GS.TSKH ..

NGUYEN MINH THAo

• (Dung cho Sinh vien va Nghien cuu sinh nqanh H6a hoc)

I

NHA XUAT BAN GIAo nu c

GS. TSKH. NGUriN MINH THAo

'"

HOAHOC

'" J. ,

CAC HOP CHAT 01 VONG

• •

(Dung cho Sinh vi'n, H9C vien cao ht;JC va Nghien CUll sinh nganh HOB h9C)

(T di ban ldn th(( nhdt)

NHA XUAT BAN GIAo DlJC

Cimg voi SI! phat trien cua h6a hoc hGu co n6i chung, til IAu h6a hQC cac hop ch«'t di vong da dl1Q'c nghien CUll va ling dung trong nhieu nganh khoa hoc, ki thuat, ding nhu trong dCri. s6ng. Nhimg chi trong khoang vai chuc narn tro lai day n6 moi diroc phat tn!n m~t each manh me va dtroc nghien CUu mot each he th6ng, dAy dU va chi ti€t tren co sCI tri thuc khoa hQC hien ~i. Ngay nay. s6 cac hop cha:t di vong diroc t6ng hQ'P va nghien ciru da wqt qua xa s6 cac hop ch6t khOng vong va vong cacbon, Thuc t€ hang nam s6 cong trinh ve cac hop chat di vong di chi€m bon nita t6ng s6 cac cong trinh ve h6a hiiu co n6i chung dUQ'c cong b6 trong cac tap chi chfnh tlnrc tren the! gioi, Chfoh vi v~y rna "Hoa h{Jc cac h(1p cMt dj vong"da tr6' thrum m~t mOo bQC quan trong, khong tM thieu dl1Q'C d6i voi cac nha h6a hQC hctu co, d4c bier d6i VO; nhtmg 'nguCri lam vi~ trong cac Iinh yVC t6ng hop h11u co, h6a diroc, san xua:t phdm nhuorn, h6a thuc v~t, h6a sinh va nghien CUu cac hop cha:t c6 hoat tfnh sinh hoc.

D~ gnip cho nghien cuu sinh, sinh vien thuoc chuyen nganh h6a hQC hihJ co, ciing nhu uft ca nhUng ai quan tarn c6 tai li~u h9C t~p, nghien coo va tham khao, cluing tOi bien SOlPl va cho xua:t ban cuon giao trlnh "H6a h{)c cac h(1p chltt dj vong" nay. Trong qua trtnh bien soan chnng tOi da tham khao chuong trinh va giao trtnh cua nhi~u mroc va nhi~u tac gia, c6 ging dua cik thanh nm mm va nhiing hieu bi€t mOO vao giao trtnh nham dam bao ttnh khoa hoc, hien ~i va sat vdi muc tieu dao tao hien nay. Thy nhien, trong 1&1 xua:t ban d.4u chA.c chAn khong tranh dircc cac tbilu OOt. Tac gia mong nhan dU<;1c nhieu y kien nhan xet, phe binh va d6ng g6p clla cac ban d6ng nghi~p va ban doc n6i chung d~ IAn xua:t ban sau hoan thj~n hem.

TACGIA

3

ChU(11Jg m9t

£)AI CLfONG V~ cAc HOP CHAT DI VONG

. ..

I - DJNH NGHlA, CACH GQI T~N V A DANH 86

1.1. I>Inh nghia

Nhu chdng ta di bi~t. cac nguyen t6 khong phAi Ut cacbon c6 cac nguyen tli trong bQ khung phan til ch,"t hUll CJ:J duqc gei chung u .. di to. Thi du: oxi, luu huynh hay nita •...

- Thong thuong ngum ta goi ctu: hop chOt dj vong la cae hlJP elull hi1u ca rna phOn Iii ella, chUng co cau tqo vong kin va trong vang co chua m~t hay nhiiu dj t(l

Trong thJ!C te'. co m<)t s6 hep cMt hfru co m~ du cting thoi min dinh nghia tren nhung l~ khong duqc' xe'p vao day cac hop ch!"t di vong. Thf d\l: etilen oxit, anhidrit sucxinic, anbidrit phtalic, phtalimit, "y-lacton. esc lactam vong kin •... Cac hqp ch~t nay ~ b] va vang, khbng b&l vtlng duOi tac dung cua nhi~t bay tac nhan oxi hOO va hoan toan khOng bie\,l lQ tinh thorn. Vi '1y, mQt each tuong Ung chang chi dugc coi nhu dAn xu!"t cua etilen glicol, axit sucxinic, axit orthophtalic, cac axit "y-halogen cacboxylic va eo-aminohexanoic •...

Glicol

CHz-COOH I CH2-COOH

Axit sucxinic

~COOH Vi-COOH

Axit o-phtalic

Etilenoxit

O-CHrCHz-CHz-COOH axit y-clobutyric

l

~O

axit m-aminohexanoic

00

y-Iacton

e-aminccaprolactam

4

V~y cac: hW chtft d! vong ma chung ta nghien coo i:J day la cac h<;1J' cha:t hGu 00 rna phon tueua chung (.'6 c:tfu tao vtlng kin, c6 chlla mt)t hay nