Kỹ thuật sản xuất Dược phẩm tập 1

B y t

K thut sn xut dc phm

Tp I

K thut sn xut thuc bng phng php tng hp ha dc v chit xut dc liu

Sch o to dc s i hc

M s: .20.Z.09

Ch bin: PGS.TS. T Minh Kong

Nh xut bn y hc

H ni - 2007

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Ch o bin son

V Khoa hc & o to, B Y t

Ch bin:

PGS.TS. T Minh Kong

Nhng ngi bin son:

ThS. Nguyn Vn Hn

KS. Nguyn Vit Hng

TS. Nguyn nh Luyn

PGS.TS. Hu Ngh

Hiu nh:

KS. Nguyn Vit Hng

Tham gia t chc bn tho:

TS. Nguyn Mnh Pha

ThS. Ph Vn Thm

Bn quyn thuc B Y t (V Khoa hc & o to)

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Li gii thiu

Thc hin mt s iu ca Lut Gio dc, B Gio dc v o to v B Y t ban hnh chng trnh khung o to i tng l Dc s i hc Cao ng iu dng. B Y t t chc bin son ti liu dy hc cc mn c s, chuyn mn v c bn chuyn ngnh theo chng trnh trn nhm tng bc xy dng b sch chun v chuyn mn m bo cht lng o to nhn lc y t.

Sch K thut sn xut dc phm c bin son da trn chng trnh gio dc cao ng iu dng ca Trng i hc iu dng Nam nh trn c s chng trnh khung c ph duyt. Sch c ThS. Trng Tun Anh, mt nh gio giu kinh nghim v tm huyt vi cng tc o to bin son theo phng chm: Kin thc c bn, h thng; ni dung chnh xc, khoa hc, cp nht cc tin b khoa hc, k thut hin i v thc tin Vit Nam.

Sch K thut sn xut dc phm c Hi ng chuyn mn thm nh sch v ti liu dy hc chuyn ngnh C nhn iu dng v Cao ng iu dng ca B Y t thm nh vo nm 2006. B Y t quyt nh ban hnh l ti liu dy hc t chun chuyn mn ca ngnh y t trong giai on 2006-2010. Trong qu trnh s dng, sch phi c chnh l, b sung v cp nht.

B Y t xin chn thnh cm n ThS. Trng Tun Anh, cng tc ti B mn iu dng thn kinh tm thn Trng i hc iu dng Nam nh ginh nhiu cng sc hon thnh cun sch ny, cm n TS. inh ng Ho, PGS.TS. Ng ng Thc c, phn bin cun sch c hon chnh, kp thi phc v cho cng tc o to nhn lc y t.

V ln u xut bn, chng ti mong nhn c kin ng gp ca ng nghip, cc bn sinh vin v cc c gi ln xut bn sau c hon thin hn.

V Khoa hc v o to

B Y t

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Li ni u

Cun gio trnh "K thut sn xut dc phm" c bin son ging cho sinh vin Dc h i hc vo hc k 8 c xut bn ln th nht nm 2001, gm 2 tp. Theo chng trnh c, thi lng ging dy mn hc ny l qu t so vi nhng kin thc chung ca Dc s i hc. c bit trong tnh hnh hin nay, sau khi c ngh quyt ca B Chnh tr (NQ-46/BCT-2005) v pht trin nn Cng nghip Dc ca t nc trong tnh hnh mi, phi u tin pht trin cng nghip sn xut nguyn liu lm thuc, trong ch trng Cng nghip Ha dc v Cng ngh Sinh hc. Ban chng trnh nh trng quyt nh tng thm mt n v hc trnh cho hc phn "Sn xut thuc bng Cng ngh sinh hc".

B mn bin son li xut bn cun gio trnh mi gm 3 tp. C ba tp u c tn chung ca gio trnh: K thut sn xut dc phm.

Gio trnh c bin son theo hai ni dung:

1. K thut sn xut cc nguyn liu lm thuc.

2. K thut sn xut cc dng thuc thnh phm.

Trong :

Ni dung th nht gm 2 tp l:

* Tp 1. K thut sn xut thuc bng phng php tng hp ha dc v chit xut dc liu.

* Tp 2. K thut sn xut thuc bng phng php sinh tng hp.

Ni dung th hai gm 1 tp l:

* Tp 3. K thut sn xut cc dng thuc.

So vi ln xut bn trc, cc tc gi bin son c gng cht lc nhng kin thc ch yu nht cung cp cho ngi hc hiu c ngnh khoa hc va hp dn va quan trng ny. Tuy nhin, vi ni dung phong ph, a dng v thi lng hn ch nn khng th i su hn c. V vy cun gio trnh khng trnh khi nhng thiu st. Cc tc gi mong nhn c s gp ca c gi chnh sa cho ln xut bn sau c hon chnh hn. Xin chn thnh cm n.

B mn Cng nghip Dc

Trng i hc Dc H Ni

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Mc lc

Li gii thiu 3

Li ni u 5

Phn I. K thut tng hp ha dc 11 Chng 1. Mt s kin thc chung v cng nghip ho dc 11

1. i cng TS. Nguyn nh Luyn 11

2. c im ca cng nghip ho dc 12

3. Phng php nghin cu sn xut thuc mi 14

4. Ngun nguyn liu ca cng nghip ho dc 17 Chng 2. Nitro ho 24


2. C ch phn ng nitro ho 24

3. Tc nhn nitro ho 26

4. Cc yu t nh hng n phn ng 27

5. Cch tin hnh phn ng 28

6. Nitrozo ha 29

7. Thit b phn ng v an ton lao ng 29

8. Mt s v d 29 Chng 3. Sulfo ha 32


2. C ch phn ng 33

3. Tc nhn sulfo ha 34

4. iu kin ca qu trnh sulfo ha 37

5. Kh nng ng dng ca phn ng 38


7. Tch cc acid sulfonic t hn hp phn ng 40

8. Mt s v d 40 Chng 4. Halogen ha 42


2. C ch phn ng 43

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3. Tc nhn halogen ha 45

4. Mt s v d 47 Chng 5. Alkyl ha 49


2. Cc tc nhn alkyl ha 50

3. Cc loi alkyl ha 51

4. Cc yu t nh hng n qu trnh alkyl ha 53


6. Mt s v d 54 Chng 6. Acyl ha 56


2. Tc nhn acyl ho 58

3. C ch phn ng 59

4. Mt s yu t cn ch trong qu trnh acyl ho 60

5. Mt s v d 61 Chng 7. Ester ho 63


2. C ch phn ng 65

3. Cc yu t nh hng n qu trnh ester ho 66

4. Cc phng php chuyn dch cn bng cho phn ng ester ho 69

5. Mt s v d 70 Chng 8. Phn ng thu phn 72


2. C ch ca phn ng thu phn 72

3. Cc tc nhn thu phn 73

4. Cc phn ng thu phn v c ch phn ng 74

5. Thit b ca phn ng thu phn 80

6. K thut an ton lao ng 81

7. Mt s v d 81 Chng 9. Oxy ho 83


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2. C ch phn ng oxy ho 84

3. Cc tc nhn oxy ho 86 4. Cc phn ng oxy ho 89 5. Thit b ca phn ng oxy ho 92 6. K thut an ton trong qu trnh oxy ha 92 7. Mt s v d 92

Chng 10. Kh ho 95 1. i cng TS. Nguyn nh Luyn 95 2. Tc nhn kh ho 96

3. ng dng ca phn ng kh ho 104 4. Hydro phn 109 5. Mt s v d 109

Chng 11. Diazo ho 112 1. i cng TS. Nguyn nh Luyn 112 2. c im ca mui diazoni 113 3. C ch ca phn ng diazo ho 113 4. Cc yu t nh hng n qu trnh diazo ho 115 5. Nguyn tc tin hnh diazo ho 116 6. Cc phn ng ca mui diazoni 117 7. Thit b v an ton lao ng 119 8. V d 120

Chng 12. Phn ng ngng t 121 1. i cng TS. Nguyn nh Luyn 121 2. Cc loi phn ng ngng t 122

Chng 13. Phn ng chuyn v 128 1. i cng TS. Nguyn nh Luyn 128 2. C ch phn ng chuyn v anion -1,2 129 3. Cc loi phn ng chuyn v 129

Phn II. K thut chit xut dc liu 145 Chng 14. Mt s kin thc c bn v chit xut dc liu 145

1. Nguyn liu chit xut KS. Nguyn Vit Hng 146 2. Mt s qu trnh xy ra trong chit xut dc liu 148

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3. Nhng yu t nh hng n qu trnh chit xut dc liu 151 4. Cc phng php chit xut 157

5. Thit b chit xut 161 Chng 15. Mt s qu trnh thng gp giai on tinh ch 177

1. Lng KS. Nguyn Vit Hng 177

2. Lc 181

3. Kt tinh 187

4. Hp ph 192 Chng 16. K thut sn xut mt s nguyn liu di dng cao thuc 199

1. Khi nim cao thuc ThS. Nguyn Vn Hn 199

2. Phn loi cao thuc 200

3. K thut iu ch 200

4. Cc ch tiu cht lng cao thuc 206

5. Bo qun, ghi nhn 206

6. Mt s v d cao thuc 207 Chng 17. Chit xut alcaloid 208

1. i cng v alcaloid PGS. TS. Hu Ngh 208

2. Tnh cht chung ca alcaloid 209

3. Cc phng php chung chit alcaloid 210

4. Cc phng php tch alcaloid di dng tinh khit 213

5. Chit xut mt s alcaloid 215 Chng 18. Chit xut cc hot cht c ngun gc t nhin khc 242

PGS. TS. Hu Ngh

1. Chit xut artemisinin v acid artemisinic t cy thanh hao hoa vng 242

2. Chit xut rutin t hoa ho 249

Ti liu tham kho 251

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Phn I. K thut tng hp ho dc

Chng 1

Mt s Kin thc chung v cng nghip ho dc

Mc tiu Sau khi hc xong chng ny, sinh vin phi trnh by c:

1. Bn c im ca cng nghip Ho dc.

2. Ni dung ca phng php nghin cu sn xut thuc mi trong k thut tng hp Ho dc.

3. Cc ngun nguyn liu v c v hu c ca cng nghip Ho dc.

1. i cng

K thut tng hp Ho dc hnh thnh v pht trin da trn c s ca K thut tng hp Hu c. Ngy nay n tr thnh mt ngnh khoa hc ring bit vi mt tim nng v cng to ln. Mt mt do nhu cu iu tr ngy cng tng, mt khc do li ch v kinh t rt ln thc y cc hng Dc phm ln trn th gii u t mnh m vo lnh vc ny.

Hin nay, do s cnh tranh khc lit trn th trng, nn c quyn trong sn xut mt sn phm thuc cng tr nn rt quan trng i vi s tn ti ca mt hng Dc phm. Chnh v vy, vic sn xut ra nguyn liu lm thuc vi gi r v nghin cu tm kim thuc mi l hai nhim v chnh ca ngnh Cng nghip Ho dc hin nay.

Cc cht hu c dng lm thuc thng c phn t lng khng ln (khng qu 500 n v C) v c cu trc kh phc tp, nhiu cht d b phn hu bi nh sng, nhit v m. Chng c iu ch bng nhiu phn ng ho hc khc nhau. Chnh v vy, cc nh nghin cu, cc dc s v k s lm vic trong lnh vc ny phi c s am hiu su sc v cc qu trnh ho hc c bn (nitro ho, sulfo ho, halogen ho, oxy ho, kh ho...) hoc nhng qu trnh ho hc c bit khc. Phi c s hiu bit c bn v cc nhm thuc v phng php tng hp chng. Ngoi ra cn phi c kin thc v thit b,

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vt liu ch to thit b dng trong cng nghip Ho dc v vn n mn thit b... trnh a tp cht vo thuc.

K thut tng hp Ho dc l mn hc nhm p ng nhng yu cu trn, ni dung gm hai phn chnh:

A. Cc qu trnh ho hc c bn ca k thut tng hp Ho dc.

B. K thut tng hp Ho dc.

Phn cc qu trnh ho hc c bn gii thiu cc phn ng c s dng nhiu trong tng hp Hu c, Ho dc. Cc phn ng ny c k thut ho vi vic s dng cc tc nhn v iu kin phn ng ti u thu c cc sn phm mong mun t tiu chun. Phn K thut tng hp Ho dc gii thiu cc phng php tng hp cc nhm thuc c th nh: Thuc h nhit gim au, Thuc st rt, Thuc cha l, Thuc tr giun sn...

V s gi ging trong i hc c hn, nn phn B c trnh by trong gio trnh Cao hc ca chuyn ngnh Cng ngh Dc phm v Bo ch.

2. c im ca Cng nghip Ho Dc

Tuy l mt trong nhng ngnh ca cng nghip ha hc, nhng mc ch ca cng nghip Ha dc l sn xut ra cc hot cht nhm iu tr bnh cho ngi. Cho nn n c nhng c im ring, rt cn ch trong qu trnh t chc v pht trin sn xut.

c im quan trng nht l cht lng thnh phm phi t tiu chun Dc in quc gia

Mc ch s dng thuc l iu tr bnh, thuc khng ch c a vo c th bng ng ung m cn bng ng tim, t hoc phn phi trc tip qua da... C ngha l c nhiu con ng a thuc trc tip vo mu ca mt c th bnh. Do hot cht dng lm thuc phi tinh khit, khng c cha tp cht hay bt k mt tc nhn no bt li cho sc kho.

T yu cu trn, trc khi xut xng, thnh phm phi c kim nghim rt cht ch v mt ha hc v sinh hc theo cc tiu chun ca Dc in. Vic qui nh hm lng tp cht c trong thuc ht sc cht ch nhm trnh cc tc dng c hi do tch lu khi s dng di ngy, loi nhng tp cht khc khng th pht hin c trong sn xut, trnh nhng tng k khng gii thch c khi bo ch hoc ko di tui th ca thuc...

c im ny i hi nh my Ha dc phi t cc yu cu sau:

Phi m bo cc tiu chun v v sinh cng nghip. Ngi lao ng phi c hiu bit v nguyn tc v sinh v v trng trong sn xut.

Thit b sn xut phi chng n mn tt khng a thm tp cht vo thuc.

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Nguyn liu dng cho sn xut phi c cht lng cao, r ngun gc loi nhng tp cht khng pht hin c trong sn xut. Cng v l do ny m hin nay khuynh hng: "Cng nghip Ha Dc t sn xut ly sn phm trung gian" ngy cng pht trin.

