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,

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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 semithio carbazide(3)[20]: 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

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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-

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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,

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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).

Synthesis of Morpholin-N-aceto thiosemicarbazide(3) : Mechanism of reaction involves The compound (2) was converted to nucleophilic attack of amino group of thiosemicarbazide derivative compound compound (2) on deficient carbon of (3) by the reaction with ammonium ammonium thiocyanate followed by , thiocyanate and hydrochloric acid in rearrangement of molecule [26] as shown in the following Scheme:

The FTIR spectra data showed in Table (2).

Synthesis of 5-(morpholin methlyl- 1H-1,2,4-Triazole-3-Thiol (4): Mechanism of reaction involving The compound (3) was converted to nucleophilic attack lead to compound (4) by reaction with1% intramolecular cyclization [27,28] ,as NaOH in absolute ethanol and acidified shown in the following Scheme : by 10%HCl, as shown in the following equatio

The FT-IR spectral data showed in Table (2).

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Preparation of 5- [(Morpholin compound (4), secondary amine and methyl)]-3-thio(methyl-N- formaldehyde, as shown in the Substituted)-1H1,2,4-Triazole (5-8): following equation: A series of new Mannich derivatives was synthesized by the reaction between

The mechanism of the reaction compound (4) gives the Mannich base depends on the nucleophilis addition of [29,30], the suggested mechanism is amine to the carbon of formaldehyde shown in the following scheme: followed by condensation with

The FT-IR spectra as shown in to give compound (9), as shown in the Table (2) and Fig. (3) besidethe (1H- following equation: NMR and 13C-NMR) analysis of these compounds (5-8) are listed in table (3 and 4) and Fig. [4,5].

Synthesis of 5-(Morpholin emethyl)- [2,3-b]-4-oxo-5-thiazolidenone-1H- 1,2,4-Triazoline (9): The mechanism of the reaction depends Treatment of compound (4) with on the nucleophilic addition, as shown bromo acetic acid in presence triethyl in the following mechanism [31]: amine affords intramolecular cyclization

Synthesis of5-(Morpholine methyl)- substituted aromatic aldehyde in [2,3-b]-4-oxo-5-thiazolidine-1H-1,2,4- presence 10% NaOH resulted the Triazoline (10-13): formation of aldol condensation of title Synthesis compounds (10-13) by compounds (10-13), as shown in the reaction of compound (9) with different following equation:

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The first step in condensation producing intermediate alkoxide ion . reaction,the hydroxyl ion abstract the This alkoxide ion protonated to form proton from carbon adjacent the aldol product and the last step form the carbonyl to forms an enolate ion .The α, β-unsaturated products (10-13) [32], next step involved nucleophilic addition as shown in the following mechanism: of enolate ion to another carbonyl group

The FT-IR spectra as shown in Table (2) compounds (5-8) are listed in Table (3 and Fig.(6) beside the (1H-NMR and and 4). and Figure [7,8]. 13C-NMR) analysis of these

Table (2): FTIR spectral data cm-1 of the prepared compounds (1-13) υ(C-H) υ(C-H) υ(C=O) υ(C=C) υ(N-H) υ(C-O-C) υ(N-N) Other Com. cm-1 cm-1 cm-1 cm-1 cm-1 cm-1 cm-1 Band No. Aromatic Aliphatic amide cm-1 υ(C-N)1307, 1 _ 2928 - _ - 1224 - υ(C=O)ester1743 2 _ 2992 1670 _ 3160 1220 1496 υ(NH2)3350,υ(C-N)1310 υ(NH2) 3350, υ(C-N) 1350, υ(C-O) 1269 , 3 - 2999 1650 - 3263 1124 1452 υ(C=S)1215 , υ(N-C- O)1068 υ(C=N) 1610 , υ(C- N)1348, υ(C-O) 1269 , 4 - 2997 1680 - 3269 1124 1464 υ(C-S)692 , υ(N-C- O)1045 ,υ(SH)2682 υ(C=N) 1645 , υ(C- 1595- 1456- 5 3030 2912 - 3150 1165 N)1369, υ(C-S)692 , υ(N- 1516 1419 C-O)1058 υ(C=N) 1653 υ(C- 6 3049 2972 - 1589 3132 1170 1448 N)1332, υ(C-S)752 , υ(N- C-O)1018 υ(C=N) 1653 υ(C- 7 - 2912 - - 3130 1172 1435 N)1371, υ(C-S)734 , υ(N- C-O)1051 υ(C=N) 1660 υ(C- 8 - 2997 - - 3155 1201 1437 N)1311, υ(C-S)698 , υ(N- C-O)1041 υ(C=N) 1651 ,υ(C- N)1317, υ(C-S)705 , 10 3003 2916 - 1527 3190 1199 - υ(N-C-O)1022 υ(C-NO2 1410 υ(C=N) 1693 ,υ(C- 11 3001 2910 - 1530 3150 1231 - N)1311, υ(C-S)700 , υ(N- C-O)1066 υ(C=N) 1662 , 12 3040 2914 - 1599 3160 1236 - υ(C-N)1336, υ(C-S)727 , υ(N-C-O)1066 υ(C=N) 1747 , υ(C- 13 3015 2935 - 1550 3228 1130 - N)1350, υ(C-S)781 , υ(N- C-O) 1031,υ(OH) 3477

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Table (3): 1H-NMR spectral Data (ᵟppm) of Compounds [1,6,7,10,13] Com. Compound Structure 1H-NMR Spectral data (δ ppm) NO

δ2.5(s,2H,CH -N), δ3(s,3H , CH ) , δ3.4(s, 2H, CH -C=Oester) and 1 2 3 2 δ3.7(s, 2H ,CH3CH2-O)

δ2.5(t,2H,CH2-N) ,δ2.5(q,2H,CH3CH2-N) ,δ3(t,3H,CH3), δ3.7(t,2H,CH2- 6 O) , δ4(S,1H,N-CH2-C) ,δ4.7(S,S-CH2-N) δ7.5(m,5H,CH aromatic) ,δ8.1(S,1H,NH).

δ2.2(t,2H,CH -N) ,δ2.5(q,2H,CH CH -N) , δ3.60(t,CH -O), δ3.7 7 2 3 2 2 (t,2H,CH3) , δ4(S,1H,S-CH2-N) ,δ7.5(S,1H,NH).

δ2.1(S,IH,NH), δ2.3(S,2H,C-CH2-N) ,δ2.5(t,2H,CH2-N), 10 δ3.6(t,2H,CH2-O) , δ4.1(S,1H,N2-CH-S) , δ4.2(S,1H,CH= ) ,δ7.5(S,1H,CH aromatic) .

δ2(S,IH,NH), δ2.5(S,2H,C-CH -N) ,δ2.54(t,2H,CH -N) , δ3.6(t,2H,CH - 13 2 2 2 O) , δ4.9(S,1H,N2-CH-S) , δ7.6(S,1H,CH= ) ,δ8.2(m,5H,CH aromatic) .

Table (3-7): 13C-NMR Spectral Data (δppm) of Compounds [1,6,7,10,13] Com. Compound Structure 1H-NMR Spectral data (δ ppm) NO

14.1(CH3); 61.1(CH3CH2-O);45(CH -N);63(CH -O); 1 2 2 163(CH2-C=O)

14(CH3) ; 39(CH3CH2-N) ; 53(N-CH2-C) ; 58(CH2-N) ; 64(S- 6 CH2-N) ; 68(CH2-O);114-129 (6Caromatic) ;161(CH=N)

10.8(CH ) ; 39(N-CH -CH ) ; 57(CH -N) ; 61(N-CH -S) 7 3 2 3 2 2 ; 65(CH2-O) ; 160(C=N)

45.5(CH2-N) ;59.43(N-CH2-C); 61.1(CH2-O) ; 90.19(S-CH- 10 NN\);124(CH=);128.52-129.17(6C aromatic) ; 164(N-C=O) ; 166(C=N)

55(CH -N) ; 66(CH -O) ; 88(S-CH-NN\) ; 123.1(CH=) ; 129- 13 2 2 144(CH aromatic) ; 166(CH-C-NN\)

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Fig. (2): FT-IR spectrum for compound (1)

Fig. (3): FT-IR spectrum for compound (6)

Fig. (4):1H-NMR spectrum for compound (6)

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Fig. (5):13C-NMR spectrum for compound (6)

Fig. (6): FT-IR spectrum for compound (10)

Fig. (7):1H-NMR spectrum for compound (10)

Fig. (8):13C-NMR spectrum for compound (10)

