bg tong hop hoa duoc c. van
TRANSCRIPT
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CHNG 1: PHN NG MICHAEL
1.1. i cng
Phn ng cng hp gia cc hp cht cha nhm CH mang tnh axit vi cc hp cht
vinylic cacbonyl c gi l cng hp Mchael hay phn ng Michael, v phn ng ny do
A.Michael pht hin u tin vo nm 1887.
R1CH
X
R2+ C C=
R3
R4
Y
R
CH C- - CH
R2
Y
R
R3
R4
R1
BAZOX
Trong :
R,R1,R2,R3 v R4 l hydro,alkyl hoc i khi l aryl
X,Y l cc nhm ht in t nh: -COOH,-CHO,-COOR,-CONH2,-CN,-NO2,i khi
l SO3RNh vy,vi phn ng ny c th to ra rt nhiu hp cht.
Trong hai cht tham gia phn ng chnh trn cht cha H hot ng (R1R2XCH)
c gi l cht cho (donor); cn cht vinylic cacbonyl (R3R4C=CRY) c gi l cht nhn
(acceptor).
Cng cn lu rng, hot ng ca nhm X,Y trong cht cho v cht nhn khng
hon ton ging nhau. Sau y l trnh t tng dn ca chng trong phn ng:
X (donor); NO2 > SO3R > CN > COOR >CHOY (acceptor); NO2 > COOR > CN >COR > CHO
Xc tc cho phn ng Michael l cc bazo,tng t nh phn ng aldol v phn ng
Claisen. Lng dng ca n cng ging nh phn ng aldol ,ch hon ton mc xc
tc, khng cn ti mc ng lng nh trong trng hp phn ng ngng t Claisen.
1.2. C ch phn ng
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Qu trnh phn ng gm nhiu bc, nhng bc chm l bc quyt nh vn tc
phn ng ph thuc kh nng phn ng ca cht cho v cht nhn, cng nh bazo ca
xc tc ( ging nh trong phn ng aldol v ngng t Claisen):
R1CH
X
R2
+ B(-) R1
C: (-)
X
R2
+ BH
R1
C: (-)
X
R2C =
R3
R4
Y
R
+ C C- -
X
Y
R
R3
R4
R1
R2 C: (-)C
C C- -
X
Y
R
R3
R4
R1
R2 C: (-) + BH CC- -
X
Y
R
R3
R4
R1
R2 C H + B(-)
C C- -
X
Y
R
R3
R4
R1
R2 C: (-) + CC- -
X
Y
R
R3
R4
R1
R2 C H +
R1CH
X
R2
R1C:(-)
X
R2
1.3.
Xc tc
Xc tc thng dng nht l natri v kali ca metylat ,etylat v tert-butylat trong dung
dch alcol . Ngoi ra i khi cn s dng c dung dch alcol ca kali v natri hidroxit , hoc
dung dch nc natri hidroxit .Trong dung mi tr i khi dng ti natri kim loi hay natri
amidua.
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Trng hp cc hp cht hot ng mnh (rt hot ho) c th dng cc amin bc hai
, bc ba nh pyperidin , pyridin , trietylamin , mui amoni bc bn (v d triton B).
Tc dng xc tc ca cc axit khng c ngha ng k vi phn ng Michael nn
y chng ta khng cp k , d rng cng c mt s cng b c dng ti botriflorua v
km clorua (axit Lewis) .
Cng phi ch rng , vi cc xc tc l baz mnh , trong mt s trng hp phn
ng dn ti hnh thnh cc sn phm trng hp .
1.4. Dung mi
Dung mi ph bin nht cho phn ng ny l cc alcol nh methanol , etanol,n-
butanol, tert butanol. Mt s dung mi tr l ete , dioxan hoc benzen , i khi dng c hnhp ch nc . Trong nhng trng hp dng ti xc tc l kim loi kim hoc natri
amidua th dung mi l loi khng cha proton , dng di dng huyn ph .
1.5. Nhit
V phn ng Michael l phn ng thun nghch , phn ng chm nn thi gian phn
ng tng i di .
Thng nhit cao to thun li cho phn ng theo chiu ngc nn phi trnh
iu ny . Khi s dng alcolat lm xc tc , thng thng ngi ta tin hnh phn ng nhit phng vi thi gian khuy t 20 n 100 gi , cn khi s dng amin bc hai hoc
bc ba lm xc tc v dung mi l alcol th phn ng tin hnh trn nhit si ca hn
hp nn thi gian ch cn t 12 n 40 gi .
1.6. X l, tinh ch hn hp phn ng
Sau khi phn ng kt thc , sn phm ca phn ng Michael a s kt ta nhit
phng , nh vy em lc v kt tinh li . Nu khng kt ta th lm long hn hp vi
icloetan hoc chloroform, sau dng axit axetic trung ho , pha hu c tch ra lm
khan , ct loi dung mi , ct chn khng thu sn phm .
1.7. Cc phn ng ph
Cc phn ng ph thng i km phn ng Michael bao gm :
1-Phn ng ngng t Claisen hoc ngng t Dieckmann . trnh iu ny khng
nn s dng lng xc tc nhiu m ch s dng mt lng nh (liu xc tc ).
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2-Phn ng andol i lc cng sinh ra , c bit l khi cht cho l andehit mch
thng . trnh iu ny , hoc dng tha cht nhn hoc thc hin trnh t cho cc cht
vo phn ng nh sau : cht nhn cng vi xc tc sau cho t t cht cho vo .
3. Phn ng Michael l phn ng hai chiu , nhit tng lm tng phn ng chiu
ngc . trnh iu ny nn thc hin phn ng nhit thp .
4. Khi cht cho cha hai nhm ht in t th c hai hydro ca n c kh nng cng
hp vo hai phn t cht nhn , trong trng hp ny trnh phn ng ph xy ra theo
hng khng mong mun , ngi ta phi iu chnh t l mol ca cht nhn hoc c th iu
chnh mnh ca xc tc . V d :
CH2
CN
+ CH2=CH-CNnuoc NaCN
C
H2C
CN
H2C
H
CN
80%
CH2
CN
+trilon B2 CH2=CH-CN
C
H2C
CN
H2C
H2C CN
H2C CN
5.Mt hp cht va c th l cht cho nhng cng c th l cht nhn do dng xeto
hoc eno ca n .V nh trng hp axetyl axetat etyl:
CH3CO-CH2-COOEt CH3-C=CH-COOEt
OH
cht cho cht nhn 1.8. Phm vi ng dng ca phn ng
1. Phn ng gia H ca dn xut manolat vi , xeton khng no:
Kt hp phn ng iu ch cc dioxo este Michael v Claisen ni di mch
cacbon ca hp cht, cng nh iu ch dioxo este:
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C
O
CH3CH
CCH3CH3
H2CCOOC2H5
COOC2H5
C
O
H2C CH3
CCH3
H3CCH
COOC2H5
COOC2H5
bazo
(p.u.Michael)
O
O
COOC2H5
H3C
H3C1 mol bazo
- C2H5OH
(p.u. Michael)
2. Phn ng gia H ca xeton vi , xeton khng no:
Kt hp phn ng Michael v ngng t aldol tng hp vng steran i t vinyl
metyl xeton vi metyl 3 vng cha H hot ng:
CH
C
OCH3
CH2
OH
CH3
H
O
OH
CO
OCH3
OH
O
C2H5OH
(Michael)
aldol
-H2O
Cng tng t nh trn nhng khi cht khi u l axetyl axetylen ta thu c vng
steran cha hai ni i C=C:
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C
CH
CH3O
OH
CH3
H
O
OH
O
+ M
aldol
3. Phn ng gia H ca dn xut nytryl manolat vi quinnon:
Dng phn ng Michael iu ch cc hp cht nhn thm thng qua quinnon nh
l mt ch nhn, li va l cht kh. Trc ht, quinnon phn ng vi cht cho trong dung
dch etanol ca etyl axetat, hp cht to thnh t thm ha, sau b quinnon cn d oxy
ho thnh cht nhn c cu trc quinnon v tip tc phn ng vi phn t th hai ca chtcho to ra hp cht cha hai mch nhnh ca nhn thm:
O
O
HCH CN
COOC2H5
OH
OH
CH CN
COOC2H5
O
O
CH CN
COOC2H5
OH
OH
CH CN
COOC2H5
CHCOOC2H5
CN
+ NaOC2H5
Michael
oOO
HCH CN
COOC2H5
NaOC2H5Michael
4. Phn ng gia H ca dn xut manolat vi acrylat:
Dng phn ng Michael tng hp axit glutamit i t - axetamido -malonat etyl
v metyl acrylat, sau em thy phn sn phm nhn c v v decacboxylic ha:
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AcNH CH
COOC2H5
COOC2H5
H2C CH COOCH3
AcNH C
COOC2H5
COOC2H5
CH2 CH2 COOCH3 H2N CH
COOH
CH2 CH2 COOH
1.thuy phn
2.loai CO2
axit glutamic
NaOC2H5+
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CHNG 2: XYANETYL HA
2.1. i cng
Phn ng xyanetyl ha l phn ng cng hp ca phn t c cha hyro hot ng
ti ni i C=C ca phn t acrylonitryl:
C th coi phn ng ny l 1 dng ca phn ng Michael nu nh khng ch quan
tm n ngha ca phn ng ca lin kt C-H m khng n phn ng ca cc lin kt
khc cha H hot ng vi acrylonitryl.
2.2. C ch phn ng
Xyanetyl ha l phn ng thuc loi cng nucleophin (cng ging nh phn ngMichael ) xy ra theo nhiu bc.Trc ht di tc dng ca xc tc baz t hp cht cha
H hot ng (RH),anion R c to ra v dng anion ca phn t cha hyro hot ng ny
tn cng vo C v tr ca phn t acrylonitryl,gy nn s dch chuyn in tch:
(-)
+ BH + B(-)
RCH2CHCN RCH2CH2CN
(-)
+ RH + R(-)RCH2CH CN RCH2CH2CN
Cc qu trnh trn u xy ra thun nghch.
Nh trong c ch cp,y l 1 phn ng cng nucleophin. Nu so snhacrylonitryl vi cc dn xut c cu trc tng t ca vinylcacbonyl v kh nng phn ng
vi cc tc nhn nucleophyl th kh nng gim dn theo trnh t lit k sau y:,-
alehit khng no (CH2=CH-CHO),, -xeton khng no (CH2=CH-COR), , -nitryl khng
no (CH2=CHCN),, -axit khng no (CH2=CH-COOH), , -amit khng no (CH2=CH-
CONHR). Khi trn cacbon v tr c cha nhm ankyl th kh nng phn ng s b
gim,v th acrylonitryl l hp cht hot ng mnh nht trong dy ng ng ca , -
R-H + CH2=CH-CN R-CH2 -CH2-CN
R-H + B(-) R(-) + BH
R(+) + CH2 CH C N + BH R-CH2-CH C N +B(-)
+ -
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nitryl khng no v n mnh hn c cc hp cht ng ng c ankyl th v tr ca , -
alehit v , -xeton khng no.
2.3. Cc phn ng phTrong s c mt ca xc tc baz, mi cht tham gia phn ng khc nhau c nhng
phn ng ph ring ca n. V d cc hp cht cacbonyl c phn ng aldol ha, nitryl c th
tham gia phn ng trng hp, v vy sau phn ng bn cnh sn phm chnh cn c th thu
c cc sn phm ph t cc phn ng ny.
2.4. Tc nhn
Tc nhn xyanetyl ha duy nht y l acrylonitryl. Acrylonitryl l cht lng khng
mu, nh hn nc, si 780
C, kh c, c th thm qua da hoc ng h hp. Trong qutrnh bo qun, acrylonitryl c th b polyme ha nn sn phm c trn th trng thng
c ngi ta cho thm cht c ch qu trnh polyme ha (mui ng).
2.5. Xc tc
to ra anion thng s dng cc xc tc mang tnh baz: nh cc hidroxit kim,
alcoxit, i khi dng natri kim loi, Ca(OH)2, KCN, aminhidroxit bc 4 (triton B). i khi
khng dng ti xc tc hoc cng c khi dng amin bc 2. Khi xyanetyl ha cc amin, cng
c th dng xc tc axit nh axit hu c, axit v c, di khi dng mui kim loi c kh nngto phc nh mui Ni2+, Zn2+, Co2+, Cu2+. Mui ng cng ng thi l cht c ch qu
trnh polime ha.
2.6. Dung mi
Xyanetyl l phn ng ta nhit, v vy tt nht nn thc hin phn ng trong dung
mi. Cc dung mi hay dng nht l benzen, toluen, pyridin, dioxan, axetonitryl. Xc tc r
tin nht l NaOH, KOH nhng v cc cht ny kh ha tan trong cc dung mi hu c
khng phn cc, do thng hay s dng dung mi l cc ancol mch di nh tert-butylic
ancol. Trong tert-butanol nhit phng KOH ha tan c 4%, d rng trn 600C th
tert-butanol b xianetyl ha nn thng dng tert-butanol lm dung mi cho cc phn ng
thc hin nhit thp. Ngoi ra cng c th dng nc lm dung mi xianetyl ha cc
amin.
2.7. Phm vi ng dng ca phn ng
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Nhm xyanetyl c th thay th cho hydro hot ng ca bt k loi hp cht no.
