key: cord-0753663-2pk55fuh authors: Chandrappa, M.; Swathi, Korrapati; Girish Kumar, S.; Pullela, Phani Kumar title: Nanomaterial assisted bulk scale synthesis of 2-methyl-6-nitroquinoline date: 2020-08-09 journal: Mater Today Proc DOI: 10.1016/j.matpr.2020.07.103 sha: 6ce15a4558189ff0c7e18564848a8f16b41b38d9 doc_id: 753663 cord_uid: 2pk55fuh Quinolines are an interesting class of moieties with various medicinal chemistry uses. The most prominent is their ability to be used as the last line of therapy for bacterial and viral infections including recent COVID-19. The synthesis of quinoline is through a cyclization reaction and overall reaction yields are about 20%. The bulky ring and the associated crowding of functional groups limit the catalyst options. In this publication, the use of Fe(3)O(4)@SiO(2) for enhancing yield improvements, especially for heterocyclics is reported. The use of the 40 nm sized silica functionalized magnetite nanoparticles seems to help in both condensation and cyclization steps of representative 2-methyl-6-nitroquinoline. Reaction time reduction due to surface enabled catalysis of nanoparticles is 110 min to 80 min. The reaction yield has doubled due to the presence of catalyst and the mechanism suggests this drastic result is due to stabilization of unstable intermediate on the acidic surface of the silica coating. This near homogeneous catalysis of 40 nm sized, silica functionalized, magnetite nanoparticles have far reaching applications in bulk drug industry for drugs like chloroquine & hydroxychloroquine, the two essential drugs for prophylactic use for COVID-1. Quinolines, as a functional group, is associated with antimalarials [1] . There are very few chemical functional groups which have vector level toxicity, and quinolines are one of them. Quinolines are also used for other purposes like pesticides [2] , insecticides [3] , anticancer, antibacterial, antivial, retroviral, antimicrobial [4] , antihistamines (antiallergic) [5] , tuberculosis effective drugs [6] etc. Quinolines and quinazolines are considered as the last line of protection for tuberculosis, the bacteria which is resistant for most antibiotics. [7] . Malaria-resistant to quinolines in the 1960s has resisted the scientific community to use quinolines as antibiotics. However, most strains of multidrug resistant (MDR) and extensively drug resistant (XDR) of mycobacterium still respond to quinolines and they are used as injectables to save lives [8] . The observation of medicinal chemistry leads has suggested that the quinoline toxicity for vectors extends to cancer cells, parasites, microbes, bacteria, virus and this broad spectrum activity has led to almost 40 clinical leads based on quinolines at different stages of development [9] . The topical creams and cosmetics applications are evolving with special attention to the minimisation of microbial growth in pimples. The other applications like antipsychotic drugs [10] , blood thinning agents [11] , anti-inflammatory agents [12] , lung and liver infection prevention, antidepressants, antihypertension etc. are under development and the process chemistry that involve yield improvements in quinoline synthesis are a necessity. The structures of antimalarials are shown in Scheme 1. Quinolines lead by chloroquine is a choice for antimalarials [13] . The molecule surprisingly has toxicity for almost all plasmodium strains and even after chloroquine-resistant versions evolved, the newer generation drugs are still based on quinoline ring [14] . Quinolines are usually synthesised by Friedlander reaction. This reaction has been used for over a century, but it is still the most https://doi.org/10.1016/j.matpr.2020.07.103 2214-7853/Ó 2020 Elsevier Ltd. All rights reserved. Selection and peer-review under responsibility of the scientific committee of the International Conference on Newer Trends and Innovation in Mechanical Engineering: Materials Science. preferred route [15] . A ketone or aldehyde upon condensation with an acyl amine gives quinoline and reaction is catalysed by either acid or base [16] . As with most reactions with acid or base catalysed, a reaction equilibrium is attained with about 30% product yield and it can be increased to 50-60% by changing parameters like temperature or reactant concentration. This reaction generated broad interest for the improvement of yield and microwave irradiated reactions give almost 70-90% yield [17] . Considering the non-adaptability of microwave assisted reactions for process