disubstituted o-phenylenediamines were screened which resulted in moderate yields of quinoxalines (Scheme 4, 5g−j). Dimethyl o-phenylenediamines (Scheme 4,



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5g-i) took around 12 hours for completion; whereas dichlorosubstituted o-phenylenediamine took longer reaction times of 36 hours (Scheme 4, 5j).

Scheme 4. Substrate scope for Quinoxaline Synthesisa,b R

NH2

3

NH2

NH2

R

1

PDA (100 wt%)

R3

N

EtOH:H2O, O2, 80 0C

4

N

5

4

N

N

N

N

N

N O

5b, 83%, 12 h

5a, 85%, 12 h

OH 5c, 78%, 14 h

N

N

N

N

N

N

5d, 79%, 24 h

F

5e, 75%, 24 h

R4

Cl

5f, 81%, 24 h

N

N

N

N

N

N

Br

O 5g, 80%, 12 h Cl

N

Cl

N

5h, 79%, 11 h

5i, 75%, 12 h

5j, 71%, 36 h aReaction

conditions: 1 (0.30 mmol), 2 (0.45 mmol), PDA (100 wt%), EtOH:H2O (1:1, 2.0 mL), 80 0C, under O2 atmosphere. bIsolated yield.


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Quinazolinone Synthesis: Table 3. Optimisation of Quinazolinone Synthesisa O

O

N

solvent, O2, temp. 24 h

NH2 6

aReaction

NH

PDA (wt%)

NH2

NH2

7

2

H2O

80

yieldb (%) 56

100

H2O

100

61

0.45

100

H2O

100

65

4

0.60

100

H2O

100

76

5

0.60

100

EtOH:H2O

100

73

6

0.60

80

H2O

100

67

7

0.60

100

H2O

80

63

entry

2 (mmol)

1

0.36

2

0.36

3

PDA amount (wt%) 100

solvent

temp. (0C)

conditions: 1 (0.30 mmol), solvent (2.0 mL), EtOH:H2O = 1:1, under O2 atmosphere. bIsolated yield.

When anthranilamide was employed as the substrate along with benzylamine, surprisingly quinazolinones were formed; thus the organocatalytic activity of polydopamine was further investigated for the synthesis of quinazolinones. Optimisation was carried out by screening parameters such as the amount of benzylamine, amount of PDA catalyst, solvent and temperature. Initially 100 wt% of PDA was studied along with 1.2 equiv. (0.36 mmol) of benzylamine and the reaction was performed at 80 0C for 24 hours in water affording the quinazolinone product in low yield of 56% (Table 3, entry 1). Under the same conditions, upon increasing the temperature to 100 0C, the product yield increased to 61% (Table 3, entry 2). Next, the amount of benzylamine was increased to 1.5 equiv. (0.45 mmol) and 2.0 equiv. (0.60 mmol) which increased the yield to 65% and 76% respectively (Table 3, entries 3 and 4). When the reaction was carried out in ethanol:water mixture, the product was obtained in a moderate yield



Page 14 of 43

of 73% (Table 3, entry 5). Thus, water was preferred as the solvent of choice as better yields were observed in water as compared to ethanol:water mixture. When the amount of PDA catalyst was reduced to 80 wt%, the product yield decreased to 67% (Table 3, entry 6). Lowering the temperature to 80 0C afforded 63% of the product yield (Table 3, entry 7). Anthranilamides being poor nucleophiles might be slowing the transamination-cyclization step, as a result the most optimised condition can be considered as entry 4 (Table 3). Scheme 5. Substrate scope for Quinazolinone Synthesisa,b O

O NH2

NH2

PDA (100 wt%)

NH2

+ R

5

H2O, O2, 100 C, 24 h

O

7

N

aReaction

NH

NH N

N

MeO 7a, 72%

7b, 68%

conditions: 6 (0.30 mmol), 2 (0.60 mmol), atmosphere. bIsolated yield.

R5

O

O NH

NH N

N

2

6

O

NH

0

CF3

Cl 7c, 61%

7d, N.R.