Phn ng c th thc hin c mt cch d dng, khng tn km. Ty thuc nhm
xyanetyl gn vo C, N hay O m gi C-xyanetyl ha, N-xyanetyl ha hoc O-xyanetyl ha
2.7.1. C-xyanetyl ha
Cc hp cht cha lin kt C-H c tnh axit u c th xyanetyl ha trong xc tc
baz. Ty thuc ha tan ca cc tc nhn trong dung mi m quyt nh chn cht xc
tc cho ph hp.
2.7.1.1. Xyanetyl ha aldehit
Aldehit trong mi trng xc tc kim d sinh ra phn ng andol ha, to sn phm
polyme ha.Vi formaldehit ch nhn c sn phm O-xyanetyl ha (di dng metylen glycol):
Vi axetaldehit v cc aldehit mch thng do b nha ha nn hiu sut thu c sn
phm tng i thp.
Vi cc aldehit c mch nhnh v tr C th hiu sut cao hn, mch cacbon cng
di hiu sut cng tng. V d:
CHCH2CHCHO
C2H5 CH2CHCNCH3CH2CCHO
C2H5
(CH2)2CN
2-etyl-2,2-xyano etyl butanal2-etyl butyl aldehit
KOH, h.s 77%
2.7.1.2. Xyanetyl ha xeton
Nhm xyanetyl c th thay th mt hoc nhiu H. V d vi axeton t l mol 1:1
th monoxyanetyl axeton c to ra vi hiu sut 30 n 35%:
CH3COCH3 CH3COCH2CH2CH2CNCH2CHCN
KOH
Khi t l gia axeton v acrylonitryl 1:3, sn phm trixyanetyl axeton c to ra vi
hiu sut 80%:
3CH2CHCN
KOH
CH3COC(CH2CH2CN)3CH3COCH3
HOCH2OH + 2 CH2CHCN NCCH2CH2OCH2CCH2CN
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i vi cc metyl xeton, nhm -metylen c xyanetyl ha mt cch chn lc v
dn xut dixyanetyl c to ra vi hiu sut tng i cao:
CH3COCH2R CH2COC(CHCH2CN)2R
2CH2CHCN
i vi cc 1,3-dixeton th hydro hot ng nm gia hai nhm cacbonyl s c
thay th bng nhm xyanetyl:
CH2CH2CN
COCH3 COCH3
OO
CH2CHCN
KOHH
Nhng i khi trng hp 1,3-dixeto xyanetyl ha hi kh v hydro hot ng
cacbon v tr th 2 qu hot ng nn d dng chuyn thnh dng proton v nh th di tc
dng ca xc tc kim n d dng chuyn sang dng enol:
2.7.1.3. Xyanetyl ha dn xut ca axit hu c
Hydro mang tnh axit mnh ca cc axit cacboxylic khng phn ng vi acrylonitryl
(k c dn xut ca 1,3-dicacbonyl). Hydro no hot ng nht th lin kt c thay th
bng nhm xyanetyl trc nht. V d axetyl amit khi xyanetyl ha th trc ht dn xut
N,N-dixyanetyl c to thnh:
CH3C O
NH2 triton B
CH2CHCNCH3CON
CH2CH2CN
CH2CH2CN
Nhng vi cc dn xut 1,3-diaxit nh dn xut amit ca axit malonic th khixyanetyl ha hydro lin kt C-H thuc v tr th 2 s c thay th:
CH2CH2CN
CONH2
C
CONH2
CH2CH2CNCONH2
CH2
CONH2
triton B
CH2CHCN
Khi xyanetyl ha cc nitryl th H s phn ng:
RCOCH2CH2R' RCOCHCR'
OH
RCH2CN R CH2CH2CN
CNtriton B
CH2CHCN
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2.7.1.4. Xyanetyl ha hp cht nitro
Do tc dng ht in t ca nhm nitro m hydro cacbon bn cnh c hot ha
v d dng phn ng vi acrylonitryl thnh dn xut nitro-xyanetyl:
2.7.1.5. Xyanetyl ha sunfon mch thng hoc thm
2.7.1.6. Xyanetyl ha cloroform
2.7.1.7. Xyanetyl ha cc hp cht dien vngDi xc tc kim, acrylonitryl v dien vng khng tham gia phn ng Diels-Alder
m c xyanetyl ha v tr cnh ni i:
2.7.2. N-xyanetyl ha
Bt k lin kt N-H no cng c th xyanetyl ha khi cho tc dng vi acrylonitryl.
2.7.1.1. Xyanetyl ha ammoniac v amin
Amoniac v amin l nhm hp cht phn ng kh d dng vi acrylonitryl. Kh nng
phn ng c xp theo trnh t sau:
Amoniac > amin bc mt > amin bc hai.
Bng vic iu chnh nhit cng nh mt s iu kin phn ng khc, c th dng
li c dn xut monoxyanetylamin hoc dixyan-etylamin. Trong nhiu trng hp
CHCl3 ClCCH2CH2CNCl
Cltriton B
CH2CHCN
CH2CH2CN
alcolat
CH2CHCN
CHNO2
CH3
CH3 C
CH3
CH3
NO2
CH2CH2CN
triton B
CH2CHCN
|
| triton B
CH2CHCNSO2CH2CH2CH2CN
CH2CH2CN
SO2C
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khng cn ti xc tc, nhng nu cn th xc tc cho nhm hp cht ny thng l baz, axit
hoc c th l cc mui kim loi:
CH3CH2NH2 CH3CH2NHCH2CH2CNCH2CHCNCH3COOH
triton B
CH2CHCNNH NCH2CH2CN
2.7.2.2. Xyanetyl ha amit, imit, lactam
Xc tc baz cho phn ng vi hiu sut kh tt. Xc tc baz c th l NaOH, triton
B:
2.7.3. O-xyanetyl ha
Nhm OH ca cc axit cacboxylic khng th xyanetyl ha bng acrylonitryl.
Nhm OH ca nc, alcol, phenol, v oxim u phn ng c vi acrylonitryl.
Vi nc:
H2O + 2CH2=CHCN NCCH2CH2OCH2CH2CN
Phn ng vi alcol l mt qu trnh thun nghch . H s cn bng theo th t alcol
bc mt, alcol bc hai, alcol bc ba. Ngha l bc alcol cng cao th tc phn ng cng
gim, phn ng cng c chiu hng dch chuyn v chiu ngc li v alcol bc mt s cho
hiu sut cao nht (hu nh ton lng ):
RCONH2 RCONHCH2CH2CNtriton B
CH2CHCN
C
O
CO
NH
C
O
CO
NCH2CH2CNtriton B
CH2CHCN
CH3C
O
NH SO2NH|CH3
CH3C
O
NH SO2N|CH3
|CH2CH2CN
CH2CHCNNaOH
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ROH + CH2=CHCN ROCH2CH2CN
Vi cc phenol, khi thc hin qu trnh xyanetyl ha xy ra hai trng hp:
a.Trng hp th nht l trng hp O-xyanetyl ha :
b.Trng hp th hai l C-xyanetyl ha, xy ra khi nhn thm c hot ha, lin kt
CH c tnh axit mnh hn OH :
H
OH
CH2-CH2-CN
OH
CH2=CH-CN
NaOH
Oxim khi xyanetyl ha to ra oximino-ete:
2.7.4. Cc phn ng xianetyl ha khc
C th S-xyanetyl ha hydro sunfua, mercaptan, tiophenol, kh nng phn ng ca
cc hp cht ny mnh hn cc dn xut oxy tng ng :
O
N
SH
+ CH2 = CH CN
O
N
S CH2CH2 CN
Cc axit v c cng cng hp vi C=C ca acrylonitryl, nhng trong s ng quan
tm hn c l phn ng vi axit clohydric v hypocloro.
OH
CH2=CH-CN
Na (xt)
OCH2CH2CN
CH3 C = NOH
CH3 C = NOH
CH2=CH-CN
NaOH
CH3 CH2O CNC =N CH2
CH3 CH2O CNC =N CH2
CH
HCl
HOCl
ClCH2
OHCH2
+ CH2 = CH CN CH2CH2
CN
CN
+ CH2 = CH CN
Claxit hypocloro
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2.8. Cch tin hnh phn ng
Phn ng xyanetyl ha l phn ng ta nhit do cn quan tm n ti vic lm
lnh. Phn ng nn tin hnh pha long bng dung mi. Ch l sau thi gian di khi mo
(induction period) phn ng xy ra rt mnh lit. Lng xc tc thng c s dng t 1
n 5 % mol. Lng acrylonitryl dng d so vi cht cha hidro hot ng (substrate) t 0
n 20% ty trng hp.
Nhit thc hin phn ng i vi cc cht c kh nng phn ng loi trung bnh l
khong nhit phng. Trng hp dng tert-butanol lm dung mi th nhit phn ng
khng c vt qu 500
C.Vi cc cht cha H hot ng mnh, ngi ta thc hin phn ng khong 00C, cn
i vi cc cht km hot ng th tin hnh phn ng trn si ca dung mi.
Thng tin hnh phn ng theo cch sau: Cho vo bnh phn ng lng dung mi,
lng xc tc v cht phn ng cha hydro hot ng (substrate), lm lnh khi hn hp
xung 0 200C, va khuy va nh git t t acrylonitryl vo. Nu sau khi cho ht khong
5 n 10% lng acrylonitryl m cha thy phn ng xy ra th tm dng vic nh
acrylonitril v tip tc khuy, thm ch nu cn th lm nng nh i cho n khi phn ngbt u khi ng (nhit ta ra).
Sau khi cho ht lng acrylonitryl cn thit bng cch lm lnh hay un nng v duy
tr khuy cho n ht thi gian quy nh (n lc phn ng kt thc) thng mt vi gi.
Sau vic s l, tinh ch ty thuc ha tan ca sn phm m la chn phng php cho
ph hp. Thng sau phn ng ngi ta loi cht xc tc bng cch ra vi mt t nc
hoc axit clohydric,lm khan pha hu c v ct loi dung mi. Sn phm ph
polyacrylonitryl ha tan rt t trong 1,2-dicloetan, nn c th dng dung mi ny chit ly
sn phm.Sau ct phn on hoc kt tinh ty trng hp c th.
2.9. Mt vi v d
Trong tng hp glutethimit, hot cht ca mt thuc ng c bit dc Doriden hoc
Noxiron, ngi ta cho 2-etyl-2-phenol axetonitryl tc dng vi acrylonitryl di tc dng
ca xc tc triton B c dn xut dixyan, tip ng vng c glutethimit:
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CHNG 3: TNG HP DIELS-ALDER
3.1. i cng
Phn ng Diels-Alder c gi l phn ng cng ng vng 1,4 [4+2] v sn phm
vng c to ra bi tng tc ca 4 electron pi(diene) v 2 electron pi(dienophile) ca
anken hay ankin.
Khi mt anken hay ankin ngho electron c thin hng phn ng vi mt diene,
n c gi l dienophile, cn thnh phn cha hai lin kt i lin hp c gi l thnh
phn ien.
Phn ng Diels-Alder cng ging nh phn ng nucleophile-electrophile. Cc ienel nhng cht giu electron, cn cc dienophile l nhng cht ngho electron. Mt ien
n gin l 1,3-butadiene. S c mt ca nhm ankyl hay alkoxy (-OR) c th lm tng kh
nng phn ng ca ien. Cc anken v ankin (ienophile) n gin l ethene v ethyne. Mt
dienophile thng thng c mt hay nhiu nhm th ht electron (-W) nhm ht mt
electron ra xa lin kt pi, (-W) c th l nhm cacbonyl cha (C=O) hay nhm cyano (-
CN):
Thnh phn ien trong phn ng Diels-Alder c th l mch h hay vng, cng c th
l mt s cc nhm th nhng phi nm trong gii hn: Cc ien phi tn ti trong cu dng
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s-cis. Nu cc nhm th ln hn hydro th s cn tr v mt khng gian c th nh hng
n bn ca cu dng. c bit, cc ien vng c cu dng s-cis tham gia phn ng
Diels-Alder, cc ien nh vy c gi l Danishefskys ien (vd:cyclopentadien). Trong
khi cc ien vng c cu dng s-trans s khng tham gia phn ng Diels-Alder. Hp cht
vng benzen him khi tri qua phn ng Diels-Alder v thng phi c ienophile hot tnh
cao. Cc ienophile c nhm ht in t lin hp gn vo anken hay ankin. Nhng c im
ny khng phi l ring bit ca ienophile Diels-Alder. C th c nhiu hn s lin hp, t
nht mt nhm phenyl hay nguyn t clo. ienophile c th c hot ha nh axit lewis
(nh NbCl5)
Cyclopentadien s khng phn ng vi cyclohexenon trong etyl axetat nu khng c
mt ca axit lewis. Hiu sut tng khi nhit phn ng c gi
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Cho n nay c ch phn ng Diels-Alder vn cha ht gy tranh lun v cn ang
c nghin cu. Theo quan im ca ha hc hu c c in, cc c ch ch thc s c
chp nhn khi cc phng php ph nghim chng minh c c s hin din ca cc hp
cht trung gian(intermediate) theo ng ng i ca c ch. Nhng trong ha hc hu c
hin i, ch cn c s chuyn ng ca obitan n mt khong cch thch hp xy ra s
xen ph to thnh lin kt mi c cho l c c ch. Tng tc chnh ca Diels-Alder l
HOMO (MO c nng lng cao nht in y cc electron) ca ien v LUMO (MO
c nng lng thp nht cha cc orbital trng) ca ienophile, c th y l 1,3-
butadiene v ethene.
Trong hnh v, hai AO p ca hai cacbon trong ethane t hp cho ra hai MO, MO
c in electron l HOMO, cn MO trn khng c in electron l LUMO. K hiu S
(symmetric: i xng) v A (antisymmetric: phn xng) m t tnh i xng ca hm sng,
s i xng y l mt phng i xng
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Tng t ta xt h thng pi lin hp ca 1,3-butadiene, HOMO l A cn LUMO l S.
Lu , HOMO v LUMO lc ny ch l HOMO pi v LUMO pi, khng phi l HOMO v
LUMO ca c phn t. Tip xy ra s tng tc cho gia HOMO ca hp phn ny vi
LUMO ca hp phn khc v ngc li:
Trong qu trnh nghin cu, Alder rt ra cc nguyn tc v lp th ca phn
ng- Nguyn tc Alder
1. Ch cc diene c cu dng cis mi c th tham gia c vo phn ng Diels-Alder, cn
cu dng trans khng tham gia c phn ng ny
2. Sn phm ca phn ng cng Diels-Alder lun c cu trc dng endo, ngha l cc
nhm th ca dienophile lun hng v pha lin kt i mi to ra. Ngc hng vi
endo l dng exo, khi ni i mi hnh thnh nm xa cc nhm th:
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3. Trong sn phm cng hp cc nhm th, cc thnh phn dienophin lun gi nguyn dng
ban u m n c trong nguyn liu, nu nguyn liu ban u c cc nhm th dng
trans hoc cis th trong sn phm cng v tr .
4. Cc nhm th y in t lm tng kh nng phn ng ca thnh phn diene, cn cc
nhm th ht in t li lm tng kh nng phn ng ca thnh phn dienophile. iu ny
cng gii thch v sao trong thnh phn dienophile lun c cha t nht mt nhm th ht
in t.
5. Chn lc lp th
Phn ng Diels-Alder c tnh c th lp th (stereospecific) vi c ien ln
ienophile
- cis-ienophile cho nhm th cis sn phm
- trans-dienophile cho nhm th trans sn phm
- Nu nhm th diene c cng ha lp th, th 2 nhm ny nm cng pha sn phm
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- Nu nhm th diene khng cng ha lp th, th 2 nhm ny nm khc pha sn phm
- iene vng c th cho sn phm ng phn lp th ty thuc vo dienophile hay diene
3.3. Nng lng ca phn ng Diels-Alder
Trong qu trnh phn ng, ba lin kt v bn lin kt bin mt, ng thi su lin
kt v mt lin kt to ra, theo tnh ton s gii phng ra 30kcal/mol nng lng v thc
t o c nng lng gii phng ra t cc phn ng loi ny thuc loi gii phng nng
lng nh.
3.4. Cc phn ng ph
C hai thnh phn diene v dienophile u l nhng hp cht c kh nng phn ng
mnh, dc bit i vi phn ng oxy ho v phn ng trng hp. Do , gim nng to
thnh cc phn ng ph, i hi tinh khit ca nguyn liu, ca dung mi l ht sc quan
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trng. ng thi, hn ch qu trnh oxy ho th phn ng nn tin hnh di lung kh
nit.
C diene v dienophile u c rt nhiu hp cht, kh nng v cng phn ng
ca chng cng khc nhau, vi vic iu chnh t l mol gia diene v dienophile hoc trnh
t np nguyn liu, ta c th loi tr c cc phn ng ph v sn phm ph.
Nhiu khi ta khng quan tm ti phn ng ph nhng i khi phn ng ph li cho
nhng sn phm hp dn nn lc n tr thnh hng chnh ca phn ng. V d khi cho
cc hp cht ca dimetylen diphenyl xyclobuten phn ng vi tetraxyan etylen (thnh phn
dienophile), bn cnh mt phn nh l sn phm ca phn ng Diels-Alder ta cn nhn c
sn phm chnh l dn xut spiro:
Ph
Ph
CH2
CH2
+
NCCN
NC CN
Ph
Ph
CH2
NC
NC
CN
CN
Benzen, 200Chs 40%
C ch ca phn ng ny cho n nay vn cha c lm sng t, hin vn cn ang
c tranh lun.
3.5. Cc yu t nh hng
Cc yu t thng nh hng ti phn ng l xc tc, dung mi, nhit , t l mol
gia cc cht tham gia phn ng.
Xc tc: xc tc axit Lewis c tc ng mnh n h phn ng c v tc ln chn
lc lp th hn l h khng c xc tc.
V d v kh nng chn lc vng khi c mt xc tc axit Lewis, l phn ng ca
piperylene v metyl acrylat, sn phm chnh v tr ortho
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Mt v d khc m t tc dng tng tnh chn lc lp th, l phn ng ca
cyclopentadiene v metyl acrylat
Dung mi: Cc dung mi c s dng trong phn ng Diels-Alder thng l dung
mi tr, vi vai tr lm cht pha long, mt khc, vi si ca dung mi c th iu khinc nhit phn ng. Cc dung mi thng hay c dung l ete du ho, hexan, benzin
(xng), benzene, ligroin, clobezen toluene, ete, xylem, etyl axetat, nitrobenzene, i khi c
nh tng trong nc.
Nhit : thng thng phn ng khi u trong khong 30 n 50oCv sau vi
nhit to ra ca phn ng, phn ng tip tc cho n khi kt thc. C mt s trng hp
nhit khi mo ca phn ng cn cao hn (t 50 n 250 oC ) trn nhit si ca cc
dung mi. Trng hp cc tc nhn c nhit si thp phi tin hnh phn ng trong thit
b kn chu p lc.
T l mol: phn ln trong cc phn ng dng tha thnh phn dienophin, i vi cc
cht d phn ng thng c s dng theo t l dien/dienophin bng 1/1.
3.6. Cch tin hnh phn ng
C thnh phn diene v dienophile u l nhng hp cht c kh nng phn ng mnh.
Khi thc hin phn ng, trc tin cn lm nng thnh phn dienophile n nhit khi
mo cn thit ca phn ng ri cho t t thnh phn dien vo, sau vi nhit lng nh ta
ra, phn ng tip tc cho ti khi kt thc.
i vi nhng cht phn ng yu hn, ch cn cho ton b dung mi v cht tham gia
phn ng vo chung mt thit b ri un hi lu cho n khi phn ng kt thc. Lu khi
dng autoclave, tin hnh phn ng ch nn cho t 1/3 n 1/2 th tch thit b.
3.7. So snh kh nng phn ng ca cc ien v ienophin
3.7.1. Kh nng phn ng ca cc ien:
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so snh kh nng phn ng ca cc ddien, ngi ta thng o bng vic cho phn
ng vi hai tc nhn ienophin mnh nht l anhydrit maleic v tetraxyan etylen v dau
y l trnh t xp hng kh nng phn ng ca cc ien:
>
CH3
CH3
> >
> >
OCH3
>
CH3
>
Ph
>
H3C
H3C
>
H3C
> >
Ph
Ph
>
Cl
3.7.2.Kh nng phn ng ca cc ienophin
Kh nng phn ng ca cc ienophin c o bng cch cho phn ng vi 2 ien
mnh l xiclopentadien v 9, 10-dimetyl antraxen. Sau dy l trnh t xp hng kh nng
phn ng ca cc dienophin:
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CN
CN
NC
NC
>> O
O
O
>
CNNC
NC
>
CNNC
>
PhO2S
SO2Ph
>
PhOC
COPh
>
CN
NC
>
CN
CN
>
CO2Et
CO2Et
>CO2Et
CO2Et
>
CO2Et
CO2Et
>
CN
>
CO2Et CO2EtH3C
>
Ngoi cc etylen th th tc dng ca cc nhm th khc nhau tun theo trnh t sau:
-COCl >> -SO2Ar >-COAr > -COCH3 > -CN > - CO2R > -Ph
3.8. Phm vi ng dng
Phn ng Diels Alder c s dng kh ph bin trong tng hp hu c, c bit ltrong lnh vc tng hp cc hp cht thin nhin. C hng ngn phn ng ng vng, ghp
vng c nghin cusau y l mt vi v d c bn:
Phn ng u tin c nghin cu nm 1928, l phn ng ng vng gia xyclo
pentadien v benzoquinon. y l phn ng Diels Alder in hnh, trong thnh phn
dienophin c nhm ht in t lin hp.
+
O
O
benzen 200C
hs 100%
O
O
Xyclopentadien cng phn ng c vi este azo-dicacbonxylic, phn ng c s
dng trong qu trnh iu ch diaminoxyclopentan
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iu ch nhng hp cht a vng, cho Xyclopentadien tc dng vi axetylen
iu kin nhit v p sut cao:
+C
C
H
H
3400C, as cao
hs 65%
Cc dn xut azo ng vai tr nh mt dienophin khi phn ng vi xyclopentadien:
+
N
N
O
N
N
O
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Cc dien mch thng tc dng vi dn xut ca axit fumaric (tun theo quy tc s-cis)
c cc dn xut ca xyclohexan:
+
COOCH3
COOH3C
H
COOCH3
COOCH3
H
toluen, 1500C
hs 84%
Cc dien mch thng tc dng vi dn xut axetylen c cc dn xut ca
xyclohexadien:
+
CHOOCH3
COOCH3
COOCH3
COOCH3
toluen, 1500C
hs 85%
Cc dn xut ca butadien tc dng vi anhydrit maleic cho cc anhydrittetrahydrophtalic:
+ O
O
O
O
O
O
toluen, 1500C
hs 90%
Ngoi ra cc nitrozo cng phn ng c vi butadiene nh l mt tc nhn
dienophile:
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+
O
NC
Cl
N CH3
CH3
O
C
Cl
CH3
CH3
Cng tng t nh butadiene, hai phn t acrolein phn ng vi nhau (va ng vai
tr ien ln dienophile) to thnh dn xut vng pyran:
O
+
O
CHO
CHO
benzen, 800C
hs 45%
Trien (1- vinyl butadien) phn ng vi anhydrit maleic cho dn xut anhydrit phtalic
cng theo quy tc s-cis:
+ O
O
OHC
H
H
O
O
O
CH2
ete, 350C
hs 45%
iu ch cc hp cht cha khung steran, ngi ta cho cc dn xut quinon tc
dng vi butaiene c dn xut cha khung naphtalen:
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H3CO
O
O
CH3
+
H3CO
CH3
O
O
H3CO
+
H3CO
H3C
O
O
CH3O
O
Cc dn xut bis-metylen-xycloankan cng tc dng c vi cc dienophile khc
nhau cho cc sn phm a vng:
+
NO2NO2
ete, 200C
hs 85%
Trng hp cc phn ng vi bis-metylen-xyclobutan, sn phm to thnh khng bn
nn vi tc dng li ca nhit to ra dn xut bis-metylen, cht ny tip tc phn ng vi
mt phn t anhydrit maleic khc ngay trong phn ng to ra hp cht 4 vng:
Tng hp tip
Tng hp tip
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+O
O
O
O
O
O
O
O
O
O
O
O
OO
O
O
O
O
benzen, 800C
hs 95%1500C
Cc hp cht cha nhn thm, nht l ng ng vi benzen rt kh tham gia phn
ng Diels-Alder. Nhng ngi ta cng thc hin c phn ng gia 1,2,4,5 tetrametyl
benzen vi peflobutin-2 cho hp cht a vng tuy hiu sut khng cao:
H3C
H3C CH3
CH3
+
C
C
CF3
CF3
CH3
CH3
F3C
CF3
H3C
H3C
2000C
hs 41%
iu ch hp cht cha nhiu Clo (ha cht bo v thc vt) ngi ta cng tin
hnh phn ng Diels-Alder gia hexancloxyclopentadien v benzen(ng vai tr l 1
dienophin):
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ClCl
ClCl
Cl Cl
+ +
Cl
Cl
Cl
Cl
Cl
Cl
1000atCl ClCl
Cl
Cl Cl
Cl
Cl
ClClCl
Cl
Furan cng phn ng c vi maleyl amit to ra cc hp cht d vng:
O + NH
O
O
O NH
O
O
ete, 200C
hs 100%
Trong lnh vc ha hc tecpen, bng phn ng Diels-Alder ngi ta iu ch ra
nhiu loi hp cht d vng c b khung c bn sau y:
1. 2. 3. 4.
1.Pinan 2.camphan 3. izo-camphan 4.phencan
3.9. Mt vi v d
1. Mt nguyn liu trung gian quan trng trong tng hp cc dn xut ca prostaglandin la
3--cacboxymetyl-4-benzyloxymetyl-5-hydroxy xclopenten-1, c tng hp theo phng
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php c hiu lp th qua dn xut cha b khung norbonen , c iu ch bng phn ng
Diels-Alder i t dn xut xyclopentadien v clorua axit 2-cloacrylic:
CH2OCH2Pn+
Cl COCl
HPnH2COH2C
Cl COCl
HPnH2COH2C
O
HPnH2COH2C
O
O
CH2OCH2Pn
CH2COOH
OH
ete, 00C
hs 85%
phn huyCurtius
chuyn viBayer - Villger
1. OH-
2. H+
2. Nm 1952, Woodward v cc ng nghip ca ng m ra con ng lch s tng hp
steroid cortisone v colesterol
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Phn ng ca quinon vi butadiene trong dung mi benzen 100oC trong 96gi bng
phn ng cng Diels-Alder to thnh sn phm cng 2 vng thng qua trng thi chuyn
tip endo.
Phn ng Diels-Alder gia antraxen vi maleic anhydric. Sn phm to thnh l 9,
10-dihydroanthracene-9,10-, -succinic anhydric. Lc ny antraxen ng vai tr l diene vmaleic anhydric ng vai tr l dienophile. Kt thc phn ng, sn phm th s c ti kt
tinh.
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3. Trong phng sinh tng hp cc alcaloit nhn aspidosperma, bc cui cng, ngi ta
s dng p Diels-Alder ng vng ni phn t dn xut secodin, to ra vincadifformin v
sau cng l 3-oxovin-cadiffomin v 3-oxominovin:
N
NOH
X
R
Toluen, 1100C
-H2O
N
N
X
RCOOCH3
COOCH3
CH2
Toluen, 1100C
N
N
X
RCOOCH3
H
Vincadiformin(khi R l H, X l H2) 3-oxovincadifformin(khi R l H, X l O)
3-oxominovin(khi R l CH3, X l O)
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CHNG 4: PHN NG ANDOL V CC LOI PHN NG TNG T
4.1. i cng
Phn ng gia mt thnh phn cha H
hot ng vi mt thnh phn cha nhm C=O
hot ng ca aldehit hoc xeton, kt qu to ra mt hp cht c cacbon ln hn v loi ra
mt phn t H2O. Phn ng nh vy c gi l phn ng andol ha:
C
R1
Z
+ C
R2
R3
O CH C
R2
R3
R1
Z1
OH
H2
Thnh phn cha H Thnh phn cha CO
C C
R1
Z
R2
R3
-H2O
(2)
Trong Z l nhm th ht in t bao gm: -COR ( R l H, alkyl ); -COOR (R l H,
alkyl ); C N ; -NO2; cn R1, R2, R3 c th l H, alkyl, aryl.
Nu phn ng dng li giai on 1 th gi l phn ng cng aldol v sn phm gi l
sn phm cng aldol; cn nu phn ng tip tc ti giai on 2 (dehydrat ha) th gi chung
c qu trnh hai giai on ny l phn ng ngng t aldol v sn phm dehydrat ha nay l
sn phm ngng t aldol.
4.2. C ch phn ng
Phn ng aldol in hnh l phn ng dime ha aldehit axetic di tc dng ca dung
dch kim trong ancol c sn phm cng hp:
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C
O
HCH3 + HO-
chm.C
O
HCH2(-)
H2O+
C
O
CH3 H
_
+ C
O
HCH2
(-)
CHCH3 CH2 CHO
_
H2O CH
OH
CH2CH3 CHO + OH(-)
O
Bc th hai ca ngng t aldol l loi phn t nc, qu trnh ny xy ra mt cch
d dng (t xy ra) vi s c mt ca axit lm xc tc. C ch nh sau:
CH3 CH
OH
CH2 C H
O
+ H(+)
CH3 CH CH2 C H
OOH2(+)
CH3 CH CH2 C H
O(+)
H2O+
CH3 CH CH2(+)
CHO CH3 CHOCHCH H(+)
+
Nh vy ngng t aldol gm hai bc, bc th nht l cng aldol, bc th hai l
tch loi nc.
Khng ch xc tc kim m axit cng c th xc tc cho phn ng gia C-H mang
tnh axit ca cc hp cht cacbonyl vi cc hp cht cacbonyl. Xc tc axit lm tng hot
lc (kh nng phn ng) ca nhm cacbonyl, ngoi ra n cn xc tc cho qu trnh enol ha
ca thnh phn cha C-H:
C
H
HR
CR
O'
H
(+)
+ C
H
HR
CR
OH'
(+)
H
(+) CR
HC
R
OH
'
+
Do tnh cht baz ca ni i C=C ca enol, n c kh nng cng vo C=O nh l
mt tc nhn nucleophyl:
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(+)H
(+)
CHO
R
CHR
'
+ C O + H(+)
HO C
R
C
H
R
C OH'
C
R
O C
H
R
C OH
'
_
Kt qu nhn c sn phm cng hp ging nh trng hp xc tc kim.Trong
mi trng axit, sn phm cng hp alcol dehydrat to ra hp cht , - khng no.
H(+)C
R
O C
H
R
C OH
'_
H(+)
C
R
O C
H
R
C OH
H'
(+)
H(+)
_H(+)_H2O
+ H2O +C
R
O C
R
C
'
Xc tc axit t ngha hn xc tc kim trong lnh vc cng hp ca ni i C=O,nhng trong mt s phn ng cng c dng ti n.
Sau y l mt s phn ng trn c s phn ng C-H mang tnh axit v C=O ca
cacbonyl:
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C O + C NH C CN
OH
C O + HC C H C COH
CH
C O + CH2 CO
H(R)C CH
OH
CO
H(R)
H2O_
C C CO
H(R)
Ar CHO + (CH3 CO)2O_CH3COOH Ar CH CHCOOH
C O + CH2
Cl
COORHCl
_C CH
O
COOR
C O + CH2X
YH2O
_C C
Y
X
R CCl
O+ CH2
X
Y
HCl_
R C
O
CHX
Y
R CO
OR+ CH2 COOR R C CH
O
COR
O
C OH
H+ H N + CH2 C
O
H(R)
H2O_
N CH2 CH CO
H(R)
,hop.tng,
xyanhydric
elynyl hoa
cng hop,. . aldol
phan ung perkin, ,
,hop este glyxit.tng,
(phan ung Darens), ,
phan ung ngung tu, , , .
Knoevenagel
ngung tu, .(Claisen)
alkyl hoa hop chtdicacbonyl-
,.
phan ung, ,
Mannich
4.3. Cc phn ng ph
a. Trng hp aldol dime ha hoc phn ng t trng ngng
Trng hp aldol dime ha hoc phn ng t trng ngng (gia hai phn t ging
nhau), ngi ta khng cn cp nhiu ti vn phn ng ph v ty thuc vo mi trng
phn ng s nhn c sn phm cng aldol hoc sn phm loi nc l hp cht cacbonyl
khng no.
b. Trng hp phn ng xy ra gia hai phn t khc nhau
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Theo nguyn tc 8 loi sn phm c hnh thnh ( hai loi dime, hai loi aldol cho
nhau, v 4 sn phm mt nc), nhng sn phm no to ra nhiu hn cn ty thuc cu trc
ca cc cht tham gia phn ng cng nh mi trng phn ng. C th phn loi theo cc
cht tham gia phn ng nh sau:
+ Trng hp mt aldehit phn ng vi mt xeton, do kh nng phn ng ca cacbonyl
(C=O) xeton v andehit khc xa nhau v th thng thng phn ng cng lun xy ra trn
C=O ca andehit
CH3CHO CH3 CO CH3 CH3 CH
OH
CH2 CO CH3+
H2O_ CH3 CH CH CO CH3
Trong trng aldehit phn ng vi xeton bt i xng th v nguyn tc s xy ra hai
loi phn ng aldol:
H2O_
CH3CHO + C OH2C
H3C
CH3
CH3 CH
OH
CH CO CH3
CH3
CH3 CH CH2
OH
CO CH2 CH3
CH3 CH C CO
CH3CH3 (A)
CH3 CH CH CO CH2 CH3 (B)
Trong thc t nu xc tc l axit th hu nh sn phm A c to thnh; cn nu xc
tc l baz th to ra hn hp sn phm B v A
+ Trng hp hai aldehit khc nhau hoc hai xeton khc nhau tham gia phn ng
aldol tt nhin nhiu loi sn phm c to ra, tr trng hp do nguyn nhn v cu trc
gia hai phn t c khc nhau rt ln v kh nng phn ng.Trng hp duy nht mt phn
t lun l thnh phn cha H hot ng ca phn t kia lun l thnh phn cha nhm
cacbonyl hot ng th lc ny s loi sn phm to ra s t i, v khng cn sn phm th
hai ca phn ng aldol cho cng nh sn phm dime gia hai phn t cng loi:
Theo nguyn tc ca Lieben, cc nhm th v tr thng lm gim kh nng phn
ng ca nhm cacbonyl bn cnh, nh vy hp cht cha t nhm th v tr s lun ng
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vai tr l thnh phn hp cht cung cp nhm cacbonyl hot ng; cn hp cht cha nhiu
nhm th hn v tr s lun l thnh phn cung cp H hot ng. V d:
CH3CHO + CH3CH2CHO KOH CH3 CH CH CHO
OH CH3 H2O_ CH3 CH C CHO
CH3
CH3CH2CHO + CH CHOH3C
H3CCH3 CH2 CH C CHO
OH
CH3
CH3
L d nhin trong phn ng th hai trn khng c th to ra sn phm loi nc v
cc sn phm ghi trn, ch mi l sn phm ca phn ng chnh cn cc sn phm c th
to ra ca phn ng ph th rt nhiu.
+ Trng hp phn ng gia hai aldehit hoc hai axeton khc nhau ch to ra duy nht
mt loi sn phm khi mt trong hai hp cht cha cacbonyl ni trn khng cha hydro v
tr . V d:
CHO + CH3CHO CH CH CHO
Nhng phi lu rng, nhng trng hp nh th nu phn ng thc hin trong
mi trng kim qu c th vi vic chuyn dch ion hydrua s to ra phn ng ph (phnng d ly) ta s c cc sn phm ca phn Cannizzaro l mt alcol v mt axit:
R CHO + CH2O R CH2OH + HCOOH
+ Trong mi trng phn ng aldol: cc este, anhydrit cacboxylic hu nh ch to ra
cc sn phm ngng t kiu Claisen:
C CH2R1
Z
+ R2 CO
Y
HY CH C2R1
Z
_
Nu phn ng gia este vi anhydrit thc hin nhit thp v s dng d lng
alhydhit th phn Claisen b kim hm, cn phn ng aldol s c u th hn:
C6H5CHO CH3COOC2H5NaOC2H5 CH CH COOC2H5
Trng hp dng xc tc axit, phn ng ph l sn phm ca qu trnh axetal ha:
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R CHO C2H5OH/HCl R HCOC2H5
OC2H5
i khi cng nhn c cc sn phm ca phn ng Michael v sn phm ngng tto ra cc hp cht cha ni i hot ng thuc ng ng ca vinyl cacbonyl, cht ny
tham gia vo phn ng Michael vi hp cht cha hydro hot ng cha phn ng cn nm
trong hn hp phn ng:
CH
X
R1
R2+ C C
R4
R3 Y
Rbazo
C C CHY
R
R1
R2
R3
R4X
R1,R2,R3,R4 l alkyl hoc arylX,Y l cc nhm ht in t : COOH, COOR, COR, CONH2, CN, hoc SO2.
4.4. Xc tc
Xc tc thng thng nht ca phn ng aldol l cc baz, do trc ht ta cp
n cc xc tc baz ny.
Xc tc baz c s dng nhiu nht l dung dch metanol ca NaOH hoc KOH
(xt v kh nng ha tan th KOH tt hn), cng nh dung dch etanol ca KOH. Trong mt
s trng hp c th dng dung dch nc alcol ca NaOH hoc KOH.
Nhng nu s dng xc tc kim c nng cao s gip cho qu trnh phn hy cc
sn phm aldol nn thng ch nn dng t l 2 n 3% mol xc tc trn 1 mol cht phn
ng, trong nhng trng hp c bit c th dng ti 5 n 10% mol. Mt khc kim cng
xc tin qu trnh dehydrat ha, do vi mc ch iu ch sn phm cng hp aldol th
xc tc hay s dng l cc mui kim loi kim ca cc axit yu nh axit xyanhydric, axit
photphoric, axit cacbonic.
Trong trng hp cc aldehit hot ng mnh, xc tc thng hay c s dng l
cc amin bc nht, bc hai, v d: pyrolidin, pyperidin. i khi cng s dng ti cc alcolat,
c bit trong trng hp cc hp cht t nhy cm vi phn ng.
Cng c nhng trng hp ngi ta ni ti xc tc l nhng baz mnh nh natri
hydrua, atri amit, thm ch c ti liu ni ti c hp cht Grignard.
ng ch l cc cht trao i ion loi baz, vi xc tc ny trong nhiu trng hp
cho hiu sut rt cao.
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Xc tc axit cng c s dng nhng khi s dng xc tc loi ny thng khng th
phn lp c sn phm cng aldol v mi trng axit xc tc ny cho qu trnh loi nc,
hn na trong nhiu trng hp sn phm ph nh c l cht nhy do kt qu ca qu
trnh polyme ha. V th xc tc axit rt t khi c s dng.
Cc xc tc axit c s dng l kh HCl, i khi H2SO4 c, axit axetic, hoc BF3.
4.5. Cc yu t nh hng ti phn ng
Dung mi: Dung mi c s dng nhiu nht l metanol, etanol. Nhiu trng hp
dng tetrahydrofuran, 1,2-dietoxyetan, dimetyl formamit v dimetyl sunfoxit. Trng hp
xc tc l axit ngi ta dng dung mi ete, benzen thay cho alcol trnh vic to ra axetal.
Nhit : Phn ng aldol thng c tin hnh nhit thp, t khi phi dng tinhit cao hn hn nhit phng; nhng i khi thc phi thc hin nhit cao hn
(trn si ca metanol hoc etanol), khi sn phm loi nc to ra hp cht cacbonyl
khng no la khng th trnh khi.
Thi gian phn ng: Thng thng phn ng thc hin n 5 gi, i khi phi ko
di ti 12 n 20 gi ( nhng trng hp phn t c lc cn khng gian ln).
T l mol: Trong trng hp n gin, t l mol gia thnh phn ca H hot ng v
thnh phn cha C=O hot ng l 1:1, nhng nu l phn ng gia hai phn t khc nhauc cha nhm cacbonyl th lun dng d lng loi km phn ng, v nh th s loi c
kh nng t ngng t (self-condensation). Phn ng nn thc hin trong lung kh nit
trnh s oxy ha ca cc enolat v , cacbonyl khng no.
4.6. Phm vi ng dng ca phn ng
Phn ng dime ha gia hai phn t aldehit c cu trc ging nhau. V d: Gia hai
phn t aldehit axetic, phn ng xy ra rt d dng nhit 5 n 10C vi xc tc dung
dch kim nc, dung mi l bn thn aldehit axetic. im quan trng y l phi khuy
mnh v sau khi kt thc phn ng (khong 1 gi) phi trung ha bng axit tactric (axit yu)
hn ch vic dehydrat ha:
CH3 CO
H+ HCH2 CHO CH3 CH CH2 CHO
OH
Sn phm to ra c ct phn on v dng lun v nu lu s dime ha chuyn
thnh parandol:
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CH3 CH CH2 CHO
OH O O
CH2 CH CH3OH
HO CH32
2
Phn ng dime ha gia hai xeton cng loi. V d hai phn t axeton t ngng t vi
xc tc l Ba(OH)2 trn si ca axeton:
CH3 COCH3Ba(OH)2
CH3COCH2 C CH3
OH
CH3
H2O CH3CO CH C CH3CH3
_2
Phn ng gia aldehit v xeton:
C6H5CHO + CH3COCH3 C6H5CHOH
CH2 CO CH3
C6H5CH CH CO CH3
C6H5CHO + CH3COCH3 C6H5 CH CH CO CH CH C6H52
Trong trng hp ny aldehit phn ln ng x nh thnh phn cha C=O hot ng,
cn xeton nh thnh phn cha H hot ng. V d khi cho benzaldehit phn ng vi
axeton, ty thuc t l mol gia aldehit v xeton m ta thu c sn phm mt ln aldol hay
hai ln.
Hp cht nitroalcan cng phn ng aldol c vi aldehit hoc xeton, xc tc l amin
bc nht, sn phm thu c hu ht l loi b dehydrat ha.
C6H5 CHO + CH3 NO2 C6H5 CH CH NO2
C6H5 C
CH3
O + CH3 NO2 C6H5 CH
CH3
CH NO2
Nhng nu dng xc tc l cht trao i ion loi amin v tin hnh phn ng nhit
phng s thu c sn phm cha ehydrat ha :
C6H5 CHO + CH2 NO2
CH3
C6H5 CH CH
OH
NO2
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Phn ng gia aldehit thm vi anhydit di xc tc mui kim loi kim ca axit
tng ng (phn ng Perkin).V d iu ch axit xinnamic(axit -phenyl acrylic) l
nguyn liu quan trng trong thnh phn tinh du qu, ngi ta cho benzaldehit phn ng
vi anhydrit axetic khi s c mt ca xc tc natri axetat:
C6H5 CHO + (CH3CO)2ONaOCOCH3 C6H5 CH CH COOH
Phn ng gia mt anldehit hoc xeton vi hp cht cha C-H hot ng do hai
nhm ht in t to ra di xc tc bazo (phn ng Knoevenagel).C ch ca phn ng
ny c bn ging vi phn ng aldol ha xc tc bazo, duy ch c iu khc l khng th
phn lp c sn phm cng hp do nc qu d dng b loi ra to thnh sn phm
ngng t:
C O
R1
R2
+ H2C
X
Y
bazo
-H2O
C C
R1
R2
X
Y
Trong : X, Y l cc nhm th ht in t: COOH, COOR, CN, CONH2, NO2,
CHO, COR. R1, R2 l H hoc alkyl
Phn ng tng t nh phn ng aldol khi mt trong nhng hp cht cha H hot
ng c cha nhm halogen ht in t ( phn ng Dazens). Phn ng ny dng natri alcolat
lm xc tc:
C O
R1
R2
+ CH2
Cl
COOC2H5 C
R1
R2
CH
OH Cl
COOC2H5
-HCl
C
R1
R2
CH
O
COOC2H5
1.thuy phan2decacboxyl hoa
CH
R1
R2
CHO
Vy phn ng Dazens m ra con ng mi tng hp cc aldehit c s cacbon ln
hn mt i t mt xeton.
Cc hp cht d vng cha nito c nhm metyl ti v tr th 2 hoc 4 cng d dng
tham gia phn ng ngng t kiu aldol vi cc hp cht oxo(phn ng Ladenburg):
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N CH3
+ OHC-H2O
NCH CH
2-picolin
N
CH3
+
OCHO NO2
-H2O
N
CH CH
O NO2
lepidin
Xc tc ca phn ng Ladenburg l pyperiddin, i khi ch cn ti s un vi axits
axetic.
Trong phn t este ca axit sucxinic d khng c H hot ng lm nhng di tcdng ca mt ng lng mol natri alcolat phn ng ngng t kiu aldol cng c xc
tin (phn ng ngng t Stobbe):
C O
R1
R2
+ CH2 CH2
COOEt
COOEtNaOEt C
R1
R2
O-
CH
COOEt
CH2
C O
OEt
O
COOEtR2
R1
O
O
COOEtR2
R1
O
+
EtO
(-)
C C
R1
R2
COOEt
CH2 COO-
thuy phn
C C
R1
R2
COOH
CH2 COOH
Aldehit hoc xeton tc dng vi cc alkyliden photphoran cng nh sn phm ngng
t aldol (Phn ng Wittig):
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P
R
R
R
* CH(+) R1
R2
X
(-)bazo
(-HX)P
R
R
R
C
R1
R2
P
R
R
R
C
(+)R1
R2
(-)
mui photphoni "photphoran" "ilid"
PR
R
R
C
R1
R2
+ O C
R3
R4
C
R1
R2
C
R3
R4
+ P
R
R
R
O
"photphinoxit"
C ch phn ng ny thc cht l phn ng cng nucleophyl ca C=O vi ilid:
P
R
R
R
C
R1
R2
+ O C
R3
R4
P C
O C
R
R
R
R1
R3
R4
R2
(+)
(-)
P C
O
R
R
R
C
R1
R2
R3
R4
P
R
R
R
O + C
R2
R1
C
R3
R4
Phn ng Witting c ngha thc t rt ln, c bit do phn ng c chn lc
cng nh kh nng phn ng cao ca n. Phn ng c s dng rng ri bin i nhiu
loi hp cht c cu trc phc tp. Hiu sut phn ng cao, thng t t 80 dn 95%.
Tc nhn ca phn ng Witting thng i t triphenylphotphin,alkyl halogenua tng
ng v butyl hoc phenyl liti hoc natri amit hay natri hydrua, ngay c natri alcolat v
NaOH:
Ph3P+ Cl CH2CH3 Ph3PCH2CH3
(+)
Cl
(-) PhLiPh3P CH2 CH3
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Vi cc alkyl halogenua c cha nhm th ht in t mnh, vic chuyn ha to
photphoran cng d, lc ny ch cn tc dng ca kim cng cho phn ng thc hin:
Ph3P + Cl CH2CN Ph3PCH2CN(+)
Cl
(-)NaOH
Ph3P CH CN
Ban u phn ng tng hp Witting t c s dng trn quy m cng nghip do gi
thnh Ph3P qu t. Nhng v sau ngi ta thy rng c th thay Ph 3P bng trimetyl hoc
trietyl photphit m hiu sut phn ng t c cng kh tt. Trong trng hp ny qu
trnh phn ng s l:
(CH3O)P + Br CH
R1
R2
(CH3O)P CH
O
R1
R2
+ CH3Br
(CH3O)P
O
CH
R1
R2
NaCH3(CH3O)2P C
O
R1
R2(-)
(CH3O)2P
O
C
R2
R1
(-)
(CH3O)2P
O
C
R1
R2
(-)+ O C
R3
R4
C C
R1
R2
R3
R4
+ (CH3O)2P O
O(-)
Photphonat
Phng php photphonat ny ch c mt yu cu l t nht mt trong hai nhm th R1
hoc R2 phi l nhm th ht in t (trong nhiu trng hp ch cn nhm aryl l ). Tc
nhn photphonat c cu trc khng gian ln nhng nh c tnh nucleophyl ln nn trong
phn ng Witting nhng hp cht xeton c kh nng phn ng hi km cng cho hiusut phn ng cao hn so vi tc nhn photphoran, v bn cht ca phn ng Witting l cng
nucleophylcuar nhm cacbonyl.
Trong phn ng Witting, bc u tin l to ra mui photphoni v hp cht ilid.
Bc ny thng c xc tin trong dung mi tr nh bezen hoc, ete i khi trong iu
kin nung chy khng c dung mi.
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Vic to hp cht ilid bng phenyl hoc butyl liti thng hay c tin hnh trong
dung mi loi ete khan nc nh dioxan, tetrahydrofuran, 1,2-dimetoxy etan hoc trong
dietyl ete, cn nu to ilid bng natri alcolat th dung mi s dng c rt nhiu loi ngay
c cc loi alcol, thm ch c nc khi dng NaOH.
Phn ng Witting vi xeton, alehit c tin hnh trong cc dung mi phn cc
mnh, v trong c hp cht ilid ln cc hp cht oxo u ha tan c mt mc
nht nh. Cc dung mi thng c s dng l dimetyl formamit, dioxan, thm ch c axit
formic.
Phn ng Witting l phng php duy nht c hiu qu iu ch cc dn xut mt,
hai ln th v tr ca axit acrylic:
CH
H3C
H3C
C
O
CH
C2H5
CH CH2
+ P
OH3C
OH3C
CH
O
(-)COOCH3
hiu sut 75%
CH
C2H5
CHH2C
C
HC(H3C)2
CH COOCH3
Hp cht ilid trong phn ng trn dc iu ch t trimetyl photphit v este ca
bromaxetic:
(CH3O)3P + BrCH2COOCH3 (CH3O)2PCH2COOCH3
O
+ CH3Br
(CH3O)2PCH2COOCH3
O
NaOCH3P
OH3C
OH3C
CH
O
COOCH3
(-)Na
(+)
Phn ng Witting c bit c s dng nhiu, c hiu qu v khng th thiu c
trong tng hp cc hp cht thin nhin dng lm dc phm nh tng hp vitamin A, D,
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cc tecpen, cc carotenoit, cc prostaglandin v cc hp cht hocmon thc vt c mch
cacbon cha nhiu lin kt kp (cc juvenin hocmon) do phn ng rt c bit v chn lc.
4.7. Cch tin hnhTy thuc cht khi u a vo thc hin phn ng aldol v sn phm cn iu ch
ra ch l sn phm cng hp hoc sn phm dehydrate ha m c nhng phng php diu
ch v x l khc nhau. Sau y l mt s phng php tin hnh c tnh cht tng qut .
4.7.1. iu ch sn phm cng aldol t alehit mch thng
Ha tan 1 mol alehit trong ete, va lm lnh va nh git t t 0.02 mol dung dch
15%KOH trong methanol, trong qu trnh ny duy tr hn hp phn ng 10 n 150C. Sau
khi cho xong, khuy nhit phng dn khi phn ng kt thc (1.5 n 2 gi). Dng axitaxetic long a v pH trung tnh, loi kali axetat, lm khan vi natri sunfat, ct loi dung
mi p sut gim, ct thu sn phm cng aldol nhit si thch hp.
4.7.2. iu ch sn phm cng aldol t alehit mch thng v xeton
Cho vo bnh 1 mol xeton, 0.03 mol dung dch 15% KOH, va lm lnh va khuy
v nh git t t dung dch 1 mol aldehit va mi ct li ha tan trong 100 ml ete vo dung
dch trn (trong vng 4 n 6 gi) nhit 10 n 150C.Sau khuy thm 1,5 gi nhit
phng.Dng axit axetic long a v pH trung tnh. Lm khan, ct loi dung mi v ctsn phm p sut gim thu sn phm cng aldol nhit thch hp.
4.7.3. iu ch ,-xeton khng no (sn phm ngng t aldol) bng phn ng gia
alehit thm vi xeton
Ha tan 1 mol alehit thm v 3 mol xeton trong 200 ml methanol khong 20 n
250C, va khuy va nh git vo 0.05 mol dung dch 15% KOH trong methanol. Sau
khuy thm 3h nhit phng. Dung axitaxetic long a pH v trung tnh. Nu sn phm
l cht rn ta ra th lc, ra vi nc sau kt tinh li trong dung mi thch hp. Nu sau
khi trung ha m sn phm khng ta ra th hn hp phn ng c pha long vi nc,
chit vi ete. Dch ete c lm khan bng Na2SO4, ct loi dung mi, cn c kt tinh
trong dung mi thch hp hoc ct di p sut gim thu ,- xeton khng no.