Do s phc tp ca phn t thuc v yu cu tinh khit cao ca sn phm, nn cc quy trnh sn xut Ho dc thng gm nhiu giai on bin i ho hc v l hc. nng cao hiu sut v trnh tht thot, cn phi s dng nhng quy trnh lin tc v t ng ho.

Thnh phm ca cng nghip Ho dc nhiu loi l thuc c, cc thuc khng t tiu chun cht lng th khng th xut xng m phi hu hoc x l thu hi nguyn liu. V vy, vic ng gi thnh phm v lu kho phi c thc hin nghim tc theo ng th tc v yu cu k thut. Vt liu ng gi v quy cch nhn bao b u phi tun theo quy nh.

Tm li, mt nh my Ho dc cn t tiu chun GMP cho mt nh my sn xut nguyn liu lm thuc.

V mt khi lng v gi tr

Khi lng ca sn xut Ho dc so vi cc ngnh cng nghip khc thng khng ln v vi mi loi thuc cng khc xa nhau.

C loi ch cn vi kg l p ng cho nhu cu iu tr trong c nc, nhng c loi phi cn ti hng trm, hng ngn tn. Trong gi thnh ca chng rt chnh lch nhau v gi tr kinh t cng rt khc nhau. V vy, trc khi a mt mt hng vo sn xut phi nghin cu rt k c k thut ln hiu qu kinh t m bo sn xut n nh v c hiu qu cao.

Mt khc, mun cho thnh phm khng qu t, cng nghip Ho dc phi trit khai thc d phm ca nhiu ngnh khc. Cn phi hp tc rng ri vi nhiu ngnh nh cng nghip ho hc, phm nhum, cht do, thuc n, luyn kim, khai thc qung, lm nghip, chn nui, giy, thc phm, ... nhm s dng lin hon cc nguyn liu.

Khng nhng thnh phm nhiu loi l thuc c m nhiu nguyn ph liu dng trong sn xut Ho dc l nhng cht c, nhiu qu trnh phn ng v tinh ch s dng cc loi dung mi d chy n.

Nhiu dung mi to hn hp n vi khng kh. trnh chy n, khng c dng khng kh nn chuyn vn cc dung mi d chy n, m phi dng kh tr hoc bm vn chuyn.

Vic tip xc vi ho cht v dung mi c nh hng khng tt n sc kho con ngi, gy nn nhiu bnh ngh nghip mn tnh. V vy phi nghim tc tun theo nhng qui nh v an ton lao ng. Phi c hiu bit su v chuyn mn, c tnh k lut v tinh thn trch nhim cao trong sn xut.

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Rt nhiu qui trnh sn xut thuc l nhng tng hp tinh vi, s dng nguyn liu t v him, thit b t ng phc tp.

V vy i ng cn b v cng nhn ca cng nghip Ha dc phi c trnh cao, thnh tho v chuyn nghip ha. c bit nhng ngi ph trch tng dy chuyn sn xut phi c o to tt, m bo hiu qu ca sn xut v cht lng thnh phm. Vic t chc, v qun l sn xut phi thng xuyn nng cao, ci tin v hp l ho.

3. Phng php nghin cu sn xut thuc mi

S i hi thng xuyn ca iu tr bnh c tc dng thc y mnh m vic nghin cu sn xut cc thuc mi. i vi mi quc gia, y l vn v cng quan trng trong chin lc bo v sc kho con ngi. Hin nay, vic nghin cu a mt thuc mi vo sn xut thng c hai xu hng:

3.1. Nghin cu tm kim hp cht mi dng lm thuc

Trn c s nhng pht minh ca cc nh khoa hc thuc nhiu lnh vc khc nhau nh sinh hc, dc l... v nhng hp cht t nhin c tc dng sinh hc, cc nh ho hc xc nh cu trc phn t v tng hp ra hp cht ny cng nhng dn xut mi ca n. Kt qu s c mt lot cc hp cht mi cho cc nh sinh hc, dc l... tin hnh th tc dng sinh hc, dc l nhm chn ra nhng hp cht p ng yu cu iu tr. Con ng ny rt kh, v trong hng trm thm ch hng ngn hp cht iu ch c c th ch mt hoc vi cht c la chn iu tr.

3.2. Nghin cu xy dng qui trnh sn xut m

Nhim v ch yu y l tm phng php tng hp mi, trn c s xy dng mt quy trnh mi tin li hn, kinh t hn sn xut cc hp cht c s dng trong iu tr. Xu hng nghin cu ny thng c thc hin nhng trng hp sau:

Cc phng php tng hp hoc quy trnh sn xut c lc hu, khng kinh t, khng c kh nng sn xut quy m cng nghip. n nay nh s pht trin ca cng ngh tng hp hu c, c kh nng thay i bng mt phng php tng hp mi hin i hn, kinh t hn.

Cc hp cht chit xut t t nhin c hot tnh sinh hc cao, hin ang c dng lm thuc, nhng do ngun nguyn liu t nhin cn kit, khng p ng nhu cu iu tr cho nn cn phi nghin cu phng php tng hp, bn tng hp.

Do nguyn nhn khng mua c bn quyn sng ch, do phi nghin cu tm mt phng php khc sn xut dc cht bit (Hin nay, i vi cc nc ang pht trin c th mua li nhng

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bng pht minh ht bn quyn tit kim chi ph nghin cu v rt ngn thi gian a mt thuc ang c s dng vo sn xut).

Vic a mt thuc mi vo sn xut bt k theo xu hng no cng gm nhng bc sau:

+ Nghin cu tng hp qui m phng th nghim: R (Research). + Nghin cu trin khai quy m pilot: D (Development). + Nghin cu sn xut quy m cng nghip: P (Production).

3.3. Nghin cu tng hp qui m phng th nghim

u tin cn tra cu, thu thp ti liu cng y cng tt v hp cht cn nghin cu tng hp nh: phng php tng hp, phng php xc nh cu trc, cc hng s ho l, phng php kim nghim, tc dng sinh hc ...

Trn c s ti liu tra cu c, phn tch chn lc nhng ni dung ph hp vi iu kin phng th nghim, iu kin sn xut trong nc. Sau tin hnh th nghim qui m nh kho st nhng yu t nh hng ti hiu sut to thnh sn phm (tc nhn phn ng, xc tc, dung mi, nhit , t l mol cc cht tham gia phn ng, nng , thi gian phn ng...), kho st phng php x l sau phn ng, phng php tinh ch, kh nng thu hi d phm, phng php xc nh cu trc, n nh ca qui trnh, ...

Sau khi c sn phm tinh khit, tin hnh th hot tnh sinh hc (in vitro, in vivo), th tc dng dc l, c tnh trn ng vt th nghim, th tin lm sng v lm sng.

Xy dng quy trnh iu ch hot cht t tiu chun dc dng (theo tiu chun ngnh hoc tiu chun Dc in).

Ni dung quy trnh phng th nghim:

Trn c s cc kt qu nghin cu, vit thnh quy trnh phng th nghim cc nh chuyn mn da vo thc hin nghin cu trin khai qui m pilot. Mt qui trnh phng th nghim tng hp Ho dc thng gm nhng ni dung sau:

1. Tn ti: cn ghi r tn ti, cc bc phn ng, cc cht trung gian mi hoc sn phm mi c to thnh.

2. Tn sn phm: cn vit tn khoa hc theo ti liu v tn gi c s dng trong nh my hoc x nghip.

3. Cc hng s ho hc, vt l: cn nu cng thc cu to, cng thc nguyn, phn t lng, mu sc, dng tinh th, im chy, si ca

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sn phm. Ring ho tan cn nu k cc loi dung mi v lng cht c th ho tan cc nhit khc nhau. Cc iu cn bit v bn vng, iu kin bo qun ca sn phm v cc s liu lin quan v tc dng sinh hc.

4. Yu cu v cht lng sn phm: cn a ra cc yu cu ca ti liu tham kho v kt qu bn thn t c v cc ch tiu cht lng ca sn phm nh mu sc, mi v, cc tnh cht vt l... V d im chy ti liu ghi l l30oC, nhng phn ng tip theo ch cn im chy l25oC l t yu cu th trong qui trnh cng ghi im chy ny.

5. Lch s tm tt ca sn phm: cc phng php sn xut, ni sn xut, ngi pht minh v thi gian lm ra sn phm.

6. Cc phng trnh phn ng iu ch, phn t lng, t l mol thc dng, im si, im chy v mt s tnh cht ca cc cht tham gia phn ng...

7. Qui trnh tm tt: ch ghi qui trnh mt cch tm tt v cc im cn ch .

8. Lit k tn nguyn liu, ph liu cn thit cho qui trnh, ghi r yu cu v cht lng v s lng.

9. Qui trnh chi tit: m t chi tit cch tin hnh, lit k cc thit b, nu chi tit cc s liu cc nh chuyn mn bit cch thc hin th nghim.

10. An ton v bo h lao ng: cn ghi r cc im cn ch v an ton lao ng trong qu trnh tin hnh th nghim.

11. Mt s kinh nghim khi thc hin th nghim: cn ghi li nhng kinh nghim c nhn trong qu trnh tin hnh th nghim ngoi nhng m t trong qui trnh chi tit.

12. Ch tiu nguyn liu ph liu: cn phi tnh ton ch tiu nguyn liu, ph liu, dung mi cn thit cho mt kg sn phm.

13. Cc ti liu tham kho: cn trch dn cc ti liu tham kho lin quan n ti thu thp c.

14. Thi gian, a im, h tn nhng ngi tham gia tin hnh ti nghin cu v ch k (c ghi r h tn) ngi vit qui trnh.

3.4. Nghin cu trin khai qui m pilot

Nhim v chnh ca giai on ny l gii quyt cc vn k thut khi "to ho" quy trnh v ti u ho cc iu kin th nghim. c bit lu n cc vn ny sinh khi m rng qui m th nghim nh an ton trong sn xut, cht lng sn phm, hiu qu kinh t... trnh nhng sai phm

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khng thy c qui m phng th nghim. Cn nghin cu gii quyt cc vn c th sau:

Vn dung mi: tm cch thay th cc dung mi d chy n, c hi bng cc dung mi an ton hn, thay cc dung mi t tin bng cc dung mi r hn.

Vn phng thc np liu: ti u ho cch thc np liu cho ph hp vi tng thit b v ton b dy chuyn sn xut.

Vn lin tc ho qu trnh: nghin cu thay cc cng on sn xut gin on thnh mt qu trnh lin tc.

Vn phn lp v tinh ch sn phm: nghin cu phng php phn lp v tinh ch sn phm thch hp cho qui m sn xut ln.

V theo di im kt thc phn ng. V vn phng php thao tc, gia nhit. Vn thit b: cc yu cu v vt liu lm thit b v cc loi thit b

cn s dng.

Vn thu hi, x l dung mi v sn phm ph. Vn nh mc nguyn liu vt t, thi gian cho mt qui trnh sn

xut.

3.5. Xy dng qui trnh sn xut qui m cng nghip

T nhng kt qu nghin cu trn, tng kt vit thnh qui trnh k thut qui m sn xut cng nghip. Qui trnh ny bao gm cc giai on sn xut rt c th. Mi giai on c cc thao tc k thut to ra sn phm trung gian hoc thnh phm. C th ho nh mc vt t nguyn liu, nng lng, thi gian sn xut, la chn v b tr thit b, phng php x l, thu hi dung mi v sn phm ph... Vi qui trnh chi tit ny ngi cng nhn c th sn xut ra cc sn phm theo ng yu cu.

4. Ngun nguyn liu ca cng nghip ho dc

Cng nghip Ho dc sn xut ra tt c cc loi nguyn liu cho cng nghip Bo ch dc phm nh: hot cht, cc cht ph tr, cc t dc v cc loi dung mi... V vy ngun nguyn liu ca cng nghip Ho dc rt rng ri, bao gm khong sn, thc vt, ng vt, hay sn phm tng hp ho hc.

4.1. Cc nguyn liu v c

Cc khong sn:

L ngun nguyn liu ch yu sn xut cc ho dc v c.

18

T nc bin c th sn xut cc mui v c nh: NaBr, KBr, NaI, KI, NaCl, KCl. Rong bin l ngun sn xut iod ng k v cng l ngun thc n b sung iod cho c th.

T nc t (nc ci sau khi phi nng kt tinh mui n t nc bin) c th iu ch c cc mui magnesi dng trong ngnh dc nh MgSO4.7H2O lm thuc ty, thuc nhun trng. Ngoi ra cc mui magnesi carbonat nh MgCO3, Mg(HCO3)2, 3MgCO3.Mg(OH)2.3H2O dng lm thuc nhun trng, chng toan mu v lm t dc.

T qung Pyrolusit c th iu ch KMnO4 dng lm thuc st trng. T qung Barytin (c cha khong 90 - 98% BaSO4) c th tinh ch

c BaSO4 dc dng dng lm cht cn quang chp d dy, ng tiu ho.

T qung Dolomi (cha carbonat kp ca magnesi v calci) c s dng sn xut mui magnesi lm t dc.

T thch cao (CaSO4.2H2O) khi nung 120 - 130oC mt nc to thnh CaSO4.1/2H2O dng lm bt b.

Vit Nam, qung Barytin c Tuyn Quang v Bc Giang (hm lng BaSO4 khong 98%), qung Pyrolusit Cao Bng (hm lng MnO2 trn 43%), qung Dolomi Thanh Ho, Vnh Phc. Chng ta khai thc sn xut cc ho cht v c phc v cho y t v cc ngnh khc.

Cc acid v kim v c:

Cc acid v kim v c (H2SO4,, HNO3, HCl, NaOH, KOH, NH4OH...) l nguyn liu khng th thiu c ca cng nghip Ho dc.

Acid sulfuric sn xut t qung Pyrit (FeS2). Acid clorosulfuric iu ch t Cl2 v acid sulfuric, c s dng trong sn xut cc sulfamid. Acid sulfuric, oleum v acid clorosulfuric c sn xut Cng ty ho cht Lm Thao t qung Pyrit (FeS2).

Acid hydrocloric c sn xut bng phn ng ca kh Cl2 vi H2 (Cl2 thu c khi in phn mui n). Natri hydroxyd l d phm khi in phn mui n NaCl. nc ta acid hydrocloric v NaOH dung dch c sn xut ti Nh my ho cht Vit Tr.

Amoni hydroxyd, acid nitric c sn xut ti Cng ty ho cht, phn m Bc Giang.

Than v du m:

Cc hp cht thu c t than v du m l ngun nguyn liu quan trng nht ca cng nghip ho cht ni chung v cng nghip Ho dc ni

19

ring. Hu ht ho cht c bn ca cng nghip tng hp ho hc v cng nghip Ha dc l sn phm ca hai ngnh cng nghip chng ct than v chng ct du m.