PDA (100 wt%), H2O (2.0 mL), 100 0C, under O2

The scope of quinazolinone synthesis was further investigated under the optimised conditions by screening the substituted benzylamines. Electron donating groups on benzylamine provided modest yields of the products (Scheme 5, 7a, b). Benzylamine substituted by chloro group at para position afforded 61% yield (Scheme 5, 7c) whereas the reaction failed to progress in the case of electron withdrawing group i.e. -CF3 substituted benzylamine at para position (Scheme 5, 7d). After the successful utility of PDA for the synthesis of nitrogen heterocycles, the versatility of the benign PDA catalyst was further evaluated for secondary amine oxidation (Scheme 6). Tetrahydroquinolines and indoline were efficiently oxidised to the corresponding quinolines and indole respectively with good to moderate yields respectively (Scheme 6, 9a-d).


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Scheme 6. Secondary Amine Oxidation Substrate Scope a,b PDA (100 wt%)

or

N H

N H

H2O, O2, 80 0C, 24 h

N

8

or

N H

9

O N

N 9b, 75%

9a, 84%

c

9c , 78%

N

N H 9d, 71%

aReaction bIsolated

conditions: 8 (0.30 mmol), PDA (100 wt%), H2O (2.0 mL), 80 0C, under O2 atmosphere, 24 h. yield. creaction at 90 0C.

Mechanistic studies: Control experiments were performed to gain insights into the reaction mechanism wherein the benzimidazole reaction was chosen with the model substrates, o-phenylenediamine and benzylamine as shown in Scheme 7. The control experiments were carried out using the optimised conditions as obtained for the benzimidazole synthesis in Table 1. The reactions performed in the presence of radical quenchers such as TEMPO and BHT had no significant Scheme 7. Control Experiments a,b NH2

NH2

NH2 1

H2O, O2 (or) Argon 80 0C

2

NH2

+

a)

NH2

NH2

+ NH2

NH2

H N N 3

PDA (100 wt%)

H N

TEMPO (100 wt%)

N

H2O, O2, 80 0C

NH2 b)

PDA (100 wt%)

PDA (100 wt%) BHT (100 wt%) H2O, O2, 80 0C

6 h, 86% H N N 6 h, 84%



NH2

+

c)

NH2

NH2

Page 16 of 43

PDA (100 wt%)

H N

H2O, Argon, 80 0C

N 24 h, 35%

NH2

+

d)

NH2

NH2

No Catalyst

H N

H2O, O2, 80 0C

N 24 h, 15%

Fe3O4

NH2

+

e)

NH2

NH2

Fe3O4@PDA (100 wt%)

H N

H2O, O2, 80 0C

N

= Polydopamine

24 h, 85%

Fe3O4

NH2

+

f) NH2

NH2

Fe3O4 (100 wt%)

H N

H2O, O2, 80 0C

N 24 h, trace

aReaction 0C,

conditions:1 (0.30 mmol), 2 (1.2 equiv., 0.36 mmol), PDA or Fe3O4@PDA (100 wt%), H2O (2.0 mL), 80

24 h. bIsolated Yield.

effect on the product yields (Scheme 7, a and b). This confirmed that the reaction does not proceed through radical pathway thus advocating a non-radical pathway. Further next, to understand the role of oxygen, reaction was carried out under argon atmosphere by thoroughly purging the reaction with argon gas to deplete any residual oxygen gas (Scheme 7, c). The reaction proceeded sluggishly and afforded only 35% of the product. This strongly suggested that the reaction proceeds through an aerobic pathway wherein oxygen is crucial for the progress of the reaction. The control reaction without any catalyst afforded only 15% yield of the product after 24 hours (Scheme 7, d) which proves the significant role of PDA. Further next, to investigate the role of quinone moieties of PDA, we supported PDA on Fe3O4 nanoparticles by our previously reported procedure.14 The quinone functionalities are known to cap the Fe atoms