4.8. Mt s v d
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Trong qu trnh tng hp khng sinh cloramphenicol bng phng php ha hc,
ngi ta s dng phn ng aldol ha ca benzendehit vi 2- nitroetanol to ra sn
phm trung gian 1-phenyl-2-nitropropandiol- 1, 3.
CHO + H2C
NO2
CH2OH CH
OH
CH
NO2
CH2 OH
CH
OH
CH
khu ha
CH2
NH2
OH
1.axetyl ha2.nitro ha
3.daxetyl ha4Cl2CHCOOCH3
O2N CH
OH
CH
NH
CH2OH
COCHCl2
cloramphenicol
Trong qu trnh tng hp thuc bo v thc vt loi juvenin hocmon ngi ta cng
s dng phn ng aldol gia dihydro xitronellal vi dimetyl glutaconat trong mi trng
phn ng este, sn phm ngng t cng b thy phn cho thnh phm mui dinatri ca
dn xut metylen glutaconat:
CHO + CH3OOC
CH2
C
CH3
CH COOCH3
NaOH/CH3OH CH
COONa
C
CH3
CH COONa
Trong qu trnh tng hp ton phn alcaloit papaverin( dc phm c tc dng h
huyt p) ngi ta cng s dng phn ng aldol ha iu ch homoveratrylamin- mt
nguyn liu chnh trong qu trnh tng hp i t vanilin:
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HO
CH3O
CHO(CH3)2SO4
OH3C
OH3C
CHOCH3 NO2
OH3C
OH3C
CH CH NO2
[H]
OH3C
OH3C
CH2 CH2 NH2
Homoveratrylamin
1)HOOC CH2OCH3
OCH3
2)POCl33)Ni_Rancy(-H2)
N
OH3C
OH3C
CH2 OCH3
OCH3papaverrin
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CHNG 5: CLOMETYL HA CC HP CHT NHN THM5.1. i cng
Clometyl ha cc hp cht thm l phn ng thay th hidro c cc hdrocacbon thmbng nhm bng nhm clometyl (CH
2Cl) thng phn ng gia hp cht nhn thm v hn
hp ca fomaldehit v axit clohydric vi cht xc tc l ZnCl2Phng trnh:
Ar - H + CH2O + HClZnCl2
Ar-CH2-ClPhn ng ny do Blanc tm ra vo nm 1923 nn cn c gi l phn ng BlancPhn ng clometyl ha ch c ngha thc t trong hp cht nhn thm.
5.2. C ch phn ngPhn ng clometyl ha thc hin n gin nht trong mi trng axit clohydrit vi
fomaldehit. Trong trng hp ny trc ht fomaldehit ly thm proton v hnh thnh cationoxymetyl:
CH2 O + H(+)
H
C
H
OH
+
CH2 OH
(+)
Chnh cc cation ny tn cng vo hp cht thm theo kiu th electrophyl to ra
dn xut hydroxymetyl ca hp cht thm:[CH2-OH]
(+) + Ar-H ArCH2OH + H(+)
Trong mi trng axit clohydric, dn xut hydroxylmetyl va to thnh li tip tcphn ng to thnh sn phm n nh hn l dn xut clometyl v diarylmetan:
Ar-CH2OH + H(+) ArCH2OH2
(+)
Ar-CH2Cl + H2O
+Cl(-)
-Cl(-)
Ar-H
Ar-CH2-Ar + H(+) + H2O
Nh vy phn ng to ra c dn xut clometyl v diaryl metan. C ch trn cng chothy axit v cht loi nc u xc tc cho vic to ra c hai loi sn phm, cn ion clorua
bo m cho s hnh thnh dn xut clometyl.5.3. Cc phn ng ph
Nh trong phn c ch phn ng cp, n xut diaryl metan s c to ra do
trong qu trnh thc hin phn ng lun phi tnh ti iu ny. Vi vic lm tng nng ion clorua trong hn hp phn ng v vi vic s dng d lng formaldehit cng nh nng axit v chn c nhit phn ng ph hp ta c th kim sot c phn ng to rasn phm diaryl metan.
Nu hp cht nhn thm l cht hot ng tng i mnh hoc mi trng phn ngqu khc nghit th n xut di- hoc tri-clometyl cng s c to thnh. nhng hp cht nhn thm c cha nhm th ha nhn ( hot ng mnh ) nh phenol vamin, cn phi tnh ti sn phm do hai loi phn ng ph kt hp vi nhau sinh ra sn
phm a trng ngng ( sn phm cao phn t ca phenol v formaldehit ). Bng cch iuchnh t l mol v khng ch nhit thch hp, ngi ta c th hn ch c hai loi phn
ng ph ny:
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OH OH
OH OH
CH 2 CH2
CH2
CH2
CH2
CH2
CH2
CH 2
OH
m + (CH2O)n
5.4. Cc tc nhn clometyl ha5.4.1. Formaldehit v axit clohidric
Formaldehit va axit clohidric l tc nhn clometyl ha c s dng ph bin nht.
formaldehit c th s dng c dng dung dch c dng polymer. Trn th trng formaldehitdung dch nc c nng khong 35 n 40%. Cc polymer formaldehit u th rn nn bo qun v d vn chuyn hn. Trong thc t cc plome mch thng ca formaldehit th
para- formaldehit HOCH2-(CH2O)n-CH2OH c ngha nht.Cc polyme mch thng c phn t lng nh ca para-formaldehit ha tan c
trong cc dung mi hu c phn cc m khng b phn hy. Cc para-formaldehit c trn thtrng thng c t 8 n 100 n v phn t. Cc polyme foramaldehit trong nc lnh
phi sau nhiu tun, trong nc nng phi 1 n 2 gi mi phn hy v ha tan c. Dungdch formaldehit c to ra t polyme rn hoc t kh u c tc dng nh nhau. Clometylha bng polyme para-formaldehit hoc bng kh foemaldehit u c.
5.4.2. Cc diaxetal formaldehit v axit clohydricHai loi diaxetal formaldehit hay dng l dimetyl v dietyl axetal formaldehit. Chng
c iu ch t formaldehit v alcol tng ng l metanol hoc etanol:CH2(OCH3)2 CH2(OC2H5)2dimetyl axetal dietyl axetalTrong qu trnh phn ng s loi ra hai phn t alcol:
OH OH
NO2
+ H2C
OCH3
OCH3
NO2
CH2Cl
+ 2CH3OH
5.4.3. Cc clometyl ete
Hai ete hay c s dng l clometyl metyl ete CH3OCH2Cl v di(clometyl) eteClCH2OCH2Cl.
y l cc tc nhn clometyl ha mnh, nu s dng cc tc nhn ny clometylha s khng cn dng axit clohydric:
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(CH3)2CH
CH(CH3)2(CH3)2HC
+ CH3OCH2ClSnCl4
(CH3)2CH
CH(CH3)2(CH3)2HC
CH2Cl
+ CH3OH
Clometyl metyl ete c iu ch t formaldehit, axit clohydric v metanol, cn
di(clometyl) ete c iu ch t para-formaldehit trong mi trng axit sunfuric c v khHCl.5.5. Cht xc tc
Proton xc tc cho qu trnh phn ng v thng ngi ta dng lun bn thn axitclohydric, nn khng nht thit cn ti xc tc ring khc. nhng phn t c i lc hotng mnh, phn ng c thc hin khng cn dng ti xc tc ca axit clohydric. C ths dng xc tc c kh nng dehydrat ha nh axit sunfuric hoc clorua kim loi (ZnCl 2,
SnCl4 ).5.6. Dung mi
Dung mi thng dng nht l nc .i vi nhng cht khng ha tan c trongnc ,c thc hin clometyl ha iu kin d th hoc trong mi trng khng c dungmi hu c tr vi tac nhn clometyl ha.Vi cc tc nhn clometylmetyl ete ,hocdi(clometyl) ete ,c th tin hnh trong mi trng khan nc trong cht phn ng hoctrong mt dung mi hu c khc.5.7. Phm vi ng dng ca phn ng
C th ni tt c cc hp cht thm u c th clometyl ha. C th clometyl ha cchp cht l dn xut ca benzen, naphtalen, phenantren, antraxen v c hp cht d vng nh
pyridin,thiophen, cc cht ha hc t than .Nhm clometyl th vo phn t nhn thm nh l tc nhn electronphyl, do ntun th tt c cc nguyn tc trong nhn thm.
Thng thng khi clometyl ha cc dn xut cha th ca nhn thm cho hiu sutcao hn so vi dn sut th ca n .C th tin hnh clometyl ha cc ng ngalkylbenzen iu kin phn ng iu kn phn ng nh nhng,sn phm to ra ch yu lcc para,c th tip tc a nhm clomettl th 2 vo nhn nhng vi hiu sut gim i sovi phn ng th 1
CH3
CH3
CH2Cl
CH3
CH3
ClCH2
CH3
CH3
CH2Cl
Vi cc dn sut ca phenol, do phn t qu hot ng nn ngay trong iu kin nhnhng vi dung dch nc ca formaldehit v axit clohydric cng khng khng ch c
phn ng dng li mc sn phm mono.Vi nhng hp hp cht nh th ,trc ht ngi
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ta phi lm gim hiu lc ca phn t nhn thm bng cch t ha nhm hydroxi ca phenolvietyclo format v clometyl dn sut mi to thnh l etylphenylcacbonat thy phn este nhn li dn xut phenol:
OH
ClCOOC2H5
OCOOC2H5
CH2O/HCl
OCOOC2H5
CH2Cl
OH-
OH
CH2Cl
Amin thm khng th clometyl ha c (v to sn phm nha ha) nhngarakylamin c th clometyl ha vi hiu sut rt tt ,sn phm la hn hp c para ln octo:
CH2NH2 CH2Cl
CH2NH2
CH2Cl
CH2NH2
i vi cc cht thm b giam kh nng phn ng (cha nhm th loi hai ngay cdn xut nitro) cng c th thc hin vic clometyl ha nhng hiu sut rt thp v thc tcc phn ng ny rt t c ngha (clometyl ha cc hp cht clobenzen, brombenzen, p-diclobenzen, axit benzoic).
Nhng nu cc dn xut cha nitro ,halogen hoc cacboxyl cn cha thm nhm OHca phenol hoc nhm alkyl (cnh nhiu nhm cng tt), n s hot ha nhn nn lc nyqu trnh clometyl ha t c hiu sut rt tt:
COOH
OHOH
CH3
Br
CH3CH3 CH3CH3
Br
CH3ClCH2
ClCH2
(ClCH2)2O
H2SO4
CH2O/HCl
COOH
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Cng c th clometyl ha cc xeton thm nu trong nhn thm ca xeton c cha ccnhm hot ha (OH hoc alkyl):
CH3
COCH3
CH3
CH3 CH3
ClCH2
CH3
COCH3
CH3
hot ha nhn thm ca cc nhm th tng dn theo trinh t sau :C3H7O >OCH3 >C3H7 >C2H5> CH3
Cn gim kh nng phn ng ca cc nhm th tng dn theo trnh t sau:NO
3> COOH >CH
2CL >I >Br >I
Sau y l gi tri tng quan v kh nng clometyl ha ca mt s dn xut benzen:Benzen : 1 toluen : 3 m-xylen : 24Mezitylen : 600 ansiol : 1300 3,5-dimetylanisol : 1000005.8. Cch tin hnh phn ng
Trng hp tc nhn clomertyl ha l hn hp formaldehit v axit clohydric, thngthng ngi ta cn ong ton b khi lng cc cht tham gia phn ng cn thit v cho vo
bnh phn ng, sau lm nng v ngoi nng hn hp phn ng ln nhit thch hp.Trng hp phn ng xy ra qu mnh lit, nn cho t t cht phn ng vo thit b
nhiu ln, mi ln tng t mt, thm ch cng c th cho formal-dehit vo bnh lm nhiu ln trnh phn ng qu mnh lit.
Cng c th tin hnh phn ng theo phng php lin tc.Sau khi phn ng kt thc ty thuc trng thi ca sn phm cng nh kh nng ha tan
ca n m c phng php x l thch hp. Nu sn phm to thnh kt ta trong qu trnhphn ng th cng vic x l ch cn lc loi khi cht lng sau ra n axit, kt tinh litrong dung mi thch hp. Nhng nu sn phm l th lng th gn tch pha, ra li pha hu c
bng dung dch baz long sau bng nc, tip l khan nc v ca loi dung mi sau ct phn on thu sn phm. Ch trc lc ct phi ra ht axit v axit s xc tc cho qu trnhhnh thnh sn phm ph.
Nu sn phm l cht ha tan trong nc th c th s dng phng php chit ly snphm bng dung mi.
5.9. Mt vi v dTrong qu trnh tng hp ancaloir paraverin (thuc h huyt p), ngi vclometyl ha
veratrol 1 (xem s di y) bng formaldehit v axit clohydric c homoveratrylclorua 2, sau cho cht ny tc dng vi natri xyanua c homoveratrylnitryl 3. Sn
phm mt phn c thy phn c axit homoveratric 4, phn khc c hydro ha c xctc niken-Raney c homoveratrylamin 5. Sau hai cht ny ngng t vi nhau khongnhit 170 n 180oC cho amit 6, cht ny c ng vng bng POCl3 cdihydropapaverin 7, tip dehydro ha c xc tc niken-Raney trong decalin 180oC cho
papaverin 8.