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[19] Mohan, S.; Ananthan, S. and [ 25] Kostecka, M .2012. Synthesis of a Murugan, K.R.2010 .Synthesis New Group of Aliphatic Hydrazide ,Characterization and Biological Derivatives and the Correlations activity of Some Novel Sulphur between Their Molecular Structure Bridged Pyrazoles.IJPSR.1(9):391- and Biological Activity. Molecules. 398. 17(3):3560-3573 . [20] Jalhan, S.; Jindal.A. and [26] Hasan, S.2008. Synthesis and Gupta,A.Hemraj. 2012. Synthesis, identification of five, six and seven Biological activities and chemistry of membered ring heterocyclic thiadiazole derivatives and Schiff derivatives M.Sc. Thesis, Chem. bases. Asian J Pharm Clin Res. Dept., College of Sci., Al-Nahrain 5(3):199-208. University . [21] Vasoya, S. L.; Paghdar, D. J.; [27] Gban,M.2011. Synthesis of new Chovatia, P.T. and Joshi,H.S.2005. heterocyclic compounds derived Synthesis of some New from 5,10-dihydrophenophosphazine Thiosemicarbazide and 1,3,4- M.Sc. Thesis, Chem.Dept. College of Thiadiazole Heterocycles Bearing Sci. university of Baghdad . Benzo[b]Thiophene Nucleus as a [28] Sxkes, P. 1966. A Guide Book to Potent Antitubercular and Mechanism in organic chemistry, Antimicrobial Agents. J. Sci. I. R. Edition Longman, London, Second Iran.16(1):33-36. Edition . 181 . [22] Ghoneim,A.A.and Mohamed, S. A. [29] Ahamed,M.R; Narren ,S.F. and 2013. Synthesis and Antimicrobial Sadiq,A.S.2015.The Preparation of activity of Some 1, 3, 4-Oxadiazoles- some New Mannich and Shiff bases 2-thione and 1, 2, 4-Triazoles derived from 2- Derivatives from Tert-Butyl Mercaptobenzimidazole.Baghdad Carbazate. Orient. J. Chem. Science Journal.12(3):516-522. 29(2):525-531. [30] Mitsumori, S.; Zhang, H.; Cheong, [23] Singh, U.K. ;Pandeya, S.N.; P.; Houk, K.; Tanaka,F.and Barbas, Singh,A.; Srivastava,B.K. and C.2006. Direct Asymmetric anti- Pandey,M.2010. Synthesis and Mannich Type Reactions Catalyzed Antimicrobial Activity of Schiff’s by a Designed Amino Acid and N-Mannich Bases of Isatin and J.Am.Chem.Soc. 128(4):1040-1041. Its Derivatives with 4-Amino-N- [31] Al-Juburi, R.M. D. 2004. Synthesis Carbamimidoyl Benzene and Biological activity of Five, Six Sulfonamide. IJPSDR.2(2):151-154. and Seven membered hetrocyclic [24] Sadiq, A.S.2012. Synthesis of 2- derivatives. M.Sc. Thesis, Mercaptobenzimidazole and Some of Chem.Dept. College of Sci. its Derivatives .M.Sc. Thesis, Chem. university of Al-Nahrain . Dept.,College of sci for women., [32] Daley, R. F. and Daley, S.J .2005 . University of Baghdad .56-59. Organic Chemistry .Chapter 20. 1049-1050.

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تحضير وتشخيص بعض المشتقات الجديدة للمورفولين

انتصار عبيد التميمي * سميعة جمعة خماس ** سرى صادق القيسي***

*قسم الكيمياء, جامعة بغداد, كلية العلوم ** قسم الكيمياء, جامعة بغداد, كلية العلوم للبنات *** قسم الكيمياء الصيدالنية, الجامعة المستنصرية, كلية الصيدلة

الخالصة: في هذا البحث تم تحضير سلسلة جديدة من مشتقات المورفولين المحضرة من خالل تصعيد المورفولين مع كلوريد خالت االثيل وثالثي اثيل امين كعامل مساعد في البنزين حيث تم الحصول على المركب مورفولين -N-خالت االثيل )2( وبمفاعلته مع الهايدرازين في االيثانول اعطى مورفولين -N-خالت الهيدرازايد )3( الذي اعطى مورفولين-N-خالت سيمي ثايو كاربازايد)2( من تفاعل المركب )3( مع امونيوثايوسيانايد وحامض الهيدروكلوريك المركز وااليثانول كمذيب.تفاعل المركب)2( مع هيدروكسيد الصوديوم وحامض الهيدروكلوريك ليعطي 5-)مورفولين-N-مثيل(H-4,2,1- 2-ترايازول-2- ثايول)2(. سلسلة جديدة من مشتقات 2,3,2- ترايازول)5-2( من تفاعل مركب )2( مع الفورمالديهايد وثنائي مثيل فورم امايد كمذيب مع مجموعة من االمينات الثانوية .حضرت مشتق واحد)2( من 2,3,2-ترايازولين من خالل تفاعل المركب )2( مع برومو حامض الخليك. تم مفاعلة المركب )2( مع الديهايدات اروماتية مختلفة بوجود ثنائي مثيل سلفوكسايد كمذيب لتحضير سلسلة من مركبات )22-22(. حيث تم تشخيص هذه المشتقات بواسطة درجات االنصهار واطياف,.FT-IR 13C-NMR 1H-NMR and

الكلمات المفتاحية: مورفولين,2,3,2- ترايازول , تفاعالت مانخ

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