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and thus would not be available freely to engage the amines in the catalytic cycle. Surprisingly, the catalyst showed good activity for the oxidative benzimidazole cyclisation reaction wherein 85% isolated yield of the product was obtained (Scheme 7, e). However this catalyst requires 24 hours for complete conversion as compared to the PDA catalyst which requires 7 hours (Table 1, entry 6). This might be due to the non-availability of free quinone sites as many are capped on Fe3O4 whereas in case of PDA, all the quinone sites are freely available to facilitate the same reaction in shorter duration of time. Lastly, the reaction was also performed only in the presence of Fe3O4 nanoparticles which provided trace amounts of the product after 24 hours (Scheme 7, f). Based on the above control experiments, we propose a reaction mechanism for the heterocycles synthesis catalyzed by PDA similar to the reported quinone mediated amine oxidation process43 (Scheme 8). We presume the reaction might take place through a transamination pathway involving the ortho-quinone functionalities of PDA. In step 1 and 2, benzylamine/phenylethylamine-PDA imine-adduct formation takes place followed by a transamination of diamine/2-aminobenzamide to form the imine adduct. Finally in step 3, it is followed by cyclization-oxidation steps to form the respective heterocyclic product. The detachment of o-aminophenol species followed by attack of water molecule and consecutive loss of ammonia probably regenerates the PDA quinone sites. The oxidation of secondary amines is presumed to proceed through a similar imine adduct followed by hydrolysis and oxidation to form the oxidised quinolines and indole.



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Benzimidazoles, Quinoxalines, Quinazolinones Synthesis: N

O

Ph H 2N

OH (or)

H 2N

N Ph Ph

NH2 (or)

Ph

OH

1

(or)

H 2N H 2N

NH2

N 2

O

NH2

O

OH

Ph

N

(or)

(or) N

3

NH2 Ph

N (or) O

N

Ph

N (or) O

O2

NH

NH2

H 2O

NH3

H N

NH2

N

Ph

Ph

Secondary Amines Oxidation:

N

(or)

O

N

N H

O 1

(or)

N H

O N

O

(or) OH

N OH

H 2O 3

N (or)

O2 N H

N (or)

N

Scheme 8. Proposed mechanistic pathway for PDA catalyzed heterocycles synthesis Scale-up and PDA catalyst recyclability study: Encouraged by these results, we further expanded our study to check for a large scale reaction (Scheme 9) as well as recyclability of PDA (Figure 2). For this, the benzimidazole reaction was


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chosen as the model reaction wherein, the reaction of o-phenylenediamine (1.5 mmol) and benzylamine (1.2 equiv, 1.8 mmol) was carried out along with 100 wt% PDA. Delightfully, the reaction afforded the product in excellent yield of 91% after 24 hours (Scheme 9). After completion of the reaction, the product was separated by addition of suitable solvent and the aqueous part containing PDA was freshly charged with substrates and heated at 80 0C. Likewise the catalyst was recycled efficiently upto 3 cycles (Figure 2). For the first two cycles, the product yields were 90% and 89% respectively; nearly similar as the yield obtained in the native reaction (Scheme 9). The yield decreased slightly to 85% in the third cycle. Thus, we were able to successfully recycle the PDA catalyst upto three cycles with no loss of catalytic activity with only marginal variation of product yields. The decrease in the yield in the third cycle might be due to change in morphology as seen in the SEM images of PDA (Figure 3), wherein disfigured Scheme 9: Scaled-up reaction for Benzimidazole Synthesisa,b (Native Reaction): NH2

NH2

NH2 1

PDA (100 wt%)

H N

H2O, O2, 80 0C, 24 h

N

2

3

aReaction

conditions: 1 (1.5 mmol), 2 (1.8 mmol), PDA (100 wt%) and H2O (4.0 mL), 80 24 h. bIsolated yield.