chemistry, other approaches were considered. Lewis acid catalysed Friedlander reaction is quite famous with BF 3 -Etherate as the catalyst [16] . The neutral alumina, silica gel, and montmorillonite clay type neutral catalysts were also attempted, but their role was to minimise side reactions than to improve reaction yield [18] . Quinoline synthesis in water at elevated temperature or prolonged reaction time and other variations gave consistent yields but was not found to be significant. Quinoline cyclisation was mostly accomplished by non-specific acid, base catalysts, Lewis acids, heterogeneous catalysts like silica, alumina, clay [18] etc. Except for a few scattered reports for nanomaterial catalysis, the near homogeneous catalysis by magnetic nanomaterials is unfound. The condensation and cyclisation reactions are minimally accomplished by homogeneous catalysis and reported metal catalysts are very few. Solid-state acidic catalysts, zeolites etc. also catalyse the quinoline synthesis, but their practical use in process chemistry is minimal. Yet, process chemistry uses simple bases and acids, like sodium hydroxide and hydrochloric acid for the synthesis of chloroquine indicating that the synthetic methods involving catalysts are of negligible use for quinoline synthesis in process chemistry. a) The yields for quinoline cyclisation are in halt at around 40-60% and attempts to improve the same is unsuccessful. b) Improvements by the use of microwave chemistry are impractical even though the latest methods and equipment are available in chemistry labs for the same. c) Quinolines are going to be drugs of the future with more ''mosquito-borne diseases" being discovered, and we need process chemistry solutions which can cut the production costs. d) Nanomaterial catalysis is a potential possibility, and we need innovations in this direction to reduce production chemistry costs and improve the purity of the reaction product. In a dry 1.5L four necked RB flask, 9.5 g (0.1 mol) of NaNO 3 and 5 g of (0.0125 mol) of NaOH are added and dissolved in 600 mL of water (solution X). The solution X is heated to 90°C for 45 min with occasional swirling. The argon is bubbled through the solution X for enabling continuous mixing and the mixture is brought to room temperature. In another container 6.95 g (0.25 mol) of FeSO 4 dissolved about 60 mL of distilled water having 10 mM H 2 SO4 (Solution Y). Solution Y is add solution X at the rate of 20 mL/min. the particles are formed as the solution are mixed and Argon gas at 1L/hr is continued for about 4 h at 90°C. The heated liquid is cooled to room temperature and transferred to a beaker. The formed magnetic nanoparticles are washed multiple times and stored for further use in distilled water. An ethanolic solution comprising of 25% water is taken in a 1L container and pH is changed to 12 using 10 N Sodium hydroxide solution. Fe 3 O 4 nanoparticles are added to the above basic ethanolic solution and sonicated for about an hour. About 12.5 mL of TEOS (0.033 mol) is added above sonicated solution slowly at 1 mL/min and stirred for an hour. The Fe 3 O 4 particles coated with silica layer are separated using external barium ferrite magnet, washing with distilled water for further use. The removal of ionic impurities is performed by heating to 90°C at 30 using 0.3 M trisodium citrate and then ageing with 0.5 M tris. The former solution is at pH 6 and later solution is at pH of 8 and ideally remove both iron impurities and unreacted components. The overall synthesis of silica functionalized magnetic nanoparticles is given in Fig. 1 . The overall yield of SMNP in this method vary from batch to batch, overall yield is 4 to 5 g. The IR spectra is used for understanding batch to batch consistency and the SEM images to judge the morphology and size. Fig. 2 shows the SEM image 40 nm silica functionalized nanoparticles. Fig. 3 shows the IR Spectra, clearing detailing batch to batch consistency. The peaks indicative of silica functionalization. The 1000-1200 cm À1 peak implies consistency in silica coating and is characteristic for the Si-O bond. The 40 nm sized particles in SEM are typical in undergoing partial aggregation and has consistency in size and performance. 3. Synthesis of 2-methyl-6-nitroquinoline 4-nitroquinoline and crotanaldehyde are procured from Sigma Aldrich and solvents were obtained from Merck Pvt Ltd. The chemicals are used without any further purification. The magnetic nanoparticles with silica coating are used after drying for overnight at 120°C overnight. 