Nguyn liu t than :

Xut pht t nhu cu cn c than cc luyn kim, cng nghip chng ct than bt u t th k XVI (1584). Sn phm chnh lc l than cc luyn kim. Ti cui th k XVIII, nn cng nghip ny sn xut c kh thp sng, s dng rng ri cho ti th k th XIX. Sau nh s pht trin ca cng nghip in lc, cc kh thu c khi chng ct than c chuyn sang dng lm nhin liu cho cc ngnh cng nghip v un nu trong gia nh. ng thi sn phm ca chng ct than c x l to ra nhng nguyn liu ho cht cho cc ngnh cng nghip ho hc (Hnh 1.1).

H O CH2CH2N(C2 H 5 ) 2 C C l 4

ClCH2CH2 O H C H C l 3

( H 2 , C H 4 , C O , C2H4, C2H2, C O 2 , N 2...)

Cc Ncamoniac

Nha Gudrng

Kh khngng t

Than

CCl 2 =CCl2C C l 4

ClCH2CH2 O H C H C l 3

( H 2 , C H 4 , C O , C2H4, C2H2, C O 2 , N 2...)

Cc Ncamoniac

Nha Gudrng

Kh khngng t

Than

CCl 2 2C C l 4

ClCH2CH2 O H C l C H 2 C H 2 C l C H C l 3

( H 2 , C H 4 , C O , C2H4, C2H2, C O 2 , N 2...)

Cc Ncamoniac

Nha Gudrng

Kh khngng t

Than

CCl 2

Pavatrin Thuc ho creozot

Dictyl phtalat Phenol Phtalein Phtalazol

Cresylas t trng

Aspirindn xutsalicylat

SulfamidXylocain Anestesin Novocain

DDS tr phong v dn xut

Vitamin PP Coramin

Rimifon

phtalic salicylicnilitxilen toluenbenzenQuinolin picolin Nitro Anhydrit AcidAcet-NitroCloro picolin

Fluoren Creozot Naphtalin CrezolPhenolAnilinXylen ToluenBenzenBase pyridin

Du Antracenic

Du nng Creozot

Du trung bnh phenolicB - re

Du nh " Naphta"

- -

tr ho

-


Dictyl Phenol Phtalein Phtalazol

Cresylas t trng



DDS Vitamin PP Coramin

Rimifon

phtalic salicylicnilitxilen toluenbenzenQuinolin picolin Nitro Anhydrit AcidAcet-NitroCloro picolin

Fluoren Creozot Naphtalin CrezolPhenolAnilinXylen ToluenBenzen

Du Antracenic

Du nng Creozot


Du nh " Naphta"

- -

tr ho

-


Dietyl- Phenol Phtalein Phtalazol

Cresylas t trng



DDS Vitamin PP Coramin

Rimifon

phtalic salicylicnilitxilen toluenbenzenQuinolin picolin Nitro Anhydrit AcidAceta-NitroCloro picolin

Fluoren Creozot Naphtalin CrezolPhenolAnilinXylen ToluenBenzen

Du Antracenic

Du nng Creozot


Du nh " Naphta"

- -

tr ho

-

Hnh 1.1. S tm tt sn phm chng ct than v kh nng s dng ca chng trong cng nghip Ho dc

20

Khi chng ct khan than trong ni kn ta c 3 phn:

Phn kh. Phn lng gm nha gurng v nc amoniac. Phn cn rn l than cc luyn kim. T 1 tn than, khi chng khan trong ni kn c th thu c 230-250 m3

kh kh ngng t; 65-70 kg nc amoniac (x l ly c 12 kg amoni sulfat dng lm phn bn); 60-65 kg nha gurng; 600-700 kg than cc dng luyn kim (theo Dupont).

T 1 tn than (theo Jukelson) c th thu c:

Benzen: 3,5 kg Naphtalin: 2,00 kg

Toluen: 1,5 kg Quinolin: 0,01 kg

Xilen: 0,7 kg Antracen: 0,15 kg

Phenol: 0,07 kg Carbazol: 0,02 kg

Cresol: 0,1 kg Pyridin: 0,02 kg

Phn kh kh ngng t, tnh theo th tch c khong trn 50% H2; 20-32% CH4; 5-8% CO, 0,5-2,2% ethan ...

Nguyn liu t du m: T du m qua x l, nh cng ngh Ho du cung cp cho cng

nghip ho cht (trong c cng nghip Ho dc) rt nhiu loi nguyn liu c bn.

Du m th cha nhiu loi hydrocarbon nh: parafin, cycloparafin v cc hydrocarbon thm. Du ca mi m c thnh phn ho hc khc nhau.

Ti nguyn du m Vit Nam rt phong ph. Tr lng cha c nh gi y , song theo c tnh ca mt s chuyn gia, c th ti hng t tn.

s dng du m vo cc ngnh cng nghip khc nhau, ngi ta phi ch bin bng cch chng ct trong cc nh my lc du.

Hnh 1.2, 1.3, 1.4, 1.5 tm tt mt s sn phm chnh t qu trnh chng ct du m v mt s qu trnh tng hp hu c t sn phm ca cng ngh Ho du.

21

Cht lm tng ch s octan trong xng du v lm dung mi

Lm dung mi v nguyn liu tng hp ho hc

Lm nguyn liu tng hp ho hc



Lm dung milm nguyn liu tng hp ho hc

Lm dung miv nguyn liu tng hp ho hc

t - Amyl methyl ether (TAME)Ethyl t -Buthyl ether (ETBE)

Methyl t - Buthylether (MTBE)

naftalenalkylbenzen

benzen

alkylacetylen

acetylen

isopentenisobutenisohexan

isobutanisopropan

butylenpropylenethylencyclohexan

cyclopentan

hexanpentanbutanpropanethanmethan

Ether

Aromatic

Isoparafin isoolefin

Olefin

Cycloparafin

Parafin

Du th

Ccacetylen

Hnh 1.2. Nhng sn phm chnh ca qu trnh chng ct du m

lm nguyn liu tng hp hu c

lm nguyn liu tng hp hu c

lm nguyn liu tng hp

lm dung mi

Lm dung mi v nguynliu tng hp ho

oxy ho

NH 3 O2+

nitro hoMethanC H 4

C + H2

CH CHCO + H2

H COOHC H2O

C H3OH

H C N

C H 3 NO2

C C l 4 C H C l 3C H 2 C lC H 3 C l

clo ho 2

Hnh 1.3. Tng hp cc nguyn liu hu c t kh metan

22

ClCH2CH2Cl

EthylenCH2 CH2

CH3CH2OH

CH2 CH2O

ClCH2 CH2OH

CH3CH2Cl

C6H5C2H5

CH3CH2CHO

CH3CH2COOH

CH3CH2NH2

Ho cht trung gian

Cht trung gian choho dc, ho hc

Ho cht trung gian

Dung mi v ho chttrung gian

Nguyn liu cho caophn t

Cht gy t

CHCl CH2

Hnh 1.4. Tng hp cc nguyn liu hu c t kh ethylen

SO 3H

Benzen

clo ho

sulfo ho

nitro ho

C H 2 CH2O

C l

N O 2

C H 2CH2OH

NaOH

P, t caooOH

O H

NaOH

300 Co OH

Fe/HCl NH2

CH2CH2I

Paracetamol aspirin

sulfamid, Mebendazol

Praziquantel

Hydroxyl ho

H2O2/HSO3F

Hnh 1.5. Tng hp cc nguyn liu hu c t benzen

Trong ngun nguyn liu du m, ngoi cc sn phm t cng nghip Ho du nh k trn, cn phi k ti thnh phn th hai l kh ng hnh. Thnh phn ca kh ng hnh v kh thin nhin ch yu l methan v ng ng, y cng l ngun nguyn liu qu. Ngoi vic s dng lm cht t, cn l nguyn liu cho cc nh my phn m, sn xut methanol, ethylen ...

23

4.2. Cc nguyn liu ng vt v thc vt

Nguyn liu ng vt:

Mt s ph tng, dch c th hay dch o thi ca ng vt c th c s dng sn xut ra thuc. V d: t tuyn tu sn xut c insulin, nc tiu nga ging l nguyn liu sn xut foliculin, t tuyn thng thn chit c adrenalin, cc acid mt l ngun sn xut mt s steroid, t phi b c th sn xut heparin, t tuyn gip ln sn xut c thyroxin...

Nguyn liu thc vt:

iu kin kh hu nhit i to cho nc ta mt ngun dc liu phong ph. Nhiu hot cht dng lm thuc c sn xut qui m cng nghip da trn ngun nguyn liu ny nh codein, vincamin, strychnin, rutin, berberin, rotundin, cc dn cht artemisinin...

Ngnh cng nghip Ho dc nc ta hin nay cha pht trin. S hiu bit v ngun nguyn liu ca ngnh ny gip chng ta nh hng nghin cu v sn xut. T c th t to ra mt s nguyn liu cho ngnh cng nghip Dc dn i vo qu o pht trin.

T lng gi

1. Trnh by v phn tch 4 c im ca cng nghip ho dc.

2. Vic nghin cu, sn xut thuc mi hin nay thng theo nhng xu hng no? Nu ni dung ca nhng xu hng .

3. Nu cc giai on cn thit thc hin a 1 thuc mi vo sn xut.

4. Trnh by cc ngun nghin liu ca cng nghip ho dc.

24

Chng 2

Nitro ho


1. Khi nim v c ch phn ng nitro ho.

2. Cc tc nhn ca qu trnh nitro ho.

3. Cc yu t nh hng n phn ng nitro ho.

4. Cc v d ng dng ca phn ng nitro ho.

1. i cng

Nitro ho l qu trnh ho hc nhm thay th mt hoc nhiu nguyn t hydro ca hp cht hu c bng mt hay nhiu nhm nitro (-NO2).

Phng trnh phn ng nh sau:

R-H + HNO3 R-NO2 + H2O Nitro ho l phn ng to lin kt C-NO2. Cc ester ca acid nitric vi

alcol (hp cht cha lin kt O-NO2) khng c xt n trong chng ny.

Cc hp cht nitro thng l cht lng hay tinh th mu vng hoc nu, mi hc c bit. Dn cht nitro c s dng lm dung mi, thuc th, thuc n. L trung gian quan trng trong nhiu qu trnh tng hp thuc v cc cht hu c. Trong thc t cng c mt s loi thuc cha nhm -NO2 nh cloramphenicol, furaxilin...

2. C ch phn ng nitro ho

Phn ng nitro ho c th xy ra theo 2 kiu c ch: Th i in t (SE) v th gc t do (SR), ph thuc bn cht cc cht c nitro ho v iu kin phn ng.

2.1. Th i in t (Electrophilic Substitution)

Khi nitro ho nhng hp cht thm bng hn hp sulfo-nitric thng xy ra theo c ch th i in t (SE). Phn ng thc hin pha lng v nhit

25

khng cao. Ion nitroni NO2+ l tc nhn i in t, c to thnh theo

phng trnh sau:

HNO3 + 2H2SO4 NO2+ + 2HSO4- + H3O+

Sau ion nitroni NO2+ tn cng vo nhn thm theo c ch th i in

t chung. Phn ng nitro ho xy ra theo hai giai on, trong giai on to phc (sigma) l giai on chm, quyt nh tc phn ng.

H2SO4 l xc tc to ion nitroni v to ra mi trng acid mnh ngn cn s phn ly ca HNO3 thnh H+ v NO3. Khi nng H2SO4 gim th tc phn ng nitro ho cng gim theo.

V d:

Khi nitro ho benzen 250C, nu nng acid sulfuric nh hn 80% th phn ng xy ra khng ng k. Nu nng acid sulfuric l 80-90% th tc phn ng tng ln 1000 ln.

Nhm th c sn trn nhn nh hng ng k n phn ng nitro ho theo qui lut:

Nhm th loi 1 lm tng qu trnh nitro ho v nh hng nhm -NO2 vo v tr ortho v para.

Nhm th loi 2 lm gim qu trnh nitro ho v nh hng nhm -NO2 vo v tr meta.

2.2. Th gc t do (Radical Substitution)

Khi nitro ho cc hp cht hydrocarbon no mch thng, ngi ta thng dng tc nhn l acid nitric long (30%-40%). Phn ng thc hin th kh, nhit cao (300-5000C) v xy ra theo c ch th gc t do:

H O N O 2 +OH NO2

R H + N O 2 + HNO2RR + H N O 3 RNO2 + OHR H + O H R + H2OR + H N O 3 ROH + NO2

R + N O 2 RNO2R + O H ROHO H + N O 2 HO NO2R + R R R

+ NO 2+

H NO 2

+

NO 2

+ H+

26

Ngoi sn phm chnh, cn thu c 1 hn hp cc sn phm ph gm alcol, hydrocarbon v 1 vi sn phm oxy ho t hydrocarbon.

3. Tc nhn nitro ho

3.1. Acid nitric (HNO3)

Dng tinh khit l cht lng trong, mi hc mnh, t0nc= -41,60C, t0s= 85,30C, d =1,502. un si hay lu ngoi nh sng b phn hu:

4HNO3 4NO2 + 2H2O + O2 Trong cng nghip thng gp cc loi nng 65-68% (d=1,42), 95%

(d =1,49, bc khi). Loi nng cao c th ng trong bnh thu tinh, snh hoc nhm. Loi nng thp c th ng trong bnh thu tinh, snh hoc thp khng g. Trnh nh sng.

Acid nitric l tc nhn nitro ho yu v b pha long bi nc to thnh trong phn ng. Mt khc, do c tnh oxy ho mnh, nn to nhiu tp cht l sn phm oxy ho cc hydrocarbon tham gia phn ng. Lng acid nitric dng cho phn ng nitro ho khong 1,5-2 ln so vi l thuyt.

3.2. Hn hp sulfo-nitric (H2SO4+ HNO3 + H2O)

khc phc nhng nhc im ca acid nitric, trong cng nghip ngi ta dng hn hp ca acid nitric v sulfuric (hn hp sulfo-nitric). Cation nitroni NO2

+ c to thnh theo phng trnh:

HNO3 + H2SO42 NO2 + HSO4 + H3O2

T l hn hp H2SO4 : HNO3 : H2O ph thuc bn cht ca cc hp cht c nitro ha:

Vi cc hp cht thm c kh nng phn ng cao (phenol, phenol-ether) ch cn dng dung dch HNO3 40%.

Cc hp cht thm c kh nng phn ng trung bnh (phn ln c nhm th loi 1, tr dn cht halogen) th nitro ho 1 mol, cn 1,5 mol HNO3 68% v 2,2 mol H2SO4 98%.