0C,

(91%)

under O2 atmosphere,

Figure 2: Recyclability of PDA catalyst for benzimidazole synthesis



aggregates were observed after recycling as compared to the smooth spheres of native PDA. Further, peak shift in the XRD spectra of the recycled catalyst, also supports the morphological changes i.e. exfoliation of the catalyst when compared to the native catalyst (Figure 5). These salient features of PDA viz. scalability and recyclability vouch PDA’s efficiency in catalysing the reaction and clearly proved that PDA can also be utilised on larger scales for driving organic reactions in water. The reaction was carried out by scaling upto five times (from 0.3 mmol to 1.5 mmol). The native and the recycled catalyst were analyzed by different spectroscopic techniques. Fe3O4@PDA catalyst recyclability study: Additionally we also carried out recyclability study using PDA supported on Fe3O4 (100 wt %) for the benzimidazole reaction on 0.3 mmol scale. This reaction afforded the product in excellent yield of 85% after 24 hours (native reaction, Scheme 10). After completion of the reaction, the product was separated by addition of suitable solvent and the aqueous part containing Fe3O4@PDA was freshly charged with substrates and heated at 80 0C under oxygen atmosphere. Likewise the catalyst was recycled efficiently upto 2 cycles. In the first cycle, the product yield was found to be slightly lower (78% isolated yield) as compared to the native reaction along with an increase in the reaction time to 30 hours for completion. In the second cycle, the yield further decreased to 73% and required 36 hours for complete conversion. Thus, the recyclability of Fe3O4@PDA catalyst was demonstrated upto two cycles. The decrease in the yield in the second cycle might be due to change in morphology as seen in the SEM and TEM images of recycled Fe3O4@PDA (Figure 8 and 10 respectively), wherein flattened aggregates (as seen in SEM), dislodged and crumpled PDA from the surface of Fe3O4 (as seen in TEM) were observed when compared to the smooth spheres of native Fe3O4@PDA. The amount of PDA on the magnetic nanoparticles was calculated (with respect to increase in the weight of nanoparticles after coating them with PDA) to be 50 wt%. It is noteworthy to mention that in the case of native Fe3O4@PDA catalysed reaction, the product


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yield obtained was 85% after 24 hours (native reaction, Scheme 10). The amount of PDA on the magnetic nanoparticles is mere less in comparison to the PDA used in the reaction (Table 1, entry 6, 100 wt%). Also, when compared to 60 wt% of PDA used in table 1, entry 3 which afforded 75% of product yield in 7 hours, Fe3O4@PDA (Scheme 10) afforded 85% of product yield which is slightly higher. This slight increase of yield might be due to the orderly orientation of quinone moieties on Fe3O4@PDA when compared to the randomly oriented quinone sites in PDA alone which is amorphous. However, the prolonged reaction time might be due to less amount of PDA in Fe3O4@PDA when compared to the conditions employed in Table 1, entry 6. Scheme 10: Fe3O4@PDA catalyst recyclability study (Native Reaction) a,b

Fe3O4

NH2

NH2

+ NH2 1

2

Fe3O4@PDA (100 wt%)

H N

H2O, O2, 80 0C, 24 h

N

= Polydopamine

3 (85%)

aReaction

Conditions: 1 (0.30 mmol), 2 (0.36 mmol), Fe3O4@PDA (100 wt%) and H2O (2.0 mL), 80 0C, under O2 atmosphere, 24 h. bIsolated yield.

PDA catalyst characterisation: 1) SEM Analysis: To study the surface morphology of the native and recycled PDA catalysts we performed the SEM analysis. For elemental mapping, EDX analysis was also carried out. In figure 3, images AF are SEM images of native and recycled PDA catalyst. The images A, B correspond to the SEM images of native PDA and they appear as microspheres exhibiting a uniform spherical shape with smooth surface. The images C-F correspond to the SEM images of recycled PDA catalyst as obtained after the third cycle. When compared to the native PDA catalyst, the spherical morphology is changed to flaky types of layers with an uneven topological surface (Figure 3, C



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A

B

C

D

E

F


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G

Figure 3. FEG-SEM images: Native catalyst (A, B); Recycled catalyst (C-F); and EDX (G) of the native PDA catalyst and D) and perforations at few sites were observed on the surface of PDA catalyst (Figure 3, E and F). The chemical composition of the catalysts was determined using the energy dispersive X-ray spectrum (EDX). The EDX spectrum shows the presence of the expected elements i.e. carbon, nitrogen and oxygen (Figure 3, G). Further the percentage of elements as seen in EDX analysis data for both the native and the recycled PDA catalysts (Table 4) confirms the presence of carbon (C), nitrogen (N) and oxygen (O) in PDA catalyst. It also proved that the catalyst is devoid of other metal impurities. Table 4. EDX data for Native and Recycled PDA catalysts: Elements (Native PDA)

