Open Access Baghdad Science Journal Vol. 13(2s(Supplement))2016 The 2nd National Conference of Chemistry DOI: http://dx.doi.org/10.21123/bsj.2016.13.3.2NCC.0253 Synthesis and Characterization of Some New Morpholine Derivatives Entesar O. AlTamiemi* Sameaa J. Khammas** Sura S. AlKaissi*** *Department of Chemistry, College of Science, University of Baghdad ** Department of Chemistry, College of Science for Women, University of Baghdad *** Department of Pharmaceutical Chemistry, University of AL-Mustansiryah, College of Pharmacy . E-mail: [email protected] Received 20/9/2015 Accepted 20/12/2015 This work is licensed under a Creative Commons Attribution-NonCommercial- NoDerivatives 4.0 International Licens Abstract: In this paper a new series of morpholine derivatives was prepared by reacting the morpholine with ethyl chloro acetate in the presence triethylamine as a catalyst in benzene gave morpholin-N-ethyl acetate(1) which reacted with hydrazine hydrate in ethanol, and gave morpholin-N-ethyl acetohydrazide (2) . Morpholin-N-aceto semithiocarbazide (3) were prepared by reacting compound(2) with ammonium thiocyanate , concentrated hydrochloric acid and ethanol as a solvent .Compound (3) reacted with sodium hydroxide and hydrochloric acid to give 5-(morpholin-N- methylene)-1H-1,2,4-triazole-3-thiol (4) .The new series of 1,2,4-triazol derivatives (5-8) was synthesized by reaction of compound(4) with formaldehyde , DMF as a solvent and different secondary amines. Preparation of new 1,2,4-triazoline derivatives (9) by reaction compound (4) with bromo acetic acid . Reaction of compound (9) with different aromatic aldehyde and dimethyl sulfoxide as a solvent obtained compounds (10-13). Key words: Morpholine , 1,2,4-triazole and Mannich Reaction. Introduction: Morpholine is a six-membered heterocyclic compound [1]. It has synonyms Tetrahydro-1,4- oxazine; 1- Oxa-4-azacyclohexane; Diethylene oximide [2] and an organic chemical compound having the chemical formula Morpholine derivative plays an important role in the treatment of O( CH2CH2)2 NH , this heterocyclic structure features both amine and ether several diseases [3]. Morpholine functional groups.As shown in the derivatives find their wide spectrum of following Figure (1): antimicrobial activity and insecticidal activity [4]. Morpholine used an emulsifier for cosmetics, rubless waxes, 352 Baghdad Science Journal Vol. 13(2s(Supplement))2016 The 2nd National Conference of Chemistry and polishes, dyes , Pharmaceuticals and triethyl amine(10 ml, 0.1mol) with catalysts[5,6]. 1,2,4-Triazole has wide benzene as a solvent in (100ml) round range of pharmacological properties[7] bottom flask was refluxed for 6 h. at and variety of biological activities such (1150c).The resultant reaction mixture as anti-inflammatory [8], Analgesic[9] , was cooled at room temperature and the antibacterial[10], antifungal, antitumoral solid was filtered dried and [11,12]. Mannich reaction is an organic recrystallized from ethanol. The compounds with the general formula - physical properties of compound [1]are CH2-NR2 they were discovered in 1912 listed in Table (1). by Mannich and Krosch[13,14]. The Synthesis of Morpholin-N- Mannich reaction which consists of an acetohydrazide (2) [19]: amino alkylation of an acidic proton A mixture of compound (1) placed next to a carbonyl functional (10ml.0.05mol), hydrazine hydrate 80% group with formaldehyde and ammonia (3ml, 0.05mol) and ethanol(20ml) were or either primary or secondary amine put in round bottom flask and refluxed [15]. Mannich base compounds have for 6 h. The mixture was concentrated, been studied intersively mainly because cooled and the white crystal was filtered of their application of organic synthesis and recrystallized from ethanol. The especially for preparing dyes ,industrial, physical properties of compound (2) are pharmaceutical ,and antimicrobial listed in Table (1). [16,17]. Synthesis of Morpholin-N-aceto [20] semithio carbazide(3) : Materials and Methods: In (150ml) round bottom flask Chemicals used in this work are dissolved compound (2) and ammonium supplied from Merck, BDH ,sigma thiocyanate (5 gm,0.06mol) in 10ml Aldrich ND Fluka companies and are DMF then added 8ml HCL in absolute used without further purification. ethanol(50ml) . The mixture was Melting points were recorded by using refluxed for 20h . The solvent was digital Stuart scientific SMP3 melting evaporated and the residue poured on point apparatus and are uncorrected. FT- crushed ice with stirring. The precipitate IR spectra were recorded on SHIMAZU was filtered,dried and recrystallized FT-IR-8400 Fourier transform Infrared from ethanol .The physical properties of spectrophotometer using KBr discs in compound (3) are listed in Table (1). -1 Synthesis of 5-(morpholin-N-methyl)- the (4000-6000) cm spectral range [21] internal reference measurements which 1H-1,2,4-Triazole-3-Thiol (4) : were made at College of Pharmacy- Al- To a solution of compound (3)(2 Mustansiriya University . 