Cc hp cht thm c kh nng phn ng thp (cc cht c nhm th loi 2) th nitro ho 1 mol, cn 2,3 mol HNO3 95-100% (d =1,49-1,5) v 2,6 mol H2SO4 98%.

Trong cng nghip ngi ta thng pha sn hn hp sulfo-nitric c nng nh sau:

27

+ HNO3: 88% (loi 60-65 %, d=1,4) + H2SO4: 9,5% (loi monohydrat hay oleum 20 %) + H2O: 2,5 %

T l trn c th pha long thm tu . Mt khc, n c th ng c trong bnh thp thng, d vn chuyn.

u im ca loi tc nhn ny l:

Tc dng nitro ho mnh hn HNO3. Gim tc dng oxy ho ca HNO3 khi dng nng cao. Trnh to thnh dn cht polynitro.

3.3. Mui nitrat v acid sulfuric

y l tc nhn c s dng khi cn nitro ho trong mi trng khan nc, thng c s dng iu ch cc dn cht polynitro.

2NaNO3 + H2SO4 2HNO3 + Na2SO4 3.4. Acylnitrat (AcONO2)

L tc nhn nitro ho mnh, dng nitro ho cc cht d b phn hu bi nc hoc acid v c. Tc nhn ny khng cha acid v c, sn phm ph ca phn ng l acid acetic.

(CH3CO)2O + HNO3 CH3COONO2 + CH3COOH

+ CH3COONO2

NO2

+ CH3COOH

Khi dng tc nhn ny nitro ho cc amin thm, ng thi vi qu trnh nitro ho nhm amin cng c bo v.

4. Cc yu t nh hng n phn ng

4.1. nh hng ca nhit

Nitro ho l qu trnh to nhit mnh. Lng nhit ny bao gm nhit phn ng v nhit pha long acid sulfuric bi nc to thnh trong phn ng.

NH2 NHCOCH3NO2

Ac2O/HNO3

28

Tc v hiu sut phn ng ph thuc nhiu vo nhit . Nhit ti u ca phn ng ph thuc vo bn cht cc cht c nitro ha (thng bin i t -100C n 5000C). Vi cc hydrocarbon no mch thng, thng tin hnh 170-5000C (phn ng theo c ch gc t do). Cn khi nitro ho cc hydrocarbon thm, th lng th tin hnh nhit thp hn (-10 n 1700C). Nhit cao sinh ra nhiu tp cht do phn ng oxy ho, v vy b phn trao i nhit ca thit b nitro ho phi hiu qu trnh hin tng qu nhit.

4.2. Tc dng ca khuy trn

Phn ng nitro ha thng l d pha: pha hu c (cc cht cn nitro ho) v pha acid (tc nhn nitro ho). V vy cn phi khuy trn mnh tng tip xc v trnh qu nhit cc b.

4.3. Dung lng kh nc

Trong qu trnh nitro ho, nc c to ra lm gim nng acid sulfuric. Phn ng s t ti cn bng khi nng acid gim ti mt gii hn nht nh. Mi cht khc nhau gi tr gii hn cng khc nhau. i lng c trng cho gi tr gii hn ca mi cht c gi l dung lng kh nc ca cht . Dung lng kh nc (D.L.K.N.) c tnh theo cng thc sau:

% H 2 SO4 a vo phn ng

% H 2 O ban u + % H2O do phn ng sinh ra D.L.K.N. =

Bit c D.L.K.N. ca mi cht c th tnh c lng acid sulfuric cn dng pha hn hp sulfo-nitric khi nitro ha cht . V d D.L.K.N ca mt s hp cht hu c nh sau: nitrobenzen: 7,4; clorobenzen: 4,4; benzen: 3,5; toluen: 2,4; naphtalen: 2,0.

5. Cch tin hnh phn ng

Nitro ho cc hp cht thm tin hnh pha lng theo nguyn tc sau:

Cht cn nitro ha c lm lnh xung di 100C. Va khuy, va nh git tc nhn nitro ha vo vi tc sao cho nhit phn ng khng vt qu 100C. Cc hp cht c kh nng phn ng cao th khuy thm 30 pht nhit phng, cc cht kh nng phn ng trung bnh th khuy thm 2-3 gi, cc cht kh nng phn ng km th 3-5 gi. Trng hp cn thit c th lm nng phn ng kt thc.

hn hp phn ng vo nc , khuy k. Nu sn phm l cht rn th lc, ra li vi nc, sau kt tinh li trong dung mi thch hp. Nu sn phm th lng th chit hn hp phn ng vi ether hoc dicloromethan, ra dch chit, lm khan v ct loi dung mi. Sn phm c tinh ch bng ct phn on.

29

Vi cc hp cht mch thng th qu trnh nitro ha thng tin hnh pha hi, nhit cao, trong thit b lin tc. Sau hn hp phn ng c ngng t, phn lp v ra li bng nc. Trung ha bng dung dch natri bicarbonat, lm khan v cui cng l ct phn on.

6. Nitrozo ha

Nitrozo ha l qu trnh a nhm -NO vo hp cht hu c. y l phn ng gia hp cht thm c cha nhm th hot ha nhn mnh (-OH, -NR2...) vi acid nitr. Nitrozo ho cng l phn ng th i in t, tc nhn i in t l ion nitrozoni NO+. Phn ng tin hnh nhit thp (

30

Phng php lin tc c tin hnh theo s sau:

c

)

O

O

U

U

U

U

1 2

3

4

5

6

78

9

10

Nitrobenzen

1,2. Bnh ong.

3. Ct nitro ho.

4. Sinh hn.

5,7. Bnh tch.

6. B phn ct.

8. Ct ct.

9. Bm.

10. Bnh ho hi.

Hnh 2.1. S thit b iu ch nitrobenzen theo phng php lin tc

Acid nitric 61% t bnh ong 1 c ho hi trong thit b s 10 ri a vo thp nitro ho 3. Ti y, phn ng vi benzen (c a xung t bnh ong 2). Hn hp phn ng khong 72-780C c a xung bnh 6, tch ly 1 phn benzen a li phn ng. Sau hn hp phn ng tip tc c dn vo ct ct 8. Ct ly hn hp acid v benzen cn li (1180C) a li phn ng v thu sn phm nitrobenzen khng bay hi (im si 2080C).

8.2. Tng hp thuc h nhit, gim au paracetamol

Paracetamol l thuc h nhit gim au, c tng hp t phenol. Qu trnh iu ch gm nhng giai on sau:

Nitro ho phenol bng hn hp sulfo-nitric thu c hn hp hai ng phn o-nitro-phenol v p-nitro-phenol. Tch ring hai ng phn ny bng phng php ct ko hi nc.

Kh ho p-nitro-phenol bng Fe/HCl hoc Na2S/NaOH thu c p-amino-phenol.

Acyl ho p-amino-phenol bng Ac2O c paracetamol. S phn ng nh sau:

31

T lng gi

1. Th no l qu trnh nitro ho? C ch phn ng nitro ho gm my loi, iu kin v ni dung ca mi loi c ch l g?

2. C bao nhiu loi tc nhn ca qu trnh nitro ho? K tn v trnh by ni dung ca mi loi ?

3. C nhng yu t no nh hng n phn ng nitro ho? Ni dung nh hng ca chng l g?

4. Trnh by nguyn tc chung ca cch tin hnh cc phn ng nitro ho.

5. Nitrozo ho thng xy ra vi nhng nhm hp cht no? Tc nhn ca chng l g?

6. Hy nu nhng iu cn c bit ch v an ton lao ng trong qu trnh thc hin phn ng nitro ho?

7. Trnh by phng php sn xut nitrobenzen v phng php tng hp paracetamol trong cng nghip?

OH OH

NO2

OH

NO2OH

NO2

OH

NH2

OH

NHCOCH3

+HNO3/H2SO4

Na2S/H2O Ac2O/AcOH

32

Chng 3

Sulfo ha


1. Khi nim v c ch phn ng sulfo ho.

2. Cc tc nhn ca qu trnh sulfo ho.

3. iu kin ca phn ng sulfo ho.

4. Phm vi ng dng, cch tin hnh phn ng v phn lp sn phm ca qu trnh sulfo ho.

5. Cc v d ng dng ca phn ng sulfo ho.

1. i cng

Sulfo ha l mt qu trnh ha hc a nhm sulfonyl (-SO3H) vo mt hp cht hu c.

R-H R-SO3H Chng ny ch nghin cu phn ng a nhm sulfonyl vo hp cht

hu c mt cch trc tip bng phn ng th hoc phn ng cng. Sulfo ha l qu trnh to lin kt C-S. Cn phn bit vi cc qu trnh sulfat ho (nhm -SO3H gn vi oxy) hoc sulfamic ho (nhm -SO3H gn vi nit). V d:

C H 3 C H 2 S O3H C H 3 CH2 OSO3H CH3 C O N H S O 3 H Acid ethyl sulfonic Ethyl sulfat Acid ethyl sulfamic

Danh php ha hc mt s nhm hp cht hu c cha lu hunh:

R-SO2H : acid sulfinic (acid alkyl sulfinic)

R-SO3H : acid sulfonic (acid alkyl sulfonic)

R-SH : mecaptan (alkyl mecaptan)

R2SO : sulfoxit (dialkyl sulfoxit)

R2SO2 : sulfon (dialkyl sulfon)

R-SR : thioether (dialkyl thioether).

33

SO2RHN NHR

Cc hp cht sulfonic c ng dng rt rng ri. Trong dc phm, vic a nhm sulfonyl vo phn t thuc lm tng ha tan ca n trong nc, thun tin cho vic bo ch cc dng thuc c hiu lc nhanh. V d B.A.L (2,3-dimecapto-propanol) chng ng c thy ngn, asen l dng thuc tim trong du. Nu chuyn thnh sulfonat natri (unithiol), c th pha dung dch nc tim.

CH2 CH CH2OH

SH SH

CH2 CH CH2SO3Na

SH SH (B.A.L.-thuc tim/du) (Unithiol)

a nhm SO3H vo phn t thuc cn l bin php lm gim c tnh ca thuc. V d nhm thuc tr lao, phong: diamin-diphenylsulfon (DDS) rt t tan v rt c, khi chuyn thnh cc dn cht sulfonat l Promin, Sunfetron, Baludon, th d tan hn v t c hn.

R Tn thuc -H D.D.S

CH (CHOH)4 CH2OHSO3Na

Promin

CH CH2 CHSO3Na

C6H5SO3Na

Sunfetron

CH CH3SO3Na

Baludon

Trong tng hp ha hc: Cc hp cht sulfonic c tnh phn ng mnh, c th thay th bng nhng nhm khc nh -OH, -H, -NH2, -Cl, -NO2, -SH, -CN, ... Cc alkyl ester ca sulfonat l nhng tc nhn alkyl ha tt (v d: methyl, ethyl ca benzen sulfonat hoc p-toluen-sulfonat).

Trong k ngh x phng, sulfonat ca cc hp cht mch thng c s carbon cao c dng lm cht din hot b mt.

2. C ch phn ng

Cng tng t nh qu trnh nitro ho, sulfo ho c th xy ra theo c ch th i in t (SE) hoc th gc t do (SR), ph thuc vo bn cht cc cht c sulfo ho, tc nhn v iu kin phn ng.

34

2.1. Phn ng th i in t (Electrophilic Substitution)

Xy ra khi sulfo ha cc hp cht thm vi tc nhn l acid sulfuric. Tc nhn i in t l SO3 c sinh ra theo phng trnh sau:

H2SO4 H3O + HSO4 + SO32

Tc nhn SO3 tn cng vo nhn thm to thnh phc dng lng cc. Sau c s chuyn v ca proton to thnh dn cht sulfonic:

2.2. Phn ng th gc t do (Radical Substitution)

Khi sulfo ho cc hydrocarbon no, mch thng nhit cao, xc tc nh sng v tc nhn l hn hp kh SO2 v Cl2.

Cl2as

2 Cl

Cl + RH R + HCl

R + SO2R RSO2

+ Cl2SO2R SO2ClR + Cl

3. Tc nhn sulfo ha

3.1. Trioxyd lu hunh (SO3) v cc phc hp ca n

3.1.1. Trioxyd lu hunh (SO3)

SO3 tn ti nhiu dng. Dng monome th hi, dng l trime ca SO3 th lng (nng chy 16,8

0C), dng l polime ca SO3 th rn (nng chy 32,50C); dng l polime ca SO3 th rn c nhit nng chy cao hn (62,30C).

(n>n) Dng hay c s dng trong cng nghip. Dng v t c s dng

do kh thao tc. Dng ny khi chng ct thu c khong 90% trime (dng )

+ SO3

H

SO3SO3H

+

O S O

O

S O

S OS

O O

O

O

O

O O

SO

OO O S

O

OO S

O

O n ( m on om e ) (trime) (polyme)

35

v 10% SO3 monome. SO3 monome trong khng kh, nhit thng sau vi gi s chuyn sang dng v . ngn cn qu trnh chuyn dng k trn ngi ta cho thm xc tc l bor trioxyd, bor, lu hunh hoc phospho.

SO3 l tc nhn sulfo ha mnh, gim tc phn ng v ngn cn cc phn ng ph (than ha, sulfo ho nhiu ln), thng phi pha long n vi dung mi nh SO2, CCl4 hoc dicloromethan.

3.1.2. Cc phc hp ca SO3

a. Cc dng hydrat ca SO3

SO3 to vi nc thnh nhiu dng hydrat. Trong cc dng hay c s dng sulfo ho l acid pirosulfuric, acid sulfuric v acid sulfuric monohydrat.

Acid sulfuric monohydrat SO 3.H 2O Acid sulfuricAcid pirosulfuric

SO

OH OHHO

HOSO

O OH

OHS O O

O S

OO

OHOH

H 2S O 4.H 2O S O 3 H 2O 2 1 Ngoi ra, lu hunh trioxyd cn tn ti di cc dng phc hp vi 3 v 5

phn t nc. iu ny l gii ti sao acid sulfuric rt ho nc:

SO3.3H2O SO3.5H2O

(H2SO4.2H2O) (H2SO4.4H2O)

trihydrat pentahydrat

74,1% H2SO4, c = 26,70C 57,6% H2SO4, c = 250C nhit thp, cc dng

hydrat trn bn vng. B phn hy nhit cao (4500C th phn hy hon ton thnh nc v SO3).

Oleum l dung dch ca SO3 trong acid sulfuric 100%. Trong thc t, cc qu trnh sulfo ha thng dng oleum. Hai loi oleum hay dng c nng 20% v 65%. Cc nng khc d b kt tinh nhit thp, gy kh khn cho thao tc trong qu trnh sulfo ha.