C

N

O

Total

Weight%

64.18

14.76

21.06

100.00

Atomic%

69.27

13.66

17.07

-

Elements (Recycled PDA)

C

N

O

Total

Weight%

63.81

19.91

16.28

100.00

Atomic%

68.54

18.34

13.13

-



2) FTIR Spectroscopy: Figure 4 shows the FTIR spectra of native and recycled PDA catalysts which was performed to investigate the surface chemical structure before and after recycling PDA. The values observed in spectra revealed the presence of broad peaks at 3364 and 3367 cm−1 in the native and recycled catalysts respectively, that are assigned to ν (O−H) and ν (N−H) stretching groups of PDA. The peaks observed at 1604 cm−1 (native catalyst) and 1602 cm−1 (recycled catalyst) are assigned to ν (C=C) stretching; whereas the peaks observed at 1512 cm−1 (native catalyst) and 1494 cm−1 (recycled catalyst) are assigned to ν (C=N) stretching modes. The peaks at 1350 cm−1 (native catalyst) and 1355 cm−1 (recycled catalyst) are assigned to indole ring CNC stretching modes. The carbonyl functionality was not discernible from this analysis, probably might have be obscured by other peaks. The IR values of native and recycled PDA catalyst are consistent with the literature58 and also prove that the functionalities/chemical structure of PDA remains intact after 3 cycles. Content of this meant for your information and should not be used for advertisement, evidence or litigation

785.42

3739.54

65

3500

3000

2500 2000 Wavenumber cm-1

C:\Program Files\OPUS_65\2016-2017\EXTERNAL\FTIR-127\127.0

127

SAIF IIT Bombay

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1500

1285.26

70

1604.40 1512.09 1447.02

1350.95

3364.10

Transmittance [%] 85 75 80

90

95

100

FTIR spectra of native catalyst:

60

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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1000

500

15/01/2018

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696.74

1355.22 1274.09 1602.68 3000

1494.37

80

3500

1500

1000

Figure 4. FTIR spectra of sP01 native SAIF andIIT Bombay recycled PDA catalyst

C:\Program Files\OPUS_65\2017-2018\EXTERNAL\ftir-178\sP01.0

3) X-ray Diffraction (XRD):

749.09

592.22

830.43

1949.08

2918.58

3057.26

1130.68 1057.67

Transmittance [%] 90 85

3367.21

95

100

of this for yourcatalyst: information and should not be used for advertisement, evidence or litigation FTIRContent spectra ofmeant recycled

75

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


500

06/04/2018

Page 1/1

The XRD patterns of the native and recycled PDA catalysts are provided (Figure 5). As observed, the spectra of native and recycled PDA show hump (broad peak) which is attributed to the diffraction of the amorphous structure of PDA. Native PDA shows a broad reflection peak at 2θ value of 22.90 which closely matches with the literature value59 (2θ = 23.20). While the recycled PDA shows marginally shifted diffraction peak to 20.80, probably due to exfoliation of the catalyst. Since both catalysts show broad peaks at similar 2θ value, it indicates that the crystallographic structure of PDA remains intact after subsequent recycling.