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HH3CO
H3CO
(CH2O)n/HClH3CO
H3CO
CH2Cl
H3CO
H3CO
CH2CN
NaCN
1) NaOH
2) H+
CH2COOHH3CO
H3CO
CH2CH2NH2H3CO
H3CO
178-180oC
NH
H2C
OCH3
OCH3
H3CO
H3COO
POCl3
H3CO
H3CON
CH2
OCH3
OCH3
-H2
H3CO
H3CON
CH2
OCH3
OCH3
H2/Ni-Raney
1 2
3
4 5
6 7
8
Clometyl ha hp cht mch thng:
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Nhm clometyl khng ch c th a c vo nhn thm m cn c th a vo thayth hydro hot ng nhng hp cht mch thng. V d iu ch 3-oxobutylcloruangi ta clometyl ha axeton vi paraformaldehit v axit clohydric:
H3C C
O
CH3
(CH2O)n/HCl
CH2 CH2ClCO
H3C
Cloetyl ha:Cng ging nh clometyl ha,cc phn ng cng c th thc hin khi thay
formaldehit bng paraaldehit(trime ca aldehit axetic). Phn ng ny ch thc hin c ivi cc hp cht nhn thm c hot ha. Hiu sut ca cc phn ng ny ch t 40n 60%. Trong cc hp cht cha nhm cloetyl, phn t HCl d dng loi ra to thnhdn xut ca vinyl.
OH
CHO
CH3HCl
OH OH
CH CH2HC CH3
Cl
-HCl++
Phn ng clopropyl ha hoc clobutyl ha cng c th thc hin c trn cc hp
cht thuc dn xut phenol v polyalkyl benzen.
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CHNG 6: PHN NG MANNICH
6.1. i cng
Phn ng Mannich l phn ng ngng t gia hp cht c cha H hot ng (hydro
mang tnh axit) vi aldehit v amin hoc amoniac, kt qu to nn hp cht cha nhm
aminometyl v c gi l baz Mannich.
R1 H + CHO
R2
+ HN
R'
R"
HCl R1 CH
R2
N
R'
R"
HCl.
Mi trng ca phn ng a s l axit,nn sn phm to ra l dng mui ca amin.Trong cc ti liu trc y, phn ng Mannich ch dnh ring cho phn ng gia
hp cht cha H hot ng vi formanldehit v amin bc nht, bc hai. Nhng trong ha hc
ngy nay, phm vi s dng phn ng Mannich c m rng ra cho c cc aldehit khc,
cng nh hp cht c H hot ng khng ch c hp cht cha lin kt C-H m c lin kt
N-H, S-H, Se-H, P-H.
Cng lu thm rng, phn ng gia mt hp cht c huydro hot ng vi
fomaldehit v amin u tin vi Marle v Tollens cp vo nm 1903, sau Petrenko v
Kricsenko lp li nm 1906, nhng t nm 1912 vi cng trnh hng chc nm nghin cu,
Mannich cng b mt cch hon chnh v lm r ngha thc tin ca n. Cng v th
phn ng ny t c mang tn l phn ng Mannich.
6.2. C ch phn ng
D rng a s Phn ng c tin hnh trong mi trng axit, nhng trong mi
trng vn lun tn ti amin t do, amin nay phn ng vi aldehit to ra dn xut
Hydroxymetylamin, tip ly thm proton v loi ra mt phn t nc hnh thnh
cation aminometyl:
R'R''NH2(+) R'R''NH H(+)+
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HC
H
O
R2 + HN
R'
R''
R2 C
HOH
N
R'
R''
R2 C N
R'
R''
H
+ H(+)
(-H2O)
Hydroxymetylamin cation aminometyl
Cation aminoaldehit phn ng vi dng anol ca hp cht cha lin kt C-H hot
ng (trng hp hp cht c H hot ng nm bn cnh nhm cacbonyl ca phn t) nh
mt tc nhn nucleophyl vo lin kt i C=C ca dng enol to ra hp cht cha nhm
aminometyl (Bazow mannich):
CO C H+H+
COH C
COH C + NHC
R'
R''
(+)
CHO
(+)
CHC
R2
N
R'
R''
CO CHC
R2
N
R'
R''
H(+)
Bazo Mannich
Trng hp hp cht cha H hot ng khng phi l hidro v tr bn cnh nhm
cacbonyl ( Nh trng hp hydro hot ng nm trong nhn Idol, pyrol, thiophen hocHydro hot ng t lin kt N-H, S-H, SE-H, P-H) c ch phn ng c gii thich nh sau
( vn k hiu hp cht cha H hot ng l R1H): Trc ht amin cng hp vi Cacbonyl
ca aldehit to ra dn xut Hydroxymetylamin, tip trong mi trng axit n cng
hnh thnh cation aminometyl. Cation ny nh mt tc nhn electrophyl tn cng vo in t
t do ca cc hp cht cha H hot ng to ra baz Mannich:
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+H+NHC
R'
R''
(+)
CHO
R2
+ HN
R'
R''
HCOH
R2
N
R'
R''
+H+
R2
-H2O
NHC
R'
R''
(+)
R2
HR1 + NHC
R'
R''R2
R1 H(+) + H2O
Phn ng Mannich bnh thng ch xy ra khi trong phn ng tnh Nucleophyl ca
amin mnh hn ca hp cht cha Hidro hot ng theo kiu phn ng Aldol (iu ny gii
thch ti sao t este malonat, formaldehit v dialkylamin khng th to ra Baz Mannichtng ng).
6.3. Cc phn ng ph, sn phm ph
Bc th nht ca phn ng nh l bc cng nucleophyl ca amin trn aldehit. Nu
hp cht cha C-H hot ng c tnh nucleotit mnh hn amin, n s y li phn ng
Mannich v xc tin phn ng aldol:
R H + R' CH
O
R'
OH
R
CH
Nu amin c kh nng phn ng mnh th bn cnh sn phm amin bazo Mannich
cn to ra cc amin khc , c hai H ca amin bc nht, ba H ca amoniac cng tham gia vo
phn ng Mannich:
R CH2 NH2 (R-CH2)2NH (R-CH2)3N
Mi phn ng xy ra mt pH nht nh , do vn quan trng l phi chn c
mt mi trng pH ti u. Nu khng chn c pH thch hp, nhng hp cht thm
cha H hot ng phn ng Mannich khng nhng khng xy ra m trong mi trng axit
clohydric v formaldehit th phn ng clometyl ha s c xc tin , lc ny khng ch
nhn thm c dn xut clometyl m cn nhn c c dn xut diarylmetan:
Ar H + CH2O Ar CH2 Cl +Ar CH2 Ar
.
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6.4. Cc tc nhn
Nh trn cp, phn ng Mannich l phn ng a nhm aminometyl va mt
hp cht c hydro hot ng.Tc nhn ca phn ng ny bao gm aldehyt v amin. C nhiu
aldehyt tham gia c phn ng ny nhng ch yu l formaldehyt, cn amin th gm cc
amin bc hai, amin bc mt v amoniac.
Formaldehit dng trong phn ng ny c cht lng nh formanldehit s dng trong
qu trnh clometyl ha cp .Trong phn ng Mannich, formaldehit dung dch nc l
ph hp nht, thm ch phn ng thc hin vi formanldehit loi ny cho hiu sut cao hn
khi dng paraformaldehit.
6.5. Xc tcThng thng phn ng cn ti xc tc proton. C th m bo pH axit bng dung
dch nc ca axit clohydric hoc axit sunfuric.Cng c th t c pH cn thit bng cch
cho amin vo di dng mui hydroclorua ca n.
Trong trng hp cc cht cha C-H c tnh axit yu , mi trng ca phan ng cn
thit c pH gn trung tnh , lc ny dng axit axetic iu chnh pH ca mi trng ,
thm ch c lc khng cn ti vic axit ha.
Mi phn ng Mannich u c ring mt pH ti u ca n, v vy i vi nhng phnng nht nh cn s dng mt dung dch m (buffer) m bo pH ca phn ng.
6.6. Phm vi ng dng
Trong phn ng Mannich, cc hp cht cha C-H hot ng khc nhau (R-H) phn
ng vi cc andehit (R-CHO) v hp cht main khc nhau(HNRR), do to ra mt s
lng cc hp cht v cng ln . V vy phn ng Mannich c coi l mt trong s cc qu
trnh c bn thng c s dng trong cng nghip tng hp cc hp cht hu c v trong
cng nghip ha dc. Mt s hp cht bazo Mannich c s dng trc tip lm hot
cht cho dc phm (ha dc) , nhiu cht khc c tip tc bin i thnh cc sn phm
c gi tr khc nhau.
Qu trnh aminometyl ha ( tin hnh phn ng Mannich) c thc hin trn nhiu
loi hp cht cha hydro linh ng (hot ng ), i t cc lin kt C-H khc nhau nh sn
xut ca cc xeton, aldehit, axit, phenol, hp cht d vng, t cc alkin, nitroalcan, hoc t
cc lin kt N-H ca mt s amin, amit, t S-H ca mt s dn xut thiol, t Se-H ca mt
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s dn xut selenophenol, t P-H ca mt s dn xut photphinic, do vy tng ng c cc
qu trnh i km l C-aminometyl ha, N-aminometyl ha, S-aminometyl ha, Se-
aminometyl ha hoc P-aminometyl ha.
6.6.1. Cc phn ng C-aminometyl ha (phn ng Mannich trn cc hp cht cha C-
H hot ng)
-Dialkyl xeton, aryl alkyl xeton, hoc xycloalcanon u c th amino-metyl ha c
bng aldehit (ch yu l formaldehit) v amin bc nht, amin bc hai, ammoniac, sn phm
thu c c th l sn phm th 1 ln, 2 ln hoc 3 ln ty thuc vo t l gia cht th v tc
nhn ca phn ng (aldehit v amin).
V d khi cho phenyl metyl xeton tc dng vi ammoniac ( mui Hidro Clorua ca n) vformaldehit, ty thuc t l formaldehit em dng m thu c cc loi sn phm khc nhau.
Nu t l 1:1:1 th thu c hn hp amin bc 1, bc 2, bc 3:
C6H5COCH3 + NH4Cl + CH2O- H2O
C6H5COCH2-CH2-NH2 .HCl
2C6H5CH2CH2NH2 (C6H5COCH2CH2)2NH + NH3
Khi t l gia phenyl metyl xeton : amino clorua : formaldehit l 3:1:3, sn phm thu
c l sn phm ng vng dn xut pyperidin:
3C6H5COCH3 + NH4Cl + 3CH2O
N
C6H5 OH
COC6H5
CH2CH2COC6H5
.HCl
Nhng khi cho aryl alkyl xeton tc dung vi sformaldehit v amin bc hai, sn phm
nhn c ch l 1 ln th:
CArCH2
O
R1 + CH2O HN
R3
R2
C CH
Ar N
R1R2
R1
H2C+
O
Khi thc hin phn ng Mannich trn diarakyl xeton vi cc amin khc nhau t l cc
tc nhn khc nhau s cho cc sn phm khc nhau:
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Ar1 Ar2
O
+ CH2O/NH31:5:2
+CH2O/R-NH21:2:1
+CH2O/R-NH21:4:2
N N
Ar1
O
Ar2
N
O
Ar2Ar1
R
N
O
Ar2Ar1
R
N
R
N
O
Ar2Ar1
R
Ar1
Ar2
O
CH2 CH2
Ar1 Ar2
O
CH2
++ +
Dn xut Phenol cha C-H hot ng cng c th aminometyl ha, ty thuc t l cc
thnh phn tc nhn s dng trong phn ng ta s thu c cc sn phm khc nhau:
OH
H
OH
CH2-NHR
NO
R
OH
R
N
OH
+ CH2O/R-NH2
+CH2O/R-NH22:1
1:1
Cc dn xut ca axit cacboxylic cha C-H hot ng cng tham gia phn ng Mannich:
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C
R2
HR1
COOH
CH2O/R-NH2C
R2
CH2 - NHRR1
COOH
N
COOC2H5
O
C2H5OOCR1CHO/R2NH2
N
COOC2H5
R2
R1 R1
O
C2H5OOC
N
COOC2H5
R2
R1 R1
O
C2H5OOC
R3
CH2O/R3NH2
Cc hp cht d vng cha C-H hot ng cng tham gia phn ng Mannich. V d
v iu ch gramin, nguyn liu tng hp triptamin, theo quy trnh cng nghip ngi ta
cho indol tc dng vi formaldehit v dimetylamin:
N
H
+ CH2O + NH(CH3)2
N
H
CH2N(CH3)2
Gramin
Cc hp cht alkin cha C-H hot ng cng cho phn ng amino-metyl ha:
R C CHCH2O/HN(R1)2
R C C CH2N(R1)2
Trn cc hp cht ca nitro-alkan cha C-H hot ng cng thc hin c phn ng
c phn ng Mannich:
NO2R
R
H
CH2O/HN(R1)2
NO2R
R
CH2N(R1)2
6.6.2. N-aminometyl ha
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Mt s amin c bit cha N-H hot ng cng c th thc hin phn ng Mannich.
