Tap chi KHOA HOC OHSP TPHCM Sd 58 ndm 2014
TONG HOP VA CHUYEN HOA
2-(ACETAMIDO)-3-(4-CHLOROPHENYL)ACRYLOHYDRAZIDE
N G U Y S N T I ^ N CONG*, N G U Y E N V I ^ T D O A N H " T A T H ! THANH HOA*"
LE TH! THU HUONG***', H O A N G T R A N LAN PHUONG***, VUONG LE Al THAO'**
TOM T A T
2-(Acetamido)-3-(4-chlorophenyl)acrylohydrazide (4) da duac tdng hap tu 4- chlorobenzaldehyde (1) vd acetylglycine (2) qua hap chdt trung gian 4-(4- chlorobenzylidene)-2-methyloxazol-5(4H)-one {3). Ngung tu (4) vdi cdc aldehyde tham khdc nhau da tao thdnh 07 hap chdt hydrazide N-the (5a-g). Cdu triic cua cdc chdt tdng hap duac da duac xdc nhdn qua phd IR, phd NMR vd MS ciia chung. O ndng do din 50 lAg/ml, cdc hidrazide N-the (5a-g) deu khdng the hien hoat tinh khdng oxi hda.
Tir khoa: 4-(chlorobenzylidene)-2-methyloxazol-5(4/f)-one, 2-(acetamido)-3-(4- chlorophenyl)acrylohydrazide, hoat tinh khang oxi hoa.
ABSTRACT
The synthesis and transformation of2-(acetamido)-3-(4-chlorophenyl)acrylohydrazide 2-(Acetamido)-3-(4-chlorophenyl)acrylohydrazide (4) was synthesized starting from 4-chlorobenzaldehyde (1) vd acetylglycine (2) via 4-(4-chlorobenzylidene)-2-methyloxazol- 5(4H)-one {3) as an intermediate compound. Condensation of (4) with aromatic aldehydes gave seven appropriate N-substituted hydrazides (5a-g). The structure of the synthesized
compounds were determined by IR, NMR and mass spectral data. At concentrations up to 50 ng/ ml, all of the N-substituted hydrazides (5a-g) did not show antioxidant activity.
Keywords: 4-(chlorobenzylidene)-2-methyloxazol-5(4/f)-one, 2-(acetamido)-3-(4- chlorophenyl)acrylohydrazide, antioxidant activity.
1. Dat van de
Cac dan xuat cua oxazolone, dugc didu chd tir aldehyde va A^-alkanoylglycine khi cd mat anhydride acetic, khdng chi la nhung hgp chit cd hoat tinh sinh hgc phong phu ma cdn la chat trung gian trong tdng hgp cac chit trir cd, trir sau, trir nim trong ndng nghidp [1]. Cac hgp chit hydrazide cung dugc thiy cd hoat tinh sinh hoc rit phong phu nhu khang cdn triing, gay chdt td bao ung thu, khang vidm, giam dau"[2,8], ddng thdi hydrazide cung la chat trung gian trong tdng hgp cac di vdng 1,2,4-triazole, 1,3,4- oxadiazole.... [8]. Mdt sd tac gia da thuc hidn chuydn hda vdng oxazolone thanh
IS, Tru'dng Oai hoc Su pham TPHCM
" HVCH, Trudng Dai hoc Vinh
Sinh vidn, Trudng Oai hpc Su- pham TPHCM
hydrazide va da thu dugc cac hgp chit cd hoat tinh khang khuin [5,7], khang oxi hda, khang vidm [6]. Tuy nhidn, vide chuydn hda 4-(4-chlorobenzylidene)-2-methyloxazol- 5(4//)-one thanh cac dan xuit hydrazide - hydrazone cdn chua thay dugc dd cap ddn.
2. Thirc nghiem
2-(Acetamido)-3-(4-chlorophenyl)acrylohydrazide (4) va cac hydrazide A^-thd (5a-g) dugc tdng hgp tir 4-chlorobenzaldehyde va acetylglycine theo cac budc dugc md ta trong so dd tdng hgp d hinh 1.
^ , _ ^ NHCH2COOH (CH3CO)P C l — ( 1 A CHO + 1 CHjCOONa V V
0 = C C H 3 *"
(1) (2)
C l — / \ — « ; - ^ XQH4CHOC1.