8000



22.9

7000

Native Recycled

0

20.8

6000

Intensity (a.u)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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5000 4000 3000 2000 1000 0 0

10

20

30

40

50

60

70

80

90

100

2

Figure 5. XRD of native and recycled PDA catalyst 4) Thermogravimetric Analysis (TGA): The TGA was performed under N2 flow with temperature ramping from 30 to 800 0C at a rate of 20.0 0C/min. Figure 6 shows TGA data for native and recycled PDA catalysts. In both cases, no sharp decline in the graph is observed which proves that the catalyst is thermally stable when exposed to heat at temperatures as high as 800 0C. The weight % of PDA is observed to decrease uniformly in both cases with increasing temperature. The initial dip in the curves observed around 100 0C is indicative of the amount of water loss in PDA. The native catalyst shows 10% water loss whereas the recycled PDA catalyst shows 5% water loss. Native PDA catalyst has more water content which declines in the recycled catalyst after subsequent cycles. The residual weight% obtained at the end of 800 0C is 56.68% and 56.75% for native and recycled PDA catalyst, respectively. These results also correspond to the literature report.59 Since, both catalysts show the same weight% remaining towards the end, it can be concluded that thermal stability of catalyst remains unaffected after recycling.


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TGA of native catalyst:

TGA of recycled catalyst:

Figure 6. TGA of native and recycled PDA catalyst 5) X-Ray Photoelectron Spectroscopy (XPS): We performed XPS analysis of native PDA catalyst to confirm the functionalities, especially the presence of carbonyl group, the chief entity responsible for the quinone based oxidative transformation (Figure 7). The presence of carbonyl functional group was not clear from the FTIR analysis, thus, the XPS analysis was required. The C 1s region was considered which



showed the peaks at 284.6, 285.0 and 288.2 eV corresponding to the binding energies of C–C/C– H, C–N and C=O groups, respectively. The observed peaks and their corresponding binding energies are consistent with the literature values for PDA.58 Thus, XPS study provided the crucial evidence for the presence of carbonyl functionality in PDA.

Figure 7. XPS of native PDA catalyst (C 1s region) 6) ICP-AES: Additionally, ICP-AES analysis of the native PDA catalyst was carried out to rule out the possibility of any metal contamination. Noble metals such as Pd, Ru, Rh as well as non-noble metals such as Co were found to be completely absent. The other non-noble metals such as Cu, Mn and Ni were present below the trace limits and were observed to be 0.003%, 0.03%, 0.002%. This clearly shows that the true catalytic activity is by the quinone moieties of PDA and not by any other possible metal contaminants, thus endorsing the ability of PDA as a biomimetic catalyst.


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Fe3O4@PDA catalyst characterisations: 1) SEM Analysis: To study the surface morphology of the native and recycled Fe3O4@PDA catalysts, SEM analysis was carried out (Figure 8, H-K). The morphology of native catalyst depicts spherical structures with a continuous PDA sheet covering Fe3O4 nanoparticles (Figure 8, H and I) and it was comparable with the previous report.60 Further the SEM images of the recycled catalyst displayed flattened aggregates along with few spherical structures (Figure 8, J and K). EDX analysis was also carried out to prove the presence of the elements Fe, C, N and O in the catalyst. The percentage of elements as seen in EDX analysis data (Figure 8, L) for both the native and the recycled Fe3O4@PDA catalysts are summarised in Table 5. The analysis clearly shows an increase in nitrogen content (0.69 weight % to 7.45 weight %) in the recycled catalyst. This increase in nitrogen content is probably due to the incorporation of ammonia into the quinone moieties either as an imine or as a Michael adduct.



Page 30 of 43

L

Figure 8. FEG-SEM images: Native catalyst (H, I); Recycled catalyst (J, K); and EDX (L) of the native Fe3O4@PDA catalyst Table 5. EDX data for Native and Recycled Fe3O4@PDA catalysts: Elements (Native Catalyst)

Fe

C

N

O

Total

Weight%

48.48

28.82

0.69

22.02

100.00

Atomic%

18.5

51.13

1.05

29.32

-

Elements (Recycled Catalyst)

