bg tong hop hoa duoc c. van

7/29/2019 BG Tong Hop Hoa Duoc C. Van

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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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-29-

+

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

bg tong hop hoa duoc c. van

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