1H-NMR and gm,0.01mol) in (5ml) DMF and (15ml) 13C-NMR spectra were recorded on of 10%NaOH were refluxed for 3h.The Burker 500M Hzistrument using mixture was treated with charcoal and then removed by hot filtration. The DMSO-d6 as solvent and TMS as internal reference measurements were solution was acidified by 10%HCl with made at the Chemistry Department, Al- cooling. The precipitate was filtered, Albyt University, Jordan . dried and recrystallized from ethanol .The physical properties of compound [4] are listed in Table (1). Experimental : General Methods for the Synthesis of Synthesis of Morpholin-N-ethyl [22] [18] 1,2,4-Triazoles(5-13) : acetate (1) : A):-Preparation of Morpholine A mixture of morpholine (9 ml ,0.1mol) Substituted 1,2,4-Triazoles (5-8): , ethylchloro acetate(12ml ,0.1mol) and 352 Baghdad Science Journal Vol. 13(2s(Supplement))2016 The 2nd National Conference of Chemistry In round bottom, flask was placed (0.3 gm, 0.002 mol ) in 10 ml of DMSO solution of compound (4) in 10ml of then added triethyl amine (1ml) .The DMF With (0.002mol) of different product was compound[9]. Then amines{N- di-phenylamine, N- mixture was refluxed for 0:30 h. and ethylaniline, N-diethylamine, N-di-n- added(0.002mol) different aromatic butylamine} and formaldehyde aldehyde{benzaldehyde, 2,4- (0.02mol) . The mixture was refluxed diethylamine benzeldehyde, m- for 3h. The solvent was evaporated and nitrobenzaldehyde, P- the residue poured on crushed ice with hydroxybenzaldehyde} in presence stirring. The precipitate was 10%NaOH then refluxed for 1h .The filtered,dried and recrystallized from solvent was evaporated and the residue DMSO . The physical properties of was poured on crushed ice with stirring compounds (5-8) are listed in Table (1). The precipitate was filtered,dried and B):-Preparation of Morpholine recrystallized from DMSO . Physical Substituted 1,2,4-Triazoline(9-13): properties of compounds (9-13) are In the round bottom, flask was listed in Table (1). dissolved(0.5gm,0.002 mol) of compound (19) an bromo acetic acid Table (1): The Physical Properties of Prepared Compounds [1-13] Compd. Yield M. P. Nomenclature Structure formula Color No. % oC Deep 1 morpholin-N-ethyl acetate 70 232-233 Brown 2 morpholin-N-acetohydrazide 78 White 105-106 morpholin-N-aceto semithio Light 3 88 216-217 cabazide Yellow 5-(morpholin methyl)-1H- 4 76 Brown 221-222 1,2,4-triazole-3-thiol 5-(morpholin methyl)-3- 5 thio(methyl-N-diphenyl 62 Whit 129-130 amine)-1H-1,2,4-triazol 5-(morpholin methyl)-3- thio(methyl-N-ethyl Light 6 55 127-128 phenylamine)-1H-1,2,4- Brown triazol-3- 355 Baghdad Science Journal Vol. 13(2s(Supplement))2016 nd The 2 National Conference of Chemistry 5-(morpholin methyl)-3- 7 thio(methyl-N-diethylamine)- 78 Yellow 130-131 1H-1,2,4-triazol 5-( morpholin methyl)-3- Light 8 thio(methyl-N-dibutylamine)- 66 132-133 Yellow 1H-1,2,4-triazolyl 5-( morpholin methyl)-[2,3-b]- 10 4-oxo-5-benzylidene 85 Whit 266-267 thiazolidine-1H-[1,2,4]triazol 5-( morpholin methyl)-[2,3-b]- 4-oxo-5-(4-dimethylamino 11 56 Yellow 200-201 benzylidene) thiazolidine-1H- [1,2,4]triazol 5-( morpholin methyl)-[2,3-b]- 4-oxo-5-(4- 12 76 Brown 273-274 hydroxybenzylidene) thiazolidine-1H-[1,2,4]triazol 5-( morpholin methyl)-[2,3-b]- Light 13 4-oxo-5-(3-nitrobenzylidene) 77 223-224 Brown thiazolidine-1H-[1,2,4]triazol Results and Discussion: Preparation of Morpholin-N- ethylacetate (1) : The synthesis is sequences for The mechanism for these reaction preparation of series new morpholine involves nucleophilic attack of amino derivatives by refluxing morpholine group in morpholine on reaction with with ethyl chloro acetate in the presence carbon in ethyl chloro acetate give the of triethylamine and benzene as a final product (1) [23], as shown in the solvent , as shown in the following following scheme: equation : The FT-IR spectra as shown in Table (2) Hydrazide derivatives attracted a and Fig. (2) besidethe (1H-NMR and lot of attention because they are 13C-NMR) analysis of these compound considered as intermediates to (1) are listed in Table (3 and 4) . synthesize several compounds and play Synthesis of Morpholin-N- a very important role owing to their acetohydrazide(2): potentially high antifungal, antibacterial, 352 Baghdad Science Journal Vol. 13(2s(Supplement))2016 The 2nd National Conference of Chemistry antiviral and antimalarial activity [24]. This reaction represents nucleophilic Hydrazide derivatives were prepared via substitution reaction and its mechanism treatment of prepared ester (1) with involved nucleophilic attack of amino hydrazine hydrate in absolute ethanol, as group in hydrazine on carbonyl group in shown in the following equation: ester followed by elimination of ethanol molecule [25], as shown in the following Scheme: The structure of the synthesized absolute ethanol as shown in the compound has been characterized and following equation: confirmed by FT-IR analysis as shown in Table (2).