Fe

C

N

O

Total

Weight%

24.62

44.20

7.45

23.74

100.00

Atomic%

7.18

59.97

8.66

24.18

-


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2) FTIR Spectroscopy: To study the surface composition of the catalyst, FTIR analysis was performed. Figure 9 shows the FTIR spectra of native and recycled Fe3O4@PDA catalysts. The peaks observed at 3395 and 3425 cm−1 in the native and recycled catalysts respectively are assigned to ν (O−H) stretching groups of PDA. The peaks observed at 2970 cm−1 (native catalyst) and 2921 cm−1 (recycled catalyst) are assigned to ν (C–C) stretching. The peak appearing at 1620 cm−1 in the recycled catalyst is related to the surface adsorbed water. The peaks observed at 1512 cm−1 and 1494 cm−1 are assigned to ν (C=N) stretching modes in the native and recycled catalysts respectively. The peaks at 1230 cm−1 (native catalyst) and 1243 cm−1 (recycled catalyst) are ascribed to ν (C–O) stretching modes. Strong peaks at 566 cm−1 and 574 cm−1 correspond to the Fe−O vibration. The IR values of native and recycled Fe3O4@PDA catalysts are consistent with the literature60 and also prove that the functionalities/chemical structure of the catalyst remains intact after recycling.

694.76 1230.65

425.05

1364.50

566.20

1512.20

1549.44

1568.13

1744.54

2970.63

3395.28

3742.85 3643.35 3668.60 3611.43

3864.67

95

Transmittance [%] 98 96 97

99

100

FTIRofspectra of for native Content this meant yourcatalyst: information and should not be used for advertisement, evidence or litigation

94

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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SAIF IIT Bombay

1000

500

07/02/2019


Content of this meant for your information and should not be used for advertisement, evidence or litigation

696.86

747.64

452.14

842.63

922.41 1075.45 1044.22 1026.30

1154.98 1243.18

574.25

1452.43

1494.10

1620.22

1352.39

2921.90 2851.79

3056.87

3425.06

Transmittance [%] 90 95

3104.31 3026.79

100

FTIR spectra of recycled catalyst:

85

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Figure 9. FTIR spectra of native and recycled Fe3O4@PDA catalyst C:\PROGRAM FILES\OPUS_65\2018-2019\EXTERNAL\FTIR-177\SP-FPDA-REC.0

3)TEM Analysis:

SP-FPDA-REC

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TEM images corresponding to Fe3O4@PDA native and recycled catalysts are shown in Figure 10. For the native catalyst, it can be clearly seen that Fe3O4 particles are well enveloped by a continuous layer of PDA polymer (Figure 10, M and N). Whereas, the recycled catalyst after second cycle clearly displays signs of slight dislodging of PDA from the surface of Fe3O4 nanoparticles and crumpling (Figure 10, O and P).

M


N

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Figure 10. TEM images: Native (M, N) and Recycled (O, P) Fe3O4@PDA catalyst 4) Zeta Potential Analysis: The native and recycled Fe3O4@PDA catalysts were analysed by zeta potential measurements to determine the charge on the particles (Figure 11). The zeta potential for native catalyst was observed to be -9.74 mV, which clearly shows that PDA coating imparted a negative charge onto the nanoparticles. Furthermore, an increase in the negative charge of -22.9 mV was observed for the recycled catalyst. This increase of negative charge on particles might be due to the deprotonation of quinone moieties of PDA by residual ammonia which is a by product of the reaction. Zeta potential of native catalyst:



Zeta potential of recycled catalyst:

Figure 11. Zeta potential of native and recycled Fe3O4@PDA catalyst 5) TGA Analysis: The TGA was performed under N2 flow with temperature ramping from 30 to 800 0C at a rate of 20.0 0C/min. Figure 12 shows TGA data for native and recycled Fe3O4@PDA catalysts. In both cases initial dip in the curves observed around 100 0C is indicative of the amount of water loss. The native catalyst showed around 4% water loss whereas the recycled catalyst showed around 2% water loss. Native catalyst has more water content as compared to the recycled catalyst. The weight % loss in the case of native catalyst was uniform after 100 0C, whereas the weight loss in the case of recycled catalyst was non-uniform, it showed a steep decrease of weight loss after 500 0C.