3.2. Synthesis of 2-methyl-6-nitroquinoline 1.5 g of 4-nitroaniline (11 mmol) was dissolved concentrated HCl under reflux at 105°C. A 0.95 g of crotonaldehyde (14 mmol) is added drop wise at 100 mL/2hr rate and the reaction mixture is heated for an hour. Then the reaction mixture is cooled to25°C (or room temperature) and neutralized with 11 N NaOH solution and the acquired product is obtained as whitish yellow precipitate and the same is recrystallized from methanol to remove the reactants. The light yellow color solid has melting point 164°C and yield is 47%. 1.5 g of 4-nitroaniline (11 mmol) was dissolved concentrated HCl under reflux at 105°C in presence of Fe 3 O 4 @SiO 2 particles. A 0.95 g of crotonaldehyde (14 mmol) is added drop wise at 100 mL/2hr rate and the contents of the reaction is refluxed for 1 h. Then the reaction is cooled to room temperature and Fe 3 O 4 @-SiO 2 particles are isolate prior to sodium hydroxide neutralization using external magnet. Later the reaction mixture is neutralized with 11 N NaOH solution and the acquired product is obtained as whitish yellow precipitate and the same is recrystallized from methanol to remove the reactants. The light yellow color solid has melting point 164°C and yield is 81%. The synthesis reaction is shown in Scheme 2. Yield: 81% (16.7 g), m.p.: 165°C. The reaction of 2-methyl-6-nitroquinoline synthesis was shown in Scheme 2. Quinolone synthesis has received minimal chemical interest in catalysis area, and the catalysis is mostly non-specific, non-metal neutral heterogeneous catalyst. The yield improvements are minimal, and low yields characterize the condensation reactions followed by cyclisation. The transition metal and rare earth metal catalyst are spares, and even they have a minimal role when deactivating substitution like nitro group one present. 2-methyl-6nitroquinoline was synthesized by the catalytic method, it was explained the synthesis in Scheme 3. Functionalized nanomaterials are increasingly playing a pivotal role in modern-day organic synthesis. The mechanism and the way these nano sized particles increased yields are as also well documented. Unlike transition metal or rare earth metal catalysis, the nanomaterials bound to reaction intermediates is only hypothesized and cannot be characterized by any of the existing spectroscopic methods. This often is the reason for an indirect proof generation as evidence. In quinoline case, we characterized with and without reaction catalyst using a graph with x-axis as the time of reaction and y-axis as reaction yield. The procedure was to set up reactions with and without a catalyst under same conditions (like flask volume, stirrer speed, the volume of solvent, bath emperature etc.) and observe the product yield as a function of reaction time. The reaction yield v/s duration of time and the two personal observations emerge from this graph. Reach of saturation (maximum) yield in shorter duration and significant improvement in reaction yield due to the presence of a catalyst. Though reduction of reaction time is a parameter to explore in the production environment, the yield improvement is of the primary significance of low yield in quinoline synthesis. In substrates with lower temperature degradation, these nanomaterials catalysis offers significant hope and will be explored in our future. The non-catalysed reaction has resulted in a 47% overall reaction yield. The reaction yields differ significantly from batch to batch, and often it was puzzling even though reaction condition is almost the same. The possible reason hypothesized in literature is the hindrance of water from condensation acting as an inhibitor for cyclisation. Interestingly none of the quinolone synthesis reactions is reported in anhydrous solvents, and the yield improvement has more molecular level mechanics then the by-product related inhibition. When we used Fe 3 O 4 @SiO 2 , the yield is improved almost 50% from the original yield. The bulk batch to batch consistency in yields is addressed and possible mechanism was shown in Scheme 3. The Fe 3 O 4 @SiO 2 is present in the reaction throughout till the product isolation and hence is part of catalysis of both condensation and cyclisation. Our previous publications in this domain have proved that Fe 3 O 4 @SiO 2 can aid in both condensation and cyclisation [19, 20] . The proof for the reduction of reaction time and yield improvement with nanocatalyst is shown in Fig. 4 . The optimization