Loi phn ng ny c bit c s dng c hiu qu iu ch cc dn xut bisamin ca
metylen:
N
H
+ CH2O +
N
H
NH2C N
Phn ng Aminometyl ha cng c th thc hin c trn mt s dn xut
Cacboxamit (amit):
CH2O/HN(R3)2CR1
N
O
H
R2
CR1N
O
CH2N(R3)2
R2
Trng hp trong hp cht c cha nhiu Hidro hot ng t cc lin kt khc nhau (
va c C-H, va c N-H), ty hot lc khc nhau ca chng m cho sn phm c cha nhm
aminometyl mt hoc tt c cc nhm c Hydro hot ng:
N
H
CH2O
N
H
CH2O
N(CH3)2
N
CH2O
N(CH3)2
N(CH3)2
H=78%
HN(CN3)2/CH2O
HN(CH3)2/CH2O
H = 90%
6.6.3. S-aminometyl ha
Phn ng Mannich cng thc hin thnh cng trn mt s dn xut thiophenol ngay
lin kt S-H:
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R1 SH
SR1 CH2 3N
SR1
NHR2 SR1
N
R2
SR1
SR1
N(R3)2
NH3/CH2O
R2 - NH2/CH2O
NH(R3)2/CH2O
OR
6.6.4. Se-aminometyl ha
Cng ging nh thiophenol, trn dn xut selenophenol cng c th tin hnh phn
ng aminometyl ha cho cc sn phm tng ng:
SeH
+ CH2O + HN(CH3)2
SeCH2N(CH3)2
SeH
+ CH2O + R-NH2
Se N Se
R
6.6.5. P-aminometyl haPhosphin v mt s dn xut hu c ca n cng phn ng vi formaldehit v amin
bc nht hoc amoniac cho cc hp cht aminometyl photphin:
PH3
CH2O/NH(C2H5)2P[CH2N(C2H5)2]3
Tng t, axit photphor v cc dn xut ca n cng phn ng vi aldehit v amin
hoc amoniac cho cc dn xut aminometyl photphonic vi hiu sut kh cao:
P HHO
HOO
N[CH2PO(OH)2]3
R - N[CH2PO(OH)2]2
[(HO)2OPCH2]2N - (CH2)n - N[CH2PO(OH)2]2H2N(CH2)nNH2/CH2O
R - NH2/CH2O
NH3/CH2O
6.7. Cch thc hin phn ng
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Thng a mt nhm aminometyl vo mt phn t cha hydro hot ng th cho
mt mol hp cht cha H hot ng phn ng vi 1,05 n 1,1 ng lng mol amin v
1,5 n 2 mol aldehit.
Thi gian cn kt thc phn ng c th ko di t vi pht n mt vi gi. Nhit
phn ng c th t 50 n 1000C ty thuc si ca dung mi dng trong phn ng.
Vi cc hp cht c hydro hot ng mnh, thng phn ng c tin hnh bng
cch nh lng ton b cht th (cht cha hydro hot ng) cho vo thit b c my khuy,
cho vo amin v lng nc cn thit, dng dung dch HCl c a hn hp phn ng
v pH cn thit. Sau va lm lnh va nh git cho formandehit vo ti tc sao cho
nhit trong phn ng duy tr trong khong 25 n 300
C. Trong qu trnh np aldehit cntheo di pH ca hn hp nu cn thit th b sung thm axit v chnh pH. Sau khi np ht
aldehit, tip tc khuy thm mt thi gian ( 10 pht n 1 gi) nhit 25 n 30 0C, sau
nu cn thit, lm nng hn hp phn ng ln n nhit si cho n khi phn ng kt
thc. Sau khi phn ng kt thc, lm lnh hn hp v ty trng hp c th m x l tinh
ch cho ph hp.
Nu lm lnh m sn phm kt tinh hoc kt ta th lc, nu khng th bo ha bng
mui n c th a v dng kt ta.Nu mui hydro clorua ca sn phm tan trong dung dch nc c th kim ha
gii phng sn phm di dng baz Mannich n kt ta hoc dng dung mi hu c
chit ly baz.
Trng hp phn ng xy ra yu, c th cho ton lng aldehit vo mt lc ngay t
u v lm nng cho phn ng xy ra.
Trng hp aldehit s dng l paraformaldehit th ton b parafomaldehit cng cc
thnh phn nguyn liu khc cng cho vo ngay t u, duy ch dung dch HCl phi cho vo
t t lm nhiu ln.
6.8. Mt s v d
1. iu ch dc phm chng st rt thuc dn xut ca cloroquin c tn la Amidoquin
v Amopyroquin, ngi ta ngi ta cung s dng phn ng Mannich chuyn p-
axetamidophenol thnh cc dn xut aminometyl tng ng, sau cho cc hp cht ny tc
dng vois4,7-dicloquinolin c cc hp cht k trn:
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OH
H
NHAc
1. HN(C2H5)2/CH2O
2. -Ac
OH
CH2N(C2H5)2
NH2
N
Cl
Cl
- HCl
+
OH
CH2HN
NCl
(C2H5)2N
OH
CH2N
NH2
N
Cl
Cl
+ OH
CH2HN
NCl
N
1. HN /CH2O
2. -Ac
Amidoquin
amopyroquin
2. ng dng phn ng P-aminometyl ha chng ti iu ch c dn xut
photphonometyl glyxin c tc dng iu ha tng trng thc vt bng cch chho axit
photphor tc dung vi formaldehit v glyxin (glyphosat) hoc diphotphonometyl glyxin
(glyphosin):
PO
HO
HO
H + CH2O + H2N - CH2 - COOH (HO)2OP - CH2 - NH - CH2COOHglyphosat
CH2O/(OH)2OPH
[(HO)2OP-CH2]2N-CH2COOH
glyphosin
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CHNG 7: NGNG T ESTE (PHN NG NGNG T CLAISEN)7.1. i cng
c trng ca qu trnh ngng t este l mt este cacboxylic phn ng vi mt hp
cht cha H hot ng (c th l H ca metylen ,metyl hoc metin ) khi c mt tc nhnngng t bazo ,trong qu trnh phn ng s loi ra mt phn t alcol v lin kt cacbon -
cacbon c hnh thnh :
R CO
OR'+ CH R CO C + R'OH
:B
Cc phn ng sau y c trng cho qu trnh ngng t este :
2 RCH2 COOR' RCH2 CO CH
R
COOR' + R'- OH
CO CH
R
COOR" + R'- OHCOOR'Ar + R CH2COOR" Ar
CO CH
R
COOR" + R'- OHCOOR'R'OOC + R CH2COOR" R'OOC
HCOOR' + H2C COOR"
NHCHO
OHC CH COOR"
NHCHO
+ R'- OH
+ R' -OHCOOR' +Ar COCH
R
CH3 COCH
R
CH3Ar CO
COOR'R'OOC (CH2)4
OCOOR'
+ R' - OH
COOR'2 R'OOC (CH2)2 + 2 R' - OH
O
O
COOR'
R'OOC
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+ 2 R' - OH
COOR'
COOR'
+ CH3COOR"
O
O
COOR"
R COOR' CH2
Ar
CN R CO CH CN
Ar
R'OH++
Trong R l ankyl ;R,R l alkyl c s cacbon t 1 n 3; Ar l aryl.
- Di y l mt v d ca ngng t Claisen ca ethyl acetate ethyl acetoacetate:
CH3 CO Et
O
CH3
CO
EtCO
CH2
O Et
O
CH3
O
CHCH3
Et CH3 CO Et
O
: C
:
COCH2
O
Et
CH3 C COCH2 Et
OO
+ EtO -C
O
CO Et
O
CH
+ EtOH
H3O+
OO
+ H2O T cc
phn ng th d trn cho thy , mt trong hai phn t tham gia phn ng l tc nhn axyl ha
,phn t cn li l cht tip nhn nhm axyl hoc cht c axyl ha (cht ny phi cha t
nht mt H hot ng).Thc cht y l mt qu trnh C-axyl ha .
Trong phn ng ny tc nhn axyl ha v cht tip nhn nhm axyl c th l mt vy cng l trng hp ph bin ca ngng t este , chnh l phn ng Claisen c in. Lc
u phn ng ngng t claisen ch b hp trong phm vi ngng t gia hai este vi nhau
,nhng v sau phn ng ny m rng ra cho c cc hp cht cha H khc ,min l cht
cha H C-axyl ha c vi axyl ca este .
Phn ng ngng t este cng c th xy ra ni trong cng mt phn t (ngng t
Dieckmann).
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Ngng t este l phn ng c s dng kh rng ri trong lnh vc tng hp hu c
,loi phn ng ny ngi ta c th tng hp c nhng phn t c khi lng phn t ln
hn so vi nguyn liu u .Sn phm to ra ca phn ng l cc hp cht cha dicacbonyl
nh - xeto este , -dixeton -andehit este , -xeto andehit . Cc dn xut dicacbonyl ny l
nhng nguyn liu tuyt vi cho nhiu lnh vc tng hp hu c ,c bit l trong tng hp
ha dc
7.2. C ch phn ngPhn ng xy ra theo c ch ion, bc u tin di tc nhn ca ngng t baz, t
thnh phn cha H hot ng cacbanion to thnh:
HCHCOYR
bazo(-H(+))
BH
(NaOR')
CHCOY
R
()
CHCY
R
O
Cacbanion
Bc th hai l: tc nhn axyl ha v cacbanion ny ( nh mt tc nhn nucleophyl )
phn ng vi nhau, sau sn phm t n nh bng cch t sp xp li in t trong phn
t. Trong phn ng, cu trc I (xem s di y) ch tn ti mt lng rt nh v n
tn ti mc nng lng cao nn c khuynh hng tch loi mt phn t ancol sinh
ra mezome anion c mc nng lng thp l dng anion axetyl axetat etyl (II):
R1CH2CO
OR'CHCOYR
R1CH2C
OR'
CHCOYR
O
R1CH2CCCOY
O
R
R1CH2CCCOY
O
R
R'OH
I
II
- Nu Y trong phn ng trn l alcoxy th y l trng hp phn ng ngng t Claisen
c in.
- Nu Y l nhng nhm th khc nhau th y l phn ng ngng t este ni chung.
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Nh thy trong c ch, y l mt phn ng cn bng nn phn ng cng chuyn
dch v pha phi nu hp cht -dicacbonyl to thnh c tnh axit mnh hn ROH. i vi
natri etylat th iu ny lun lun c p ng, v vy trong cc phn ng loi ny ngi tahay dng etyl este ca axit cacboxylic .
Thc nghim cho thy, ng lc ca qu trnh ngng t este l c gng dn ti s
trung tnh. Phn ng ch c th kt thc mt cch thnh cng nu anion mezome to thnh
c tnh kim yu hn anion ca tc nhn ngng t hoc anion ca este ( C-H hot ng ) lc
a vo phn ng.Ni cch khc, este to thnh ( v d etyl axetyl axetat ) phi c tnh
mnh hn dng HB ca tc nhn ngng t hoc phi c tnh axit mnh hn este khi u.
Trong trng hp phn ng iu ch etyl axetyl axetat, axit ca cc cht theo trnh tsau: etyl axetyl axetat > ancol > etyl axetat.
Trong trng hp etyl -izo-propyl axetat vi natri etylat, khng th thc hin phn
ng ngng t este to ra -xeto-este v cht to thnh c axit nh hn etanol:
O
CH32CHCH2CCHCOOEt
CHCH3
C2H5OH
Nh vy, iu kin cho mt phn ng este thc hin c l -xeto-este to thnh
phi c axit ln hn axit ca ancol loi ra v axit ca este a vo phn ng.
Trng hp ngc li phn ng ngng t este khng th thc hi c. Trng hp nh th
phi cn ti tc nhn ngng t c tnh kim mnh hn hoc tnh axit yu hn.
7.3. Xc tcXc tc trong cc phn ng ngng t este l cc baz.
Baz dng trong cc phn ng ngng t este thng s dng vi lng t nht lng lng mol so vi thnh phn este dng lm tc nhn axyl ha. Nh vy baz s dng
trong phn ng khng ch ng vai tr mt xc tc m cn ng vai tr l mt tc nhn
ngng t.
Cht xc tc c s dng ph bin nht trong phn ng ngng t Claisen l Natri
alcolat ,m ancol dng lm alcolat c nhm alkyl ging vi nhm alkyl ca este. V d nu
etyl este l tc nhn axyl ha th s dng xc tc l natri etylat.
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Cc baz khc mnh hn hay c s dng trong cc phn ng ngng t este l natri
hydrua, natri amidua, natri triphenylmetyl.
L d nhin tm xc tc ph hp cho mt phn ng ngng t este trc ht ngi
ta s dng th nghim phn ng vi xc tc natri alcolat, nu khng thnh cng th sau
mi th nghim vi cc xc tc khc mnh hn theo trnh t nu trn.
Dung mi c nh hng quan trng n phn ng Claisen. Nhng dung mi cng
phn cc c khuynh hng xc tin phn ng ny. Nhng dung mi c kh nng to lin kt
hydrogen s cho hng s vn tc phn ng cao nht. V d nh h dung mi ethanol/nc
cho hng s vn tc phn ng 10 ln nhanh hn sulfolane (tetramethylene sulfone, hay
2,3,4,5-tet