-

-

-

--

-

-

-+ + + + +

20

40

0

60 80 100 % SO34020

t0 C0( )

H2SO4

Hnh 3.1. S ph thuc gia nhit nng chy ca cc dng SO3 hydrat vo nng ca n

36

Hin tng ny c gii thch bng biu hnh 3.1.

b. Cc phc hu c ca SO3

Nguyn t lu hunh trong phn t SO3 c kh nng nhn in t. Do n d to phc vi mt s hp cht hu c c i in t t do.

Cc phc ca SO3 vi dioxan, thioxan, pyridin v amin bc 3 hay c s dng. Chng c dng sulfo ha nhng hp cht hu c d b ph hy bi acid hoc hn ch tc ca phn ng sulfo ha.

N

R1NR2

R3

OO

OS S OSO3

SO3

SO3 SO3

SO3

SO3OO SO3SO3

3.1.3. Cc acid halogen sulfuric

Acid clorosulfuric l tc nhn quan trng nht ca nhm ny. Acid fluorosulfuric v t nn ch dng trong cc trng hp c bit. Dng acid clorosulfuric sulfocloro ha khng cn nhit cao, sn phm tinh khit hn khi dng acid sulfuric hoc oleum. Acid clorosulfuric c dng nhiu trong sn xut cc sulfamid.

A r H C l SO3H ArSO2OH HCl

ArSO2Cl H2SO4

+ +

A r S O 2 O H + ClSO 3 H +

A r H + ClSO3H2 ArSO2Cl + H2SO4 + HCl

3.1.4. Acid sulfamic (NH2-SO3H)

Acid sulfamic c acid mnh nh H2SO4. Trong sulfo ha hoc sulfat ho, n tc dng nh phc hp amin SO3, nhng khc vi phc amin SO3 l n dng c trong mi trng khan nc v nhit cao. Thng dng sulfo ho cc hp cht thm khng no (stirol) v phenol.

C6H5-CH= CH2 + NH2-SO3H C6H5 CH = CH-SO3H + NH3

37

3.2. Cc dn cht ca SO2

3.2.1. Cc mui sulfit, bisulfit

Dng iu ch cc sulfonat ca hydrocarbon mch thng t dn cht halogen tng ng (phn ng Strecker). Phn ng xy ra theo c ch th i nhn.

R-X + Na2SO3 R-SO3Na + NaX Cc dn cht halogen thm ch tc dng c vi mui sulfit hoc bisulfit

nu trn nhn thm c nhm NO2 v tr ortho hoc para.

3.2.2. Sulfonyl clorid (SO2Cl2)

sulfo-cloro ha cc alkan, cycloalkan, arakan, ngi ta dng SO2Cl2 c mt base yu (pyridin).

3.2.3. Hn hp kh SO2 v Cl2

Dng hn hp kh SO2 v Cl2 sulfocloro ho cc parafin. Phn ng xy ra theo c ch gc t do di tc dng ca nh sng.

4. iu kin ca qu trnh sulfo ha

Phn ng sulfo ha l phn ng thun nghch:

Ar-H + H2SO4 Ar-SO3H + H2O

chuyn cn bng v pha phi thng dng lng H2SO4 (tnh ra nng SO3) tha khong 2-5 ln.

Trong qu trnh phn ng, nng H2SO4 gim dn do b tiu th to nhm -SO3H v b pha long bi nc to thnh. Tc phn ng cng gim dn v n mt gii hn no th ngng. Ngi ta gi gii hn nng H2SO4 m phn ng sulfo ha khng xy ra na l pisulfo ha (-sulfo ha). Gi tr ph thuc vo nguyn liu em sulfo ha v nhit thc hin phn ng. Pisulfo ha c biu th bng nng ca SO3 trong hn hp phn ng.

V d: -sulfo ha benzen nhit 600C l 66,4. -sulfo ha naphtalen l 56 ( 600C) v 52 ( 1600C). -sulfo ha benzen l 66,4 c ngha l khi nng SO3 trong hn hp

phn ng gim xung 64,4% (tnh ra nng H2SO4 l 66,4 : 0,8164 = 81,3%) th khng th to ra sn phm benzen sulfonic na.

Khi bit gi tr -sulfo ha ca mt cht mt nhit no ta c th tnh c lng SO3 phn ng c thc hin hon ton. Trong thc t, lng H2SO4 cn thit sulfo ha 1 kmol hp cht hu c c tnh nh sau:

38

=

aX )100(80

Trong : X: s kg H2SO4 cn tnh.

a: nng ban u ca SO3 trong tc nhn sulfo ha.

: gi tr sulfo ha ca cht hu c nguyn liu. (H2SO4 100% c nng SO3 l 81,64%)

T cng thc trn ta thy cht no c gi tr -sulfo ho nh th cng d phn ng.

5. Kh nng ng dng ca phn ng

5.1. Sulfo ha cc hp cht mch thng

Cc hydrocarbon no mch thng khi sulfo ha vi H2SO4 to ra nhiu tp do cc phn ng oxy ho v ng phn ho. Do trong cng nghip ngi ta thng dng tc nhn SO2Cl2 th kh theo c ch th gc (SR).

Nhiu dn cht sulfonic ca hp cht mch thng c iu ch t cc halogenid tng ng ca n bng phn ng Strecker (nung alkyl halogenid vi mui natri hoc amoni sulfit).

R-X + Na2SO3 R.SO2ONa + NaX R-X + (NH4)2SO3 RSO2ONH4 + NH4X X = halogenid

Cc olefin khi tc dng vi acid sulfuric to thnh alkylsulfat theo c ch cng hp Marconyikov:

R CH CH2 + H2SO4 R CH CH3OSO3H

Acid hu c mch thng d dng sulfo ho vi oleum to ra acid -sulfo-carboxylic.

R CH2 COOH + SO3 R CH COOH

SO3H Vi acid clorosulfonic cng to ra acid -sulfo-carboxylic.

R CH2 COOH + ClSO2OH R CH COOH

SO3H

39

5.2. Sulfo ha cc hp cht thm

Khc vi cc hp cht mch thng, cc hp cht thm d sulfo ha hn nhiu. Ch cn nhit thp v nng acid sulfuric khong 65-100% cng c th sulfo ha c. Phn ng xy ra theo c ch i in t.

Benzen c sulfo ha vi H2SO4 98% 800C cho acid benzen sulfonic. Nu tip tc sulfo ho 2200C cho dn xut disulfonic v 3000C cho trisulfonic.

Naphtalen khi sulfo ha vi H2SO4 nhit khc nhau th cng cho cc sn phm khc nhau.


6.1. Sulfo ha cc hp cht thm

Thng thng cht phn ng c ha tan trong cc dung mi thch hp (cloroform hoc tetraclorocarbon). Sau va khuy, va cho tc nhn sulfo ha (theo tnh ton) vo khi phn ng vi vn tc sao cho gi c phn ng nhit cn thit (t -100C n 1500C tu cht tham gia phn ng). Sau khi phn ng kt thc, lm ngui v va khuy va t t hn hp phn ng vo nc . Khuy k v tin hnh tch sn phm t khi phn ng.

6.2. Sulfo ha cc hp cht mch thng

Thng c thc hin th kh, nhit cao, tc nhn l hn hp SO2 + Cl2. Khi phn ng khi ra khi thp sulfo ha c ngng t. Sau , dch ngng t c cho t t vo nc v phn lp.

S O 3 H SO3H

SO3H

S O 3 H

S O 3 H HSO3

H2SO4/800C 300

0CH2SO4/2200C

S O 3HS O 3H SO3H

S O 3 H

+ H2SO4

1600C400 C

9 6 4 15 85% % % %

40

7. Tch cc acid sulfonic t hn hp phn ng 7.1. Tch bng mui n

Mui kim ca acid sulfonic tan tt trong nc nhng li t tan trong dung dch mui. Do c th dng mui n to dung dch bo ha y sulfonat kim ra khi dung dch ca n.

7.2. Tch bng cch to mui vi kim loi kim th

Da trn kh nng ha tan khc nhau ca mui sulfonat vi kim loi kim th.

V d: Khi trung ha vi nc vi trong, ng phn naphtalen-2-sulfonat calci tch ra khi dung dch v kh nng ha tan ca n km ng phn naphtalen-1-sulfonat calci.

7.3. Tch bng nc

Mt s acid sulfonic a vng t tan trong nc. V vy khi hn hp phn ng ca chng vo nc , chng c tch ra. Lc v thu sn phm.

8. Mt s v d

8.1. iu ch acid benzensulfonic

Benzen c phn ng vi acid sulfuric 100% trong thit b sulfo ha (1). Acid benzensulfonic to thnh c chit bng nc hoc dung dch NaOH trong thit b chit (2). Benzen cha phn ng c lm khan trong thit b (3) v c a tr li phn ng.

Kh SO3 c dn vo thit b sulfo ho m bo nng H2SO4 lun t 100%.

H2S O 4 100%

S O 3

Benzen

Nc hoc dd xt

Acid benzensulfonic

1

2

3

Hnh 3.2. S thit b iu ch acid benzensulfonic theo phng php lin tc

41

8.2. Sn xut cc thuc sulfamid

Acyl ha anilin thu c acetanilid. Acetanilid tc dng vi acid clorosulfuric thu c p-acetylamino-benzen-sulfonyl clorid. Phn ng ca sulfonyl clorid vi amin tng ng to ra dn xut sulfonamid. Cui cng l thy phn loi nhm acetyl thu c sulfamid tng ng. Phng trnh cc giai on phn ng nh sau:

NH2

A c N H S O 2 Cl

AcNH S O 2 Cl A c N H H

H 2 NR'+

CS O 3 H+

SO 2 NHR' SO 2 NHR'

SO 2 NHR'

A c N H

AcNH

AcNHN H 2 + ( C H 3 C O ) 2 O

- hay OHH

t lng gi

1. Qu trnh sulfo ho l g? Mc ch ca n?

2. C ch phn ng sulfo ho gm my loi, iu kin v ni dung ca mi loi c ch ?

3. Tc nhn ca qu trnh sulfo ho gm c nhng loi no? Hy trnh by chi tit ni dung ca mi loi ?

4. Trnh by hiu bit ca anh (ch) v iu kin ca qu trnh sulfo ha? Phn ng sulfo ho thng c ng dng trong cc nhm hp cht no?

5. Trnh by phng php chung tin hnh cc phn ng sulfo ho.

6. Hy nu cc phng php ch yu dng tch cc acid sulfonic t hn hp phn ng sulfo ho?

7. Trnh by phng php sn xut acid benzensulfonic v phng php chung tng hp cc sulfamid?

42

Chng 4

Halogen ha


1. Khi nim v c ch phn ng halogen ho.

2. Cc tc nhn ca qu trnh halogen ho.

3. Cc v d ng dng ca phn ng halogen ho.

1. i cng

Halogen ha l qu trnh ha hc nhm a 1 hay nhiu nguyn t halogen vo hp cht hu c. Ty bn cht halogen m ngi ta gi qu trnh ny l fluoro ha, cloro ha, bromo ha hoc iodo ha.

a halogen vo phn t hu c nhm cc mc ch sau:

To hp cht trung gian c tnh phn ng cao cho cc qu trnh tng hp ho hc. T dn cht halogen, c th thay th bng cc nhm -OH, -OR, -CN, -NH2 to nn hp cht mi. Mt s dn cht halogen c dng lm tc nhn alkyl ho (CH3I, C2H5Br), tc nhn acyl ho (R-COCl).

To ra cc hp cht c tnh ng dng cao hn. Nhiu dn cht halogen hu c c dng lm dung mi (dicloromethan, cloroform, tetraclorocarbon...).

Nhiu ho dc l hp cht cha halogen (thuc st trng CHI3, thuc ho CHBr3, thuc cn quang cha iod Urokon, thuc li tiu clorthiazid ...). Cc dn cht cha fluor c u im l bm chc vo h enzym ca c th. Do nhiu thuc cha fluor c thi gian bn thi di v tc dng mnh (thuc st rt mefloquin, cc quinolon khng khun peflacin, ciprofloxacin).

Qu trnh to dn xut halogen c th dng cc phng php sau:

1. Th hydro hay nhm nguyn t khc bng halogen.

2. Cng hp halogen vo lin kt kp ca phn t hu c.

43

2. C ch phn ng

2.1. Halogen ho theo c ch ion

Thng xy ra nhit thp (150-2000C) vi xc tc l cc cht to ion (acid, base, mui kim loi).

2.1.1. Th i in t (Electrophilic Substitution)

Phn ng ny c th thay th mt hay nhiu nguyn t H ca nhn thm bng mt hoc nhiu nguyn t halogen. Xc tc cho qu trnh l acid Lewis (FeCl3, AlCl3):

2.1.2. Cng hp i in t (Electrophilic Addition)

Phn ng cng hp ca halogen, acid hydro-halogenid v acid hypohalogenid vo olefin nhit thp v trnh tc dng ca nh sng xy ra theo c ch cng hp i in t. Xc tc acid Lewis (FeCl3, AlCl3) c tc dng lm phn cc halogen v acid hydro-halogenid, to ra tc nhn i in t.

CH2 CH2 + Br2 C CBr H

H

H

H+ Br CH2 CH2

Br Br

Phn ng cng HX vo olefin khng i xng tun theo nguyn l Markonyikov:

CH CH2CH3 + HBr CH3 CH CH3Br

CH CH3CH3Br

Nu c nhm ht in t mnh lin kt vi olefin th sn phm cng hp

ngc vi nguyn l Markonyikov:

Br+CH CH2CF3 CH2 CH2CF3HBr CH2BrCH2CF3

Cl2 + F e C l 3 Cl+ + (FeCl4)-

C l Cl H Cl

C l + C l + + H+H + -

H + + (F e C l 4 ) -

HCl + FeCl3

44

2.1.3. Th i nhn (Nucleophilic Substitution)

Khi cc alcol tc dng vi cc acid hydro-halogenid:

R-OH + HX R-X + H2O Phn ng xy ra qua ba giai on v c gii thch nh sau:

H-X H+ + X-

RBr+- Br+R

H2O++RR O H

H

+H+ROH

2.2. Halogen ho theo c ch gc

Phn ng halogen ha xy ra theo c ch gc t do khi c tc dng ca nh sng, nhit cao hoc xc tc to gc t do (peroxyd).