of silica functionalized magnetic nanoparticles (catalyst) concentration for the quinoline synthesis was done in our lab. The catalyst optimization of Fe 3 O 4 @SiO 2 nanoparticles was done for the quinoline derivative. The overall reaction yield was calculated for every batch, on yield basis the catalyst ratio for the reaction was optimized. In this case 6% (w/w) of the catalyst is given greater yields, 6% (w/w) catalyst is optimal ratio for the reaction. The ratio of Fe 3 O 4 @SiO 2 catalyst taken concerning reagents. After optimization of catalyst ratio, we have developed a process for the bulk scale synthesis of quinoline derivative using the 6% catalyst (w/w) and the catalyst ratio and the improvement in yield was given in Table 1 . The mechanism of the Doebner-Miller synthesis of quinolines has been the topic of many researchers, leading to the currently accepted mechanism which involves an aldol condensation producing an a,b-unsaturated aldehyde followed by Michael addition of the aromatic amine. The reaction was carried out with crotanaldehyde, 4-nitroaniline in the presence of silica functionalized nanocatalyst. The Fe 3 O 4 @SiO 2 is initiated of a, b-unsaturated Scheme 2. Synthesis scheme of quinoline derivative: The conjugative addition, cyclization, and aromatization reactions happened in situ of the reaction. aldehyde for the reaction and stabilizes the intermediate. The Fe 3 -O 4 @SiO 2 catalyst is providing its surface area for cyclisation through Michael addition. The possible mechanism for the complete synthesis for the 2-methyl-4-nitroquinoline in above Scheme 3. Nanomaterial assisted bulk synthesis of 2-methyl-6nitroquinoline has for reaching applications in bulk drug synthesis. The yield improvement and possibility of reduction in reaction time are possible take a ways from the study. The 40 nm sized nanomaterials are increasingly receiving interest and this study Scheme 3. Mechanism for synthesis of 2-methyl-6-nitroquinoline: The reaction mechanism with silica functionalized magnetic nanocatalyst for the synthesis of 2-methyl-6nitroquinoline. Fig. 4 . Reduction of reaction time via the Fe 3 O 4 @SiO 2 catalyst: The graph shows the relation between the reaction yields versus reaction time. This the proof that of Fe 3 O 4 @SiO 2 catalyst will reduce the reaction and essential improvement in product yield (Green peak). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.) Table 1 Optimization of catalyst (Fe 3 O 4 @SiO 2 ) ratio for the synthesis of 2-methyl-6nitroquinoline on a small scale. paves way for usage of functionalized nanomaterials at the 40 nm size. The reaching of saturation yield in shorter time can be explored further for drugs like stavudine, which often suffer from the decomposition of the product formed during reaction. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Drug discovery studies on quinoline-based derivatives as potential antimalarial agents Synthesis of novel quinolinebased 4,5-dihydro-1 H -pyrazoles as potential anticancer, antifungal, antibacterial and antiprotozoal agents Anti-breast cancer activity of some novel quinoline derivatives Discovery of a new antileishmanial hit in 8-nitroquinoline series Natural and synthetic quinoline derivatives as antituberculosis Agents Recent developments on antimicrobial quinoline chemistry Quinoline and quinolones: Promising scaffolds for future antimycobacterial agents Synthesis and in vivo fungicidal activity of some new quinoline derivatives against rice blast Quinoline-and isoquinoline-sulfonamide analogs of aripiprazole: novel antipsychotic agents? Quinoline drug-heme interactions and implications for antimalarial cytostatic versus cytocidal activities Medicinal chemistry of quinolines as emerging antiinflammatory agents: an overview Quinolines and structurally related heterocycles as antimalarials Quinoline: a diverse therapeutic agent Microwaveassisted Friedländer synthesis of quinolines derivatives as potential antiparasitic agents Metal-free domino one-pot protocols for quinoline synthesis Microwave-assisted a-halogenation of 2-methylquinolines with tetrabutylammonium iodide and 1,2-dichloroethane (1,2-dibromoethane) Organic synthesis using clay and clay-supported catalysts Critical Modification to Bulk Scale Synthesis of 2-Amino-5-carboethoxy-4-hydroxypyrimidine Fe3O4@SiO2 magnetic nanoparticles for bulk scale synthesis of 4 0 -chloro-2,2 0 :6 0 This project is funded by Department of Science and Technology, DST Nanomission project, SR/NM/NT-1034/2015(G).