W //-^,
CH3CNH g O
(5a-g) H
JC—C-NHN=C—(-^ ^) "*" \ - ^ C—C-NHNH2
X = 4-N(CH3)2 (5a), 4-CH3O (5b), H (5c), 4-F (5d), 4-NO2 (5e), 3-NO2 (5f), 2-HO (5g) Hinh 1. So dd tdng hop
T6ng hop 4-(4-chlorobenzylidene)-2-methyloxazol-5(4.H)-one (3): dun ndng (each thiiy) hdn hgp ciia 7,03 g (-0,05 moi) 4-chlorobenzaldehyde, 5,85 g (0,05 moi) acetyl glycine, 4,1 g (0,05 moi) natri acetate khan va 20,5 g (0,2 moi) anhydride acetic trong binh ciu 100 ml khoang 3,0 gid. Dd ngudi hoan toan rdi dat trong tii lanh qua ddm. Thdm 50 ml nude vao hdn hgp phan umg, khuiy ddu, dd ydn trong 30 phiit rdi lgc liy chit rin. Kdt tinh lai trong ethanol thu dugc 6,62 g san phim d dang tinh thd mau vang nhat, ndng chay d 158-160 °C (tai lieu [7] 158-160 °C). Hidu suit 60%. IR: 1800 va 1772 cm-' (vC=0), I66I, 1605 va 1584 cm"' (vC=C, vC=C). ' H - N M R : 5 8,19 (2H, doublet, J= 8,0 Hz, Ar-H), 5 7,57 (2H, doublet, J= 8,0 Hz, Ar-H), 5 7,23 (IH, singlet, CH=Hr), 5 2,39 (3H, singlet, CH3).
T6ng hop 2-(acetamido)-3-(4-chIorophenyI)acrylohydrazide (4)': Vira khuay vira them tir tir 10,0 ml (0,04 moi) hydrazine hydrat 50%© vao dung dich cua 2,22 g (~0,01 moi) (3) trong 50 ml ethanol d nhidt do phdng. Sau khi cho hdt hydrazine, tidp tuc khuiy th|m 30 phiit niia. Lgc liy chit rin, ket tinh trong ethanol thu dugc 1,4 g san phim d dang chat rin mau tring cd nhidt do ndng chay 156-158 °C. Hidu suat 55%. IR:
Tap chi KHOA HOC OHSP TPHCM Sd 58 ndm 2014
331A va 3217 cm"' (vN-H), 2990 cm"' (vC-H), 1672 cm"' va 1653 cm"' (vC=0), 1624 cm"' (vC=C). 'H-NMR: 5 9,40 (IH, singlet, N-H), 6 9,33 (IH, singlet, N-H), 6 7,53 (2H, doublet, J= 9,0 Hz, Ar-H), 5 7,43 (2H, doublet, J = 9,0 Hz, Ar-H), 5 6,99 (IH, singlet, CH=Hr), 5 4,36 (2H, singlet, NH2), 5 1,97 (3H, singlet, COCH3).
T6ng hop cac hop chit aryliden 2-(acetamido)-3-(4- chlorophenyl)acrylohydrazide (5a-g): Hda tan 0,76 g (-3,0 mmol) hgp chit (4) trong 25 ml ethanol, thdm 3,0 mmol aldehyde roi dun hdi luu hdn hgp phan img trong 1,0 gid. Dd ngudi hdn hgp sau phan img, lgc liy chit rin dem kdt tinh lai trong dung mdi thich hgp. Kdt qua tdng hgp va mdt sd tinh chit vat li ciia cac hgp chit (5a-g) dugc bidu didn d bang 1.
Phd hdng ngoai cac chit khao sat dugc do theo phuong phap ep vidn vdi KBr, may do Shimadzu FTIR 8400S tai Khoa Hda hgc, Trudng Dai hgc Su pham TPHCM.
Phd cdng hudng tir hat nhan dugc do trong dung mdi DMSO (chat chuan ndi TMS) trdn may do Bruker NMR Avance (500 MHz ddi vdi phd ' H - N M R va 125 MHz ddi vdi phd '"'C-NMR) tai Vidn Hda hgc, Vidn Han lam Khoa hgc va Cdng nghd Viet Nam, Ha Ndi.
Phd MS dugc do trdn may Agilent 6490 Triple Quadrupole LC/MS tai Trung tam Phap y, Sd Y td TPHCM.