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TGA of native catalyst:

TGA of recycled catalyst:

Figure 12. TGA of native and recycled Fe3O4@PDA catalyst



CONCLUSION: In conclusion we have demonstrated polydopamine as a biomimetic catalyst mimicking the activity of amine oxidase enzymes under aqueous conditions wherein the synthesis of benzimidazoles, quinoxalines, quinazolinones and oxidation of secondary amines was achieved. Mechanistic studies suggested the tandem reactions to be proceeding through an oxygen mediated cyclization pathway. The catalytic activity of polydopamine is presumed to stem from the catechol-quinone moieties via oxidative transamination of the benzylic or phenylethyl amine further leading to the in situ formation of imine followed by a nucleophilic attack of the diamine to form the corresponding heterocyclic products. The catalsyt showed good selectivity and efficiency for the formation of products impeding possible side product formation and could be recycled up to three cycles with no loss of catalytic activity. We hope such protocols may pave way for the further development of several promising sustainable methods in near future. Associated content Supporting Information Experimental procedures, 1H NMR & 13C NMR Author Information Corresponding Author Tel.: +91 22 33612614 E-mail: [email protected] ORCID A. Vijay Kumar: 0000-0001-9753-0590 Notes The authors declare no competing financial interest. ACKNOWLEDGEMENTS SAP is grateful to Department of Science and Technology, DST-SERB (YSS/2015/002064), Government of India for the Research Fellowship. AVK is thankful to Department of Science and


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Technology for the research grant, DST-SERB (YSS/2015/002064), Government of India. We acknowledge the Department of Pharmaceutical Sciences and Technology, ICT for carrying out the NMR analysis and Department of Chemistry, ICT for TGA analysis. We also acknowledge Department of Chemical Engineering, ICT for carrying out zeta potential analysis. We are grateful to SAIF, IIT-B for SEM, TEM, FTIR and ICP-AES analysis. Also, Department of Metallurgy, IIT-B for XRD analysis and Department of Physics, IIT-B for XPS analysis.

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R.N.;

Kumar,

A.

V.

Unprecedented

concomitant

formation

of

Cu2O–CD

nanosuperstructures during the aerobic oxidation of alcohols and their catalytic use in the propargylamination reaction: a simultaneous catalysis and metal waste valorization (scmwv) method. ACS Omega 2017, 2, 6405–6414. 57) Dubey, A. V.; Gharat, S.; Kumar, A. V. Glycerol as a recyclable solvent for copper-mediated ligand-free C-S cross-coupling reaction: application to synthesis of gemmacin precursor. Chemistry Select 2017, 2, 4852–4856. 58) Zangmeister, R. A.; Morris, T. A.; Tarlov, M. J. Characterization of polydopamine thin films deposited at short times by autoxidation of dopamine. Langmuir 2013, 29, 8619−8628. 59) Luo, H.; Gu, C.; Zheng, W.; Dai, F.; Wang, X.; Zheng, Z. Facile synthesis of novel size-controlled antibacterial hybrid spheres using silver nanoparticles loaded with poly-dopamine spheres. RSC Adv. 2015, 5, 13470−13477.


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60) Veisi, H.; Sarachegol, P.; Hemmati, S. Palladium (II) anchored on polydopamine coatedmagnetic nanoparticles (Fe3O4@PDA@Pd(II)): A heterogeneous and core–shell nanocatalyst in Buchwald–Hartwig C–N cross coupling reactions. Polyhedron 2018, 156, 64–71.

TOC:

Ph

Ph

NH2 + (or) NH2

NH2

NH2

+

H N

HO

R (or)

10 examples 85-71%

O

OH

NH

OH

N

N

3 examples, 72-61%

Ph

R

HO N H

N N

15 examples 92-52%

HN NH2

Ph Ph (or)

N

NH2

N H

H N

OH

NH2 O

Ph

HO

Polydopamine

N

(or)

4 examples, 84-71%

N H

Sustainable Protocol Biomimetic Catalyst  Green Solvent  Recyclable Catalyst  Additive free  Benign oxidant

Polydopamine as a recyclable sustainable catalyst mimicking the function of amine oxidase enzymes for the synthesis of benzimidazoles, quinoxalines, quinazolinone heterocycles and the oxidation of secondary amines is developed under aqueous conditions.


Polydopamine: An Amine Oxidase Mimicking Sustainable Catalyst for

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