2.2.1. Phn ng th gc hydrocarbon no mch thng

Phn ng th H cc hp cht parafin hoc H trn mch nhnh cc hp cht thm nhit cao, xc tc nh sng. Qu trnh xy ra qua ba giai on:

To gc t do: Di tc dng ca nh sng hay nhit cao (3000C). Cl2 Cl2

Gc t do tham gia phn ng vi hydrocarbon to chui phn ng dy chuyn:

Cl2R CH2 R CH2Cl Cl+ +Cl R CH3+ + HClR CH2

Cc gc t do phn ng vi nhau, kt thc qu trnh:

Cl2

R CH2 CH2 RR CH22

+R CH2 Cl R CH2Cl

Cl + Cl

45

2.2.2. Phn ng cng hp halogen vo hydrocarbon thm

Di tc dng ca nh sng, clor v brom c th cng hp vo nhn thm theo c ch gc t do:

Cl

Cl

Cl

Cl

Cl

Cl

Cl+Cl

ClCl2

Cl

Cl

Cl2Cl2as

2.2.3. Phn ng cng hp halogen vo olefin

Phn ng cng hp halogen phn t vo olefin di tc dng ca nh sng thng xy ra theo c ch gc t do.

Trong s cc hydro-halogenid th ch HBr di tc dng ca peroxyd cng hp vo olefin theo c ch gc t do. Cn HCl v HF do nng lng lin kt H-X ln, kh c kh nng tch thnh gc t do tham gia phn ng ny.

+CH CH2CH3H2O2HBr CH3 CH2BrCH2

3. Tc nhn halogen ha

3.1. Cc halogen phn t

Clor l kh mu vng lc, d=2,49, ho lng -34,50C. Trong cng nghip clor c s dng kh ph bin, thng c ng trong bnh thp di dng lng. Clor phn t c s dng clor ha cc hp cht thm theo c ch th i in t. N cng c dng clor ha cc hp cht hydrocarbon no bng phn ng th gc vi xc tc l nh sng v nhit cao. Ngoi ra cn dng cng hp vo cc lin kt kp. Clor l mt kh rt c.

Brom l cht lng mu nu sm, d bay hi, d=3,1, si 590C. C th ng trong bnh thu tinh. Dng halogen ho ging nh clor.

Iod l tinh th mu tm sm, nng chy 1130C, t khi c s dng v kh nng phn ng km.

Fluor l kh mu lc, ho lng -1880C. N hu nh khng th s dng c fluor ha trc tip v phn ng qu mnh lit. Hp cht fluor phi iu ch bng phng php gin tip (qua mui diazoni hoc dng phn ng thay th halogen).

46

3.2. Cc acid hydro-halogenid

Gm HCl, HBr, HI v HF. Thng dng cng hp vo cc lin kt kp ca hydrocarbon khng no theo c ch phn ng cng hp, hoc th nhm -OH alcol bng halogen theo c ch th i nhn.

3.3. Cc hipohalogenid v mui ca chng

Cc hp cht ny l HOCl, NaOCl. Cng hp vi ethylen to ethylenclorhydrin l nguyn liu quan trng tng hp metronidazol.

CH2 = CH2 + HOCl HO-CH2-CH2-Cl c bit khi cho phenol tc dng vi NaOCl th ch to thnh ng phn

ortho:

Mt ng dng kh quan trng ca NaOCl l clor ha cc sulfamid

iu ch cc cht st trng (cloramin T).

3.4. Cc clorid acid v c

Nhm ny c SOCl2, SO2Cl2, COCl2, PCl3, POCl3, PCl5. Chng tn ti dng rn hoc lng, rt nhy cm vi nc. Thng c dng iu ch clorid acid t cc acid carboxylic tng ng.

3.5. Cc mui ca halogen vi kim loi kim

Nhm ny gm NaF, NaCl, NaBr, NaI. Thng c dng chuyn ha cc sulfon ester, cc mui hydroclorat ca amin thnh dn xut halogen:

R O SO3H + NaF RF + NaHSO4R NH2.HCl + NaF RF + NaCl + NH3

hoc thay th clor thnh iod.

OH + NaOCl OH

Cl

+ NaOH

SO2NH2R+ NaOCl SO2NNaCl

R

47

CH2 CH CH2Cl OH Cl

+ 2NaI 2NaClCH2 CH CH2I OH I

+

3.6. Cc tc nhn halogen ha khc

l S2Cl2, SbF3, N-brom-succinimid. S2Cl2 c ng dng trong cng nghip sn xut tetraclorid carbon:

CS2 + 2S2Cl2 CCl4 + 6S

Vi SbF3 ngi ta c th iu ch c cc dn xut fluor t cc dn xut clor tng ng:

CF3CCl3 SbCl3+130C

SbF3+o

4. Mt s v d

4.1. Clor ho toluen

Tu xc tc v iu kin phn ng, c th to thnh cc sn phm khc nhau. Clor ho nhit si ca toluen, vi tc dng ca nh sng, phn ng xy ra th hi theo c ch gc t do. Sn phm l benzylclorid, benzyliden-clorid v benzylidinclorid.

CH3

Cl2/as

t0

CH2Cl

Cl2/as

t0

CHCl2

Cl2/as

t0

CCl3

Cn nu clor ho nhit phng vi xc tc l FeCl3 th thu c sn phm l cc dn xut clor th trn nhn.

CH3 CH3ClCl2

FeCl3+

CH3

Cl

4.2. iu ch cht cn quang Urokon

Urokon c s dng khi chp cn quang ng mt. N c iu ch t N-acetyl-meta-amino-benzoic theo phng trnh sau:

48

CH3COOH+

COOH

II

I

NHCOCH3

COOH

NHCOCH3

ICl3

t lng gi

1. Th no l qu trnh halogen ho? Mc ch ca qu trnh ny l g?

2. C ch phn ng halogen ho c phn lm my nhm? iu kin xy ra v cc v d ca mi loi c ch?

3. Trnh by cc loi tc nhn ca qu trnh halogen ho?

4. Nu cc v d ng dng ca qu trnh halogen ho trong tng hp hu c v ho dc.

49

Chng 5

Alkyl ha


1. Khi nim v cc tc nhn ca qu trnh alkyl ho.

2. Cc loi phn ng alkyl ho.

3. Cc yu t nh hng n phn ng alkyl ho.

4. Cc v d ng dng ca phn ng alkyl ho.

1. i cng

Alkyl ha l qu trnh thay th mt hoc nhiu nguyn t hydro ca hp cht hu c bng mt hoc nhiu nhm alkyl.

Nhm alkyl c th lin kt trc tip vi carbon, oxy, nit, hoc lu hunh, tng ng ta c cc qu trnh C-alkyl ha, O-alkyl ha, N-alkyl ha hoc S-alkyl ha.

C-alkyl ha:

Mc ch ko di mch carbon ca phn t hu c. V d trong tng hp cc dn cht ester ca acid malonic lm trung gian cho tng hp cc thuc chng ng kinh nhm barbituric.

O-alkyl ha:

Alkyl ha cn thu c cc ether, cn alkyl ho acid carboxylic thu c cc ester tng ng.

R-OH + ROH R-OR + H2O ether R-ONa + RX R-OR + NaX

H2CCOOC2H5

COOC2H5

NaOC2H5 NaCHCOOC2H5

COOC2H5

RXR CH

COOC2H5

COOC2H5

50

R-COOH + ROH R-COOR + H2O ester

R-COONa + R-X R-COOR + NaX

N-alkyl ha:

Sn phm ca phn ng l cc amin.

S-alkyl ha:

Sn phm ca phn ng l thioether.

R-X + NaSH R-SH R-S-R Qu trnh alkyl ha c s dng nhiu trong k thut tng hp ha

dc. Nhiu thuc quan trng l sn phm ca qu trnh alkyl ha (codein, antipyrin, analgin...)

2. Cc tc nhn alkyl ha

2.1. Cc alcol (R-OH)

Methanol v ethanol l nhng tc nhn alkyl ha quan trng. Hu nh trong mi trng hp alkyl ha, phi s dng acid v c lm xc tc.

Alcol thng dng alkyl ha cc amin hoc alcol khc. Sn phm l cc amin hoc ether.

2.2. Cc alkyl halogenid (R-X)

Cc alkyl halogenid mch carbon ngn (C=1-3) l cht lng c si thp. Tc nhn hay dng l methyl halogen v ethyl halogen. Alkyl halogenid c s dng alkyl ha cc amin.

2.3. Cc arakyl halogenid (Ar-(CH2)n X)

Benzyl clorid hoc benzyl bromid c s dng nhiu. N thng c dng bo v nhm -OH ca ng hoc cellulose trong ha hc cc hydratcarbon.

2.4. Cc ester ca acid v c cha oxy

Gm cc dialkyl sulfat, alkyl nitrat, alkyl phosphat, dialkyl carbonat. Tc nhn c s dng nhiu nht l dimethyl sulfat. N c th alkyl ha nhm -OH phenol trong mi trng kim, nc, nc-alcol, thm ch c trong mi trng acid. Cc alkyl nitrat rt t khi c s dng v d gy n.

R NH2 + R'X RNHR'R'X R N

R'

R'R'X

R NR'3 X

51

2.5. Cc ester ca acid sulfonic

Cc ester hu c ca acid sulfonic thm c ngha trong thc t. Vic s dng n ging vi dialkyl-sulfat. Nhm tc nhn ny thng c dng alkyl ha nhm -OH phenol hoc -NH amin. Mt s tc nhn in hnh l methyl-benzensulfonat, benzyl-benzensulfonat hoc methyl, benzyl ester ca acid p-toluen sulfonic.

2.6. Cc mui amino bc 4

Trong phenyl-trimethyl-amoni clorid l tc nhn hay c s dng. Tc nhn ny methyl ha chn lc nhm -OH phenol trong mi trng kim. V th n c s dng methyl ha morphin thnh codein.

2.7. Cc tc nhn alkyl ha khc

Cc epoxyd: c s dng iu ch cc polyether-alcol, cht c tc dng lm gim sc cng b mt.

Cc hp cht c kim: Hp cht c magnesi dng iu ch cc ether hn tp.

C2H5MgCl + ClCH2OCH3 C2H5CH2OCH3 + MgCl2 3. Cc loi alkyl ha

3.1. C-alkyl ha

C-alkyl ha thng l phn ng alkyl ho cc hp cht cha nhm methylen hot ng. l cc hp cht c nguyn t hydro gn cc nhm ht in t mnh (V d: ester malonat, ester ca acid cyanacetic, malon dinitrin, acetoacetat ethyl).

Tc nhn alkyl ha c s dng y l alkyl halogenid, dialkyl sulfat, alkyl sulfonat, i khi l alkyl nitrat, epoxyd, arakyl halogenid.

NC-CH2-COOR + B

NC-CH-COOR + BH

R CH2OH

CH2 CH2O RCH2OCH2CH2OH

CH2 CH2O RCH2OCH2CH2OCH2CH2OH

RX + HCCN

COOR'RCH

CN

COOR'+ X

52

Xc tc cho phn ng l cc base (alcolat kim loi, Na-hydrid, cc kim loi Na hoc K). Dung mi thng l alcol, mt s trng hp c th dng ether hoc benzen.

3.2. O-alkyl ha

Gm cc phn ng alkyl ho nhm -OH alcol hoc phenol, sn phm l cc ether. Ring alkyl ha nhm -OH ca acid carboxylic s c nghin cu trong chng ester ha.

Cc ether c iu ch bng ba phng php sau:

Loi nc t hai phn t alcol:

ROH + R'OHH2SO4 / 140

0 CROR' + H2O

Tc dng ca natri alcolat vi alkyl halogenid (phn ng Williamson): R-ONa + RX R-OR + NaX (X = -Br, -Cl, -I)

Cng hp ca alcol vi olefin:

+ R'OHR CH CH2H2SO4 R CH CH3

OR'

Cc phenol-ether c iu ch ging vi ether mch thng. Tc nhn alkyl ho thng dng l alkyl-halogenid, dialkyl sulfat hoc alkyl-toluensulfonat trong mi trng kim (natri alcolat).

3.3. N-alkyl ha

Khi alkyl ha amin bc nht hoc amoniac vi alkyl halogenid, c th thu c mt hn hp amin bc cao hn hoc mui amin bc 4.

RX + NH3 RNH3XHX-

+ HXRNH2

RNH2 R2NHRX RX R3N RX R4NX

Nu dng tc nhn l alcol th qu trnh dng li amin bc 3.

Mun to amin bc hai, cn phi bo v mt nguyn t hydro ca amin bng phn ng acyl ho, sau mi alkyl ha v cui cng thy phn nhm bo v.

53

R NH2ClSO 3H

R NHSO3HR'X R NSO3H

R'

HOH R NH

R'

Gn y, nh s dng nhm alcolat lm tc nhn alkyl ho, hiu sut phn ng cao hn v khng ln tp cht dialkyl ho.

(C2H5O)3Al + ArNH23 ArNH

C2H5+ Al(OH)33

3.4. S-alkyl ha

S-alkyl ha thng l phn ng gia hp cht mecaptan vi alkyl-halogenid, sn phm l cc thioether.

SHR + R'X OH SR R' + HX

4. Cc yu t nh hng n qu trnh alkyl ha

4.1. Nhit

Khi dng tc nhn alkyl ha l alcol (methanol, ethanol) hoc alkyl-halogenid th phn ng cn c thc hin nhit cao hn so vi alkyl sulfat. Alkyl ha pha hi th i hi nhit ln ti 4000C. Vi cc amin thm, khi nhit tng nhm alkyl c xu hng chuyn vo nhn.

4.2. p sut

Hu ht cc phn ng alkyl ho khng lm gim s phn t v thng tin hnh pha lng, v vy khng cn p sut. Tuy nhin tng tc phn ng, i khi phi thc hin phn ng nhit cao.

i vi cc tc nhn c nhit si thp hoc cn dung mi ho tan cc cht tham gia phn ng th cn thit tin hnh phn ng trong ni chu p sut (autoclav).

4.3. T l mol cc cht phn ng

Vic s dng tha tc nhn alkyl ho nh hng n mc alkyl ho sn phm, c bit l alkyl-halogenid v dialkyl-sulfat. C th loi c nh hng ny bng cch s dng alcol l tc nhn yu hn.

Vi cc amin vic la chn t l mol ban u c ngha quyt nh n t l to thnh cc bc amin trong sn phm.

54


Phn ng alkyl ha pha lng c tin hnh bng phng php gin on hoc lin tc, cn pha hi th lun c thc hin bng phng php lin tc.