Thir nghidm tham dd hoat tinh khang oxi hda ciia cac chit dugc thuc hidn bdi Phdng Sinh hgc thuc nghidm, Vidn Hda hgc cac hgp chit thidn nhidn, Vidn Han lam Khoa hgc va Cdng nghd Viet Nam, Ha Ndi
2. Ket qua va thao luan
4-(4-Chlorobenzylidene)-2-methyloxazol-5(47/)-one (1) dugc tong hgp tir 4- chlorobenzaldehyde va acetyl glycine khi cd mat anhydride acetic phdng theo phuong phap tdng hgp dugc md ta trong cac tai lieu [4-7]. San phim ma chiing tdi thu dugc co nhidt do ndng chay phii hgp vdi hgp chit 4-(4-chlorobenzylidene)-2-methyloxazol- 5(4//)-one [7], cac du lieu phd IR, phd NMR phii hgp vdi hgp chit 4-(4- chlorobenzylidene)-2-methyloxazol-5(4//)-one. [4]
Vide tdng hgp hydrazide (4) dugc tien hanh phdng theo quy trinh tong hgp a- benzamidocinnamhydrazide dugc md ta trong tai lieu [6]. Phan ung xay ra thuSn lgi ngay d nhidt do phdng va cd thd quan sat thiy sir doi mau dung dich tir vang sang tring ngay sau khi cho hydrazine vao binh phan iing. Mac dii phan iing giua hgp chit 4- arlylidene-2-alkyloxazole-5-(4/0-one vdi hydrazine cd thd tao thanh hydrazide [6] hay dan xuat cua imidazole [3]. Trong didu kidn phan iing cua chung tdi, san phim (4) thu dugc cho hai hap thu manh d 1672 cm'' va 1653 cm"' trdn phd IR, iing vdi hai nhdm C - 0 trong phan tir; trdn phd ' H - N M R cua (4) cd hai tin hidu ciia cac proton N-H (din xuat imidazole ndu tao thanh se khdng cd 2 tin hidu nay) d 9,40 ppm va 9,33 ppm.
Ngoai ra, tin hidu cua nhdm CH3 d hgp chit (4) cd sy chuydn manh vd tin sd thip so vdi tin hidu ciia nhdm CH3 gin vdi vdng oxazole-5-(4//)-one (1,97 ppm so vdi 2,39 ppm). Cac diu hidu nay chiing td hgp chit (4) la 2-(acetamido)-3-(4- chlorophenyl)acrylohydrazide ma khdng la 3-amino-5-(4-chlorobenzylidene)-2-methyl- 3,5-dihydro-4//-imidazol-4-one.
Hgp chat (4) dugc ngung tu vdi cac aldehyde thom khac nhau dd tao thanh cac hydrazide N-Xht (5a-g). Kdt qua tdng hgp va mdt sd hap thu tidu bidu trdn phd IR cua cac hgp chit (5a-g) dugc tdm tit d bang 1.
Trdn phd IR cua cac hydrazide A^-thd (5a-g), lidn kdt C=0 trong nhdm hydrazino thudng cho tin hidu xuat hidn d tan sd cao hon so vdi hydrazide chua thd (xem bang 1).
ESI-MS ciia cac hgp chat (5a-g) ddu xuat hidn cac pic ion phan tir nhu du kidn.
Tuy thudc vao didu kidn do mau, pic ion phan tii cd thd xuat hidn dudi dang ion (M + H)"^ hoac (M + Na)"^ (xem bang 1). Kdt qua nay mdt lan niia xac nhan cac hydrazide N- thd da dugc tao thanh.
Bdng 1. Ket qud tdng hop vd mdt sd hdp thu tieu bieu tren phd IR cua cdc hop chdt (5a-g)
(Hgp chat) X (5a) 4-N(CH3)2
(5b) 4-CH3O
(5c) H (5d)
4-F (5e) 4-NO2
(5f) 3-NO2
(5g) 2-OH
t„c (°C)
181-183
207-209
215-218
231-233
273-274
270-272
258-259
Hidu suat (%)
38,8
57,4
30,6
45,4
59,5
47,4
46,9
Dung mdi ket tinh
EtOH
EtOH
EtOH
EtOH
Dioxane
DMF:EtOH
DMF:EtOH
Phd IR (v, cm"') N-H,
O-H 3275 3150 3271 3148
-
3237 3233 3179 3200 3316 3239
C-H 3013 2893 2994
3060
3009 3013 2965 3048
3070
C=0 1674 1651 1694 1651 1715 1651 1686 1663 1678 1661 1655 1636 1697 1662
C=C 1613 1593 1620 1595 1591 1632 1611 1638 1598 1605
1620
M S
385 (M+H)
394 (M+Na)
382 (M+Na)
409 (M+Na)
409 (M+Na)
380 (M+Na)
Tap chi KHOA HOC OHSP TPHCM Sd 58 ndm 2014
Phd 'H-NMR va '^C-NMR cua cac hydrazide iV-thd deu xuit hidn diy du cac tin hidu nhu du kidn. Trdn phd 'H-NMR, ngoai trir tin hidu cua cac proton trong cac^nhdm NH (H'° va H'^) xuit hidn d viing trudng ydu va tin hidu ciia nhdm CH3CO (H ) xuat hidn d vimg trudng manh, hiu hdt cac tin hieu ciia cac proton cdn lai ddu nim d viing thom (6,80-8,50 ppm). Dua vao dac didm ciu tao ciia cac hydrazide, chung tdi da tidn hanh quy ket cac tin hidu va bieu didn ket qua quy kdt 0 bang 2.
Trdn phd '^C-NMR cua cac hydrazide ^-thd (5b-g), ngoai tin hidu cua carbon d nhdm thd cua hgp phin benzyliden (ndu cd), cac hgp chit (5b-e) vdi nhdm the d vi tri sd 4 d vdng benzen cho 14 tin hidu; cac hgp chit (5f) va (5g) cho 16 tin hifu (ridng hgp chit (5d), do cd tuong tac spin-spin cua '^F vdi '^C iidn cac nguydn tii C'^-C'^ ddu bi tach thanh 2 tin hidu vdi nhiing gia tri phu hgp vdi hing so tuong tac spin-spin a timg vi tri). Hai tin hidu d vimg trudng ydu nhit, mdt d gin 161,5 ppm va mdt d gan 169,5 ppm la cac tin hidu cua cac nguydn tir carbon carbonyl (C' va C"); tin hidu d viing no (gin 22,7 ppm) la ciia carbon sp^ (C'^) trong nhdm CH3CO. Cac tin hidu iing vdi cac nguydn tir carbon sp^ cdn lai thudng nim trong viing 110-150 ppm (xem bang 3). Viec quy kdt chinh xac cac tin hidu cua cac nguydn tir carbon nay la khd khan neu khdng c6 sir hd trg ciia phd hai chidu.
Bdng 2. Tin hieu tren phd 'H-NMR cua cdc hydrazide N-thi (5, ppm vd J, Hz)
Cl- "A\2 3 16
'2CH3CNH "
O
O (5a-h)
Vi
•
tri 3 5,9 6,8 10 12 13
X 4-N(CH3)2
6,89 {s) IH 7,59 {d), 2H,J=8,5 7,47 {d), 2H,J=8,5 9,55 (5),
IH 2,01 {s),
3H 11,23(5),
4-CH3O 6,91 (5)
IH 7,60 {d), 2H, J=8,5 7,47 {d), 2H, J=8,5
9,60 {s), IH 2,03 (5),
3H 11,44(5),
H 6,91 (5)
IH 7,69 {d), 2H,J=8,0 7,61 {d), 2H,J=8,0 9,62 (5),
IH 2,02 (5),
3H 11,56(5),
4-F 6,91 (5)
IH 7,61 {d), 2H, J=8,0 7,48 {d), 2H, J=8,0 9,63 (5),
IH 2,03 (5),
3H 11,59(5),
4-NO2 6,92 (5)
IH 7,61 (d), 2H,J=8,5 7,49 (d), 2H,J=8,5
9,68 (5), IH 2,03 (5),
3H 11,89(5),
3-NO2 6,91 (5)
IH 7,61 (d), 2H, J=8,5 7,48 (d), 2H, J=8,5 9,67 (5),
IH 2,03 (5),
3H 11,85(5),
2-OH 6,96 (5)
IH 7,62 id), 2H,J=8,5 7,48 {d), 2H,J=8,5 9,68 (5),
IH 2,03 (5),
3H 11,84(5),
14
16
17
18
19
20
Hkhac
8,24 (5), IH 7,51 (d), 2H, J=9,0 6,75 (d), 2H, J=9,0
-
6,75, 2H, J=9,0 7,51 {d), 2H, J=9,0 2,97 (5),
6H, (CH3)2N
8,34 (5), IH 7,65 {d), 2H, J=8,5 7,01 {d), 2H, J=8,5
7,01, 2H, J=8,5 7,65 {d), 2H, J=8,5 2,80 (5), 3H, CH3O
8,39 (5), IH 7,48 {d), 2H,J-8,5 7,46 (m),
3H 7,46 im),
3H
7,46, 3H, m 7,48 id), 2H,J=8,5
-
8,40 (5), IH 7,76 {dd), 2H,'J=8,0,
V=6,0 7,29 {dd),
2H, 'J=V=8,0
7,29, 2H, 'J=V=8,0 7,76 {dd), 2H,'/=8,0,
V=6,0
8,49 (5), IH 7,96 {d), 2H,J=8,0 8,30 {d), 2H,J=8,0
8,30, 2H, J=8,0 7,96 {d), 2H,J=8,0
8,51(5), IH 8,51 (5),
IH
8,25 {d), 1H,J=8,0
7,75, IH, 'y=^J=8,0 8,12 ( ^ , 1H,J=8,0
-
8,58 (5), IH
6,92 (m), 2H 7,50 (m),
IH 7,29 {ddd),\n,
V-1,5 'J=V=8,0
6,92 (m), 2H 11,26(5),
1H,0H
Bdng 3. Tin hieu tren phd C-NMR cua cdc hydrazide N-the (5, ppm) (Xem cdng thuc o hdng 2)
(HC)X (5b) 4-CH3O
(5c) H (5d)
4-F (5e) 4-NO2
(5f) 3-NO2
(5g) 2-OH
C=0 169,53' 161,79 169,47 161,94 169,45 161,93 169,51 162,25 169,51 162,24 169,61 161,72
C=C, C=N
160,83; 147,43; 133,08; 132,96; 131,10; 130,52; 128,64;
128,59; 126,97; 125,24; 114,35.
147,42; 134,39; 133,01; 131,10; 130,44; 130,00; 128,83;
128,58; 126,97; 125,27;
(164,03; 162,05; '/C-F=246,8HZ); 146,24; 132,98; 132,93;
131,07; (131,00; 130,98; VC.F=2,6HZ); 130,42; (129,14;
129,08; Vc-F=8,4Hz); 128,55; 125,24; (115,93; 115,76;
Vc.F=21,9Hz).
147,77; 144,77; 140,71; 133,04; 132,86; 131,12; 130,27;
128,58; 127,85; 125,45; 124,02.
148,23; 144,87; 136,27; 133,28; 133,01; 132,89; 131,12;
130,44; 130,30; 128,58; 125,36; 124,13; 120,76.
157,42; 147,96; 133,09; 132,91; 131,32; 131,18; 129,96;
129,46; 128,64; 125,75; 119,35; 118,71; 116,40.
CH3 55,30 22,77 22,73
22,70
22,64 22,66 22,77
Tap chi KHOA HOC OHSP TPHCM Sd 58 nam 2014
Nhan thiy phan tir cac hydrazide 7V-thd (5a-g) deu chira cac bd phan lidn hgp keo dai, cd the giai tda cac gdc tu do, chiing tdi da thii tham dd kha nang khang oxi hda cua chiing. Tuy nhidn, d ndng do ddn 50 |ig/ml, cac hgp chit (5a-g) ddu khdng thd hidn hoat tinh khang oxi hda.
3. Ket luan
•
Da tong hgp dugc 2-(acetamido)-3-(4-chlorophenyl)acrylohydrazide va bay dan xuat hydrazide //-thd cua nd, tat ca ddu chua thay trong cac tai lieu tham khao. Cau triic cua cac chat tdng hgp dugc da dugc xac nhan qua phd IR, phd ' H - N M R , ' ' ^ C - N M R va phd MS cua chiing. Ci ndng do ddn 50 fj.g/ml, cac hidrazide A^-thd (5a-g) ddu khdng thd hidn hoat tinh khang oxi hda.
TAI LIEU THAM KHAO
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Technology, Vol. 3(3), pp. 3064-3082.
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