5.1. Phng php gin on

i vi cc cht d phn ng, khng cn thc hin nhit cao, phn ng ta nhit nhiu nn cn lm lnh. Cht alkyl ha c ha tan trong dung mi thch hp, thm xc tc, sau nng nhit v cho dn tc nhn alkyl ha vo. Khng ch nhit cn thit trong sut thi gian phn ng. Sau khi kt thc, lm lnh, hn hp phn ng vo nc , tch pha hu c, ra li vi nc. Lm khan v ct phn on thu sn phm p sut gim.

i vi cc cht kh phn ng th cho nguyn liu, tc nhn v xc tc vo ni phn ng (autoclav). un n nhit cn thit v duy tr cho ti lc phn ng hon thnh. Kt thc phn ng, ct loi nguyn liu tha v x l hn hp phn ng nh trng hp trn.

5.2. Phng php lin tc

Tin hnh trong thit b chu p lc hnh thp. Cht cn alkyl ha, tc nhn v xc tc c ha hi v dn lin tc vo thit b phn ng. Tnh ton duy tr thi gian cho hn hp phn ng nhit cn thit. Sn phm ly ra khi thp phn ng mt cch lin tc, c ngng t v x l nh trong trng hp gin on.

6. Mt s v d

6.1. Sn xut thuc gy ng diethyl barbituric (Veronal)

Qu trnh tng hp Veronal gm hai giai on:

Giai on 1: Tng hp diethyl malonat diethyl ester bng phn ng alkyl ho diethyl malonat vi ethylbromid, xc tc natri alcolat trong mi trng alcol.

Giai on 2: Ngng t diethyl malonat diethyl ester vi ur to thnh diethyl barbituric (Veronal).

55

S phn ng nh sau:

6.2. Sn xut thuc gim ho, gim au codein bng phng php alkyl ho morphin

Codein c bn tng hp t morphin bng phng php methyl ho vi tc nhn l mt mui amoni bc bn (phenyl trimethyl amoni hydroxyd). u im ca tc nhn ny l ch methyl ho nhm -OH phenol v khng to mui amoni bc bn vi nit bc ba ca phn t morphin nn cho hiu sut cao.

HO

HO

N CH3O + C6H5N CH3

CH3

CH3OH

CH3O

HO

N CH3O

t lng gi

1. Th no l qu trnh alkyl ho? Cch phn loi v mc ch ca qu trnh alkyl ho?

2. Tc nhn ca qu trnh alkyl ho gm c nhng loi no? Trnh by tnh cht v cch dng ca mi loi ?

3. Nu nhng yu t nh hng n phn ng alkyl ho?

4. Trnh by cc phng php tin hnh phn ng alkyl ho.

5. Trnh by phng php tng hp Veronal v phng php sn xut codein trong cng nghip?

H 2 C C O O C 2 H 5

C O O C 2 H 5

1.NaOC 2 H 5 2. C2H5B r

C 2 H 5 CHCOOC2H5

COOC2H5

1.NaOC2H52. C2H5Br

CCOOC 2 H 5

COOC 2 H 5

H 5 C 2

H 5 C 2 + C O

H 2N

H 2N

-2C2H5OHC N H

C N H C

C H5 C 2

H5 C 2 O

O

O

(C2 H 5 ) 2 C C O O C 2 H 5

C O O C 2 H 5

56

Chng 6

Acyl ha


1. Khi nim v phn loi phn ng acyl ho.

2. Cc tc nhn ca qu trnh acyl ho.

3. C ch phn ng v cc yu t nh hng n qu trnh acyl ho.

4. Cc v d ng dng ca phn ng acyl ho.

1. i cng

1.1. nh ngha

Acyl ha l qu trnh thay th nguyn t hydro ca hp cht hu c bng nhm acyl (RCO-).

Acyl l gc cn li khi loi i nhm -OH t acid v c c oxy, acid carboxylic

hoc acid sulfonic. Cc nhm acyl quan trng c nu trong bng 6.1. Bng 6.1. Cc nhm acyl quan trng

Tn acid xut x Cng thc nhm acyl

Acid carboxylic R-CO-

Acid sulfonic R-SO2-

Bn ester ca acid carbonic R-OCO-

Acid carbamic R-NH-CO-

Trong R l mch thng hoc nhn thm.

nh2 nhcoch3

+ ch3cooh + H2O

57

Chng ny ch nghin cu phn ng acyl ho ca cc nhm acyl c to thnh t acid hu c.

Qu trnh acyl ho c dng vo cc mc ch sau:

To ra hp cht vi nhng tnh cht mi. V d: Khi acyl ho anilin thu c acetanilid l thuc h nhit, t c hn anilin nhiu ln. Ur khi acyl ho vi cc dn cht ca acid malonic to thnh nhiu thuc ng v chng ng kinh nhm barbituric

To nhm bo v cho mt qu trnh tng hp ho hc. V d: Trong tng hp cc sulfamid, trc khi lm phn ng sulfocloro ho anilin, ngi ta phi bo v nhm amin bng cch acetyl ho.

To hp cht trung gian trong qu trnh tng hp ho hc. V d: Amid ca homoveratrilamin vi cc acid carboxylic khc nhau l trung gian tng hp nhn isoquinolin trong tng hp cc thuc papaverin, emetin.

1.2. Phn loi phn ng acyl ha

Nhm acyl (RCO-) c th thay th H trong cc lin kt -OH, -NH, -SH hoc -CH, tng ng ta c cc loi phn ng O-acyl ha, N-acyl ha, S-acyl ha, hoc C-acyl ho.

O-acyl ho: L qu trnh acyl ho nhm -OH ca alcol, phenol, enol hoc acid carboxylic. Sn phm l cc ester hoc anhydrid acid.

ROH + RCOX ROCOR + HX 2RCOOH (RCO)2O + H2O

N-acyl ho: L qu trnh acyl ho amoniac hoc cc amin hu c (bc nht, bc hai), sn phm ca phn ng l cc amid.

R-NH2 + RCOX RNHCOR + HX S-acyl ho: l qu trnh acyl ho nhm -SH ca thioalcol hoc

thiophenol. Sn phm ca phn ng l thioester.

R-SH + R COX RSCOR + HX C-acyl ho: L qu trnh thay th hydro ca nhng hp cht hu c

cha hydro hot ng.

H2C(COOR)2 + NaOC2H5 NaCH(COOR)2 NaCH(COOR)2 + CH3COCl CH3COCH(COOR)2

58

2. Tc nhn acyl ho

Tc nhn acyl ho c cng thc chung nh sau:

Trong X c th l:

OH: acid carboxylic OR: ester NH2: amid OCOR: anhydrid X: halogenid acid.

Sau y l mt s tc nhn acyl ho hay gp:

2.1. Cc acid carboxylic

Thng dng acyl ho amin v alcol. Acid carboxylic khng c kh nng acyl ho phenol. Sn phm l cc amid hoc ester. Cc acid hay c s dng l acid formic, acid acetic. Acyl ho alcol l phn ng thun nghch, v vy nng cao hiu sut phn ng cn c bin php loi nc ra khi khi phn ng. Acyl ho vi tc nhn acid thng c tin hnh nhit cao (khong 2000C).

2.2. Cc ester

Cc ester khng phi l tc nhn acyl ho mnh. Nhng n c s dng trong nhiu trng hp, c bit l nhng ester c nhm ht in t mnh trong phn t. V d clorocarbonat ethyl l mt tc nhn c s dng rng ri a nhm ethyl carbonat vo phn t hu c.

Ester c dng trong cc trng hp O, N, C-acyl ho. Tuy nhin, trong cng nghip ngi ta t dng ester lm tc nhn N-acyl ho, tr trng hp iu ch formamid v dimethyl formamid. Acid formic khng c dng anhydrid hoc clorid acid tng ng, nn ch c th s dng dng acid hoc ester ca n.

NH3 + HCOOCH3 HCONH2 + CH3OH

2.3. Cc amid

Cc amid l nhng tc nhn acyl ho yu nn t khi c s dng. Hai tc nhn hay s dng hn l formamid (HCONH2) v carbamid (H2NCONH2).

Carbamid c dng acyl ho alcol thnh uretan:

C2H5OH + H2NCONH2.HNO3 C2H5OCONH2 + NH4NO3

r co

x

59

2.4. Cc anhydrid acid

Anhydrid acid l tc nhn acyl ho mnh, c th acyl ho c amin, alcol v phenol. Khng to ra nc trong qu trnh phn ng. Tc nhn hay c s dng l anhydrid acetic. N t b thu phn trong nc nn c th acyl ho trong mi trng nc hoc mi trng kim.

Nu tc nhn l anhydrid hn tp (anhydrid ca 2 acid khc nhau) th nhm acyl no hot ho hn s th vo phn t cn acyl ho.

Xc tc cho phn ng acyl ho thng l cc amin bc ba (trietylamin, pyridin, 4-dimethyl-amino-pyridin).

2.5. Cc halogenid acid

Halogenid acid l tc nhn acyl ho rt mnh, trong cc clorid acid c s dng nhiu nht. Halogenid acid thng l nhng cht lng, d b phn hu bi nc. Qu trnh acyl ho to ra HX, v vy ngi ta thng phi dng cc base hu c nh pyridin, triethylamin, quinolin, diethylanilinlm cht hp th. Vi cc clorid acid t b thu phn bi nc (clorid acid ca acid thm, sulfonyl clorid) th c th acyl ho trong dung dch kim 10-20% hoc carbonat kim.

Cc tc nhn in hnh ca nhm ny l acetyl clorid, benzoyl clorid, photgen, benzensulfo clorid

Halogenid acid c th acyl ho cc nhm -OH, -NH2:

ROH + RCOX R-OCOR + HX RNH2 + RCOX R-NHCOR + HX

2.6. Xeten

Xeten (CH2 = CO) l tc nhn acyl ho mnh nht, c s dng rng ri trong cng nghip. N c s dng acyl ho cc nhm -OH alcol, -NH amin, -OH acid. L tc nhn acyl ho chn lc nhm -NH amin, v nhit thng n phn ng mnh vi -NH ca amin m khng phn ng vi -OH ca alcol.

3. C ch phn ng

Lin kt C-X c th b ct theo 3 kiu:

o

x+r c

o

x+r cr + xc

o

60

Tng ng ta c cc loi c ch sau:

3.1. Acyl ho theo c ch gc

Di tc dng ca tc nhn peroxyd, gc acyl to thnh v tham gia vo cc phn ng theo c ch gc t do.

c h 3c h 2c h 2c o c h 3 c h 3 c h =c h 2O C 3 H C +

+ H C C 3 O C H peroxid

c h 3c h o

3.2. Acyl ho theo c ch i in t

Nhm acyl d b phn cc do i in t lch v pha nguyn t oxy c m in ln hn. Nu X l nhm ht in t mnh th tc nhn ny cng d b phn li thnh cation acyli (RCO+). Nguyn t C ca nhm acyl mang in tch dng nn l tc nhn i in t.

C ch phn ng c th vit nh sau:

RCOX RCO + XR'OH

RCOOR' + HX

RCOX + R'OH R C X

OH

OR'

RCOOR' + HX

3.3. Acyl ho theo c ch i nhn

Trong thc t rt t gp qu trnh acyl ho xy ra theo c ch ny. Bi v kh nng to anion acyli (RCO-) l rt kh. Cc aldehyd trong mi trng kim mnh to thnh hp cht dimer l mt trng hp c bit:

4. Mt s yu t cn ch trong qu trnh acyl ho

4.1. Xc tc

Xc tc cho qu trnh acyl ho c th l base hoc acid.

+ C H

O

CN

Ph C

O

C N

Ph

H

P hC H O C

OH

CN

Ph C O

H

P h

P hC H O CN

C CHPh

O

Ph

OH

61

Acyl ho alcol hoc amin bng tc nhn halogenid hoc anhydrid acid th xc tc l cc amin bc ba nh triethylamin, pyridin, quinolin, 4-dimethylamino-pyridin, mt s trng hp c th dng carbonat kim hoc kim.

Acyl ho alcol bng acid carboxylic (ester ho) th xc tc l acid sulfuric.

4.2. Dung mi

Dung mi thng l cc cht tham gia phn ng (cc alcol hoc amin) hoc chnh tc nhn acyl ho. Trng hp cc cht tham gia phn ng khng ho tan tc nhn acyl ho th dng mt dung mi tr tan thch hp (benzen, toluen, clorobenzen, cloroform, tetraclorocarbon, dicloromethan...).

4.3. Nhit

Acyl ho l qu trnh to nhit. Tuy nhin giai on u cn cung cp nhit cho phn ng. Sau c th phi lm lnh loi bt nhit phn ng. Giai on cui cn cung nhit li phn ng kt thc. Tu cc cht tham gia phn ng v tc nhn m nhit phn ng khc nhau. V d vi tc nhn l acid carboxylic, khi acyl ho alcol cn tin hnh 200oC, acyl ho amin 120-1400C. Tc nhn halogenid acid ch cn nhit di 500C.

5. Mt s v d

5.1. iu ch thuc h nhit gim au aspirin

Cho acid salicylic tc dng vi anhydrid acetic, xc tc l acid sulfuric c nhit 80-900C trong thi gian 30-45 pht. ngui, lc thu tinh th. Ra bng nc v sy thu sn phm.

5.2. Bn tng hp thuc st rt artesunat

Acyl ho dihydroartemisinin bng anhydrid succinic vi xc tc l cc amin bc ba nh pyridin, triethylamin hoc 4-dimethylamino-pyridin.

O

O

C

H H

C OCOCH2CH2COOH

H3C O OO

O

OO

O

CH3

H H

CH3 OH

H3C O O +

COOH

OH+ (CH3CO)2O

COOH

OCOCH3

+ CH3COOH

62

5.3. iu ch acetanilid

Phng trnh phn ng nh sau:

NH2

+ CH3COOH

NHCOCH3

+ H2O

Anilin v acid acetic c cho vo bnh phn ng 1 (Hnh 6.1), nng nhit ln 1400C v gi trong 8-10 gi. Trong qu trnh phn ng, nc to thnh c ct ra lin tc. Sau , khi phn ng c x l vi nc thu tinh th sn phm. Ra li bng nc, lc v sy.

AnilinAcOH

1

2

3

4 5 6

H2ONc

H2O

AcOH H2O

Hnh 6.1. S thit b iu ch acetanilid

1. Bnh phn ng, 2. Ct tch, 3. Sinh hn, 4. Ni kt ta, 5. My vy li tm, 6. T sy

T lng gi

1. Trnh by nh ngha qu trnh acyl ho? Cch phn loi v mc ch ca qu trnh acyl ho?

2. Trnh by cng thc chung v cc loi tc nhn ca qu trnh acyl ho?

3. C ch phn ng acyl ho v mt s yu t cn ch trong qu trnh thc hin phn ng acyl ho?

4. Trnh by phng php tng hp aspirin, artesunat v acetanilid.

63

Chng 7

Ester ho


1. Khi nim v phn ng ester ho v cc phng php iu ch ester.

2. C ch ca phn ng ester ho.

3. Cc yu t nh hng n qu trnh ester ho v phng php chuyn dch cn bng cho phn ng ester ho.

4. Cc v d ng dng ca phn ng ester ho.

1. i cng

Qu trnh to hp cht ester bng phn ng gia acid carboxylic vi alcol, xc tc acid v c c gi l qu trnh ester ha.

Ester ha l phn ng thun nghch, phng trnh nh sau:

R COOH + R'OH RCOOR' + H2O

C nhiu phng php iu ch ester, trong gio trnh ny chng ti chia cc phng php lm ba nhm: acyl ho, alkyl ho v phng php oxy ho kh.

1.1. iu ch ester bng phng php acyl ho

Phn ng ester ho (esterification): R-COOH + R-OH R-COOR + H2O

Phn ng ru phn (alcoholysis):

C2H5OH+

NH2

COOCH2CH2N(C2H5)2

HOCH2CH2N(C2H5)2+

NH2

COOC2H5

64

Phn ng acid phn (acidolysis):

CH3COOCH=CH2 + C11H23COOH C11H23COOCH=CH2 + CH3COOH

(Acid laurinic) (Vinyl laurinat)

Phn ng chuyn i ester:

HCOOC(CH3)3 + R-COOCH3 R-COOC(CH3)3 + HCOOCH3

Phn ng ca anhydrid vi alcol hoc phenol: (CH3CO)2O + R-OH CH3COOR + CH3COOH (CH3CO)2O + Ar-OH CH3COOAr + CH3COOH

Phn ng gia halogenid acid vi alcol hoc alcolat: Cl-CO-Cl + C2H5OH ClCOOC2H5 + HCl

Phn ng gia amid vi alcol: R-CONH2 + R-OH R-COOR + NH3

1.2. iu ch ester bng phng php alkyl ho

Phn ng gia mui carboxylat vi alkyl halogenid hoc arakyl halogenid:

CH3COONa + C2H5Br CH3COOC2H5 + NaBr CH3COONa + Cl-CH2-C6H5 CH3COOCH2-C6H5 + NaCl

Phn ng alkyl ho nhm OH ca acid bng epoxyd: H2C

OCH2 + CH3COOH OH CH2 CH2 O CO CH3

Phn ng cng hp vo ni i C=C ca acid v c v hu c: CH2=CH2 + H2SO4 CH3CH2-OSO2OH CH2=CH2 + CH3COOH CH3COOCH2CH3

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1.3. iu ch ester bng phng php oxy ho-kh

Phn ng Canizzaro (benzaldehyd trong mi trng kim c):

C6H5 CHO2OH C6H5 CH2 O CO C6H5

Phn ng Tischenko (aldehyd/nhm -alcolat): 2CH3CHO CH3COOC2H5

Phn ng gia carbon-monoxyd vi alcol trong alcolat kim loi nhit v p sut ln:

R-OH + CO HCOOR Sn phm ester ho c s dng rng ri trong cc lnh vc sau:

Trong dc phm, dng lm thuc (aspirin, novocain, diethylphthalat, artesunat...)

Lm cht trung gian trong tng hp ho hu c v ho dc. Trong ho m phm, cc ester dng lm hng liu. Lm dung mi (ethylacetat, butylacetat...).

2. C ch phn ng

Phn ng ester ho kinh in l phn ng to ester gia acid carboxylic v alcol. y l phn ng thun nghch, xc tc l acid v c.

Phn t nc to thnh trong phn ng ester ha c th theo 2 cch:

H2O+OR' R CO

+ R'H OR C

O

O H

R'H O+R C

O

O HH

Kt qu ca nhiu cng trnh nghin cu chng minh rng bc carbon

trong phn t alcol quyt nh phn t nc loi ra theo kiu no. Trong thc t c hai kiu c ch tng ng vi hai trng hp sau:

2.1. Ester ho vi alcol bc 1 v bc 2

Di tc dng ca acid v c, qu trnh ester ho c th xy ra theo c ch n phn t hoc lng phn t:

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Hoc:

chnh

R C OHOH

O

H

R'

R CO H

OH+H+R C

O

OH nhnh

R'OH

nhch R C

OH

O R'nhnh

R CO

OR'

+ H_ H2O

C hai trng hp u ly nhm -OH ca acid carboxylic to thnh phn t nc.

2.2. Ester ho vi alcol bc 3

Trng hp ny phn t nc c to thnh t nhm -OH ca alcol. C ch phn ng nh sau:

3. Cc yu t nh hng n qu trnh ester ho

3.1. Xc tc

Xc tc c tc dng y nhanh qu trnh ester ho. Cc xc tc hay dng l acid proton mnh nh: sulfuric, hydrocloric, sulfonic, percloric, phosphoric. Ngoi ra cn s dng mt s acid Lewis khc (BF3, ZnCl2, SnCl4, SiF4, FeCl3).

R CO

OH+ H+R C

O

OHR C

O

OH

H

R CO

+ H2O

R CO

+ O R

H

R CO

OR

H

R CO

OR+ H+

nhnh

chnh

nhch

nhch

C O H C H 3

C H 3

C H 3

+ H+ C OHC H3

CH3

C H

C CH3

C H 3

C H 3 H3

+ H 2 O

R C O O H n h c h

n hn h

chnh

RO

O H C ( C H3 ) 3

RO

OC(CH3)3

+ H + n hn h

C C

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Gn y ngi ta dng cc cht trao i ion lm xc tc thay cho acid. Vi xc tc loi ny qu trnh x l sau phn ng s n gin v c th s dng li xc tc.

Xc tc khng nh hng n cn bng ca phn ng.

3.2. Dung mi

Dung mi ca qu trnh ester ho thng l cc alcol tham gia phn ng c dng qu tha. Nu acid carboxylic khng tan trong alcol th cn mt dung mi tr tan thch hp (aceton, benzen, toluen, cloroform, dicloromethan...)

3.3. Nhit

Cng nh nhiu phn ng khc, nhit c tc dng lm tng tc phn ng ester ho. Vic tng nhit ca phn ng ch n si ca alcol, nu mun nng nhit ln cao hn th phi dng thit b chu p sut.

3.4. iu kin cn bng ca phn ng

3.4.1. Hng s cn bng ca phn ng ester ho

Ester ho l phn ng thun nghch. Mi phn ng c th c mt hng s cn bng ring. Hng s cn bng c tnh theo cng thc sau:

K =ester . nc

acid alcol

Gi tr K cng ln th kh nng chuyn ho thnh ester cng cao. Cng thc ny cho php tnh c nng ca ester to thnh trong phn ng nu s dng qu tha mt trong hai thnh phn tham gia phn ng.

3.4.2. nh hng ca cu trc alcol ti vn tc ester ho v nng ester ti im cn bng

Th nghim ca Mencsutkin (1897) khi ester ho cc alcol vi acid acetic c th hin bng 6.2.

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Bng 6.2. Tc dng ca cc alcol khc nhau n vn tc ester ho

Khi lng ester to thnh [%mol] S TT Tn alcol

Sau 1 gi im cn bng

K

1 Methanol 55.59 69,59 5,24

2 Ethanol 46,95 66,57 3,96

3 Propanol 46,92 66,85 4,07

4 Buthanol 46,85 67,30 4,24

5 Allyl alcol 35,72 59,41 2,18

6 Benzyl alcol 38,64 60,75 2,39

7 Izopropanol 26,53 60,52 2,35

8 Methyl, ethyl carbinol 22,59 59,28 2,12

9 Diethyl carbinol 16,93 58,66 2,01

10 Diallyl carbinol 10,31 50,12 1,01

11 Menthol 15,29 61,49 2,55

12 Trimethyl carbinol 1,43 6,59 0,0049

13 Dimethyl propyl carbinol 2,15 0,83 0,00007

14 Phenol 1,45 8,64 0,0089

15 Thimol 0,55 9,46 0,0192

Kt qu cho thy methanol c vn tc phn ng ln nht v nng ester ti im cn bng cng cao nht. Cc alcol bc nht, cc alcol no c vn tc phn ng v h s cn bng cao hn cc alcol bc hai hoc cc alcol khng no tng ng. Cc alcol bc ba c vn tc ester ho b nht. Tm li, alcol cng phn nhnh v mch nhnh cng gn nhm -OH th vn tc ester ho cng gim, nng ester ti im cn bng cng thp.

3.4.3. nh hng cu trc ca acid ti vn tc ester ho v nng ester ti im cn bng

Cng tng t nh cc alcol, Mencsutkin kho st kh nng ester ho ca mt s acid c cu trc khc nhau vi alcol isopropylic 1500C (Bng 6.3). Kt qu cho thy nh hng ca mch carbon khng nh trong trng hp ca alcol. Tc ester ho v gi tr nng ester ti im cn bng khng t l theo s phn nhnh ca mch carbon.

Bng 6.3. Tc dng ca cc acid khc nhau n vn tc ester ho

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Khi lng ester to thnh [%mol] S TT Tn alcol

Sau 1 gi im cn bng

K

1 Formic 61,69 64,23 3,22

2 Acetic 44,36 67,38 4,27

3 Propionic 41,18 68,70 4,82

4 n-Butyric 33,25 69,52 5,20

5 Isobutyric 29,03 69,51 5,20

6 Methyl, ethyl acetic 21,50 73,73 7,88

7 Trimethyl acetic 8,28 72,65 7,06

8 Dimethyl, ethyl acetic 3,45 74,15 8,23

9 Phenyl acetic 48,82 73,87 7,99

10 Phenyl propionic 40,26 72,02 7,60

11 Benzoic 8,62 72,57 7,00

12 p-Toluenic 6,64 76,52 10,62

4. Cc phng php chuyn dch cn bng cho phn ng ester ho

C hai phng php chuyn dch cn bng lm tng hiu sut ca qu trnh ester ho:

1. Tng nng mt trong hai cht tham gia phn ng (acid hoc alcol). Vn ny thc hin n gin v thng dng alcol tha nhiu ln.

2. Loi khi phn ng mt trong hai cht to thnh. Trng hp ny c thc hin bi hai bin php sau y:

Loi nc ra khi phn ng:

Nu c acid ln alcol dng trong phn ng ester ho u l nhng cht c si cao th loi nc bng cch ct ko lin tc, c th sc kh tr vo tng tc loi nc.

Nu acid c si cao, alcol c si thp hn nc th dng alcol tha nhiu ln, ct loi nc v alcol lin tc trong qu trnh phn ng.

Thm mt dung mi to hn hp si ng ph ba cu t (nc-alcol-dung mi) c nhit si thp hn nhit si ca nc v ct loi chng ra khi hn hp phn ng. Hn hp hi c ngng t,

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tch loi pha nc, pha hu c cha alcol c dn tr li bnh phn ng. Cc dung mi hay dng l benzen, toluen, cloroform, dicloroethan, tetraclorocarbon.

Loi ester ra khi phn ng:

C hai phng php sau:

Nu ester to thnh c si thp nht trong hn hp phn ng th lin tc ct thu ester trong qu trnh phn ng.

Nu ester to hn hp ng ph hai hoc ba cu t vi cc cht tham gia phn ng, th hn hp hi ct ra c ngng t tch ly ester. Pha nc acid c dn tr li khi phn ng.

5. Mt s v d

5.1. iu ch diethylphthalat

Hi lu anhydrid phthalic v ethanol tha (3-5 ln) vi xc tc l acid sulfuric c trong hai gi. Phn ng xy ra qua hai giai on: giai on u ethanol cng hp vo anhydrid phthalic to thnh monoester. Sau ester ho monoester ny thnh diethyphthalat.

Kt thc phn ng, ct thu hi alcol tha. Ra ester bng nc, sau trung ho vi dung dch natri carbonat loi acid xc tc. Ra li bng nc n trung tnh, lm khan v ct phn on thu ester tinh khit.

S cc giai on phn ng nh sau:

COOC2H5

COOC2H5+

H2SO4

C2H5OHCOOC2H5

COOHC2H5OH+

CO

C

O

O

5.2. iu ch methyl salicylat

Hi lu hn hp acid salicylic v methanol (tha gp 10 ln) trong 10 gi vi xc tc l acid sulfuric c. Phn ng kt thc, ct loi methanol v ra hn hp phn ng vi nc nhiu ln. Sau trung ho vi dung dch natri hydrocarbonat n trung tnh. Ra li bng nc, lm khan v ct phn on thu methyl salicylat tinh khit.

COOH

OH

COOCH3

OH+ CH3OH

H2SO4+ H2O

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T lng gi

1. Qu trnh ester ho c hiu nh th no? Mc ch ca n?

2. iu ch ester gm c nhng phng php no? Vit phng trnh phn ng mi loi ?

3. Trnh by c ch phn ng ester ho?

4. Nu cc yu t nh hng n qu trnh ester ho v cc phng php chuyn dch cn bng nng cao hiu sut ca qu trnh ester ho.

5. Trnh by phng php sn xut diethylphthalat v methyl salicylat.

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Chng 8

Phn ng thu phn

Mc tiu

Sau khi hc xong chng ny, sinh vin phi trnh by c:

1. Khi nim v phn ng thu phn v cc loi tc nhn thu phn.

2. Cc loi phn ng thu phn v c ch ca n.

3. Mt s v d v phn ng thu phn.

1. i cng

Thu phn l qu trnh phn hu mt hp cht no bng nc to ra hai hp cht mi. Trong cc thnh phn ca phn t nc u tham gia vo cu to hai hp cht mi ny.

V d: Phn ng thu phn ester:

Xc tc cho phn ng thu phn l cc acid, kim v enzym. Chng ny khng cp n phn ng thu phn xc tc enzym.

Thng thng thu phn xc tc acid l phn ng thun nghch, cn thu phn xc tc kim l phn ng khng thun nghch.

2. C ch ca phn ng thu phn

Thu phn l phn ng th i nhn (SN), tc nhn i nhn l nc. Xc tc cho phn ng l acid hoc base.

Vi cc nhm hp cht khc nhau v xc tc khc nhau, phn ng thu phn cng xy ra vi c ch khc nhau. V vy, i vi tng nhm hp cht c th s c c ch phn ng ring.

R COOR' + H2O R COOH + R'OH

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3. Cc tc nhn thu phn

3.1. Thu phn bng nc

Phn ng thu phn bng nc c th khng cn xc tc. Nhit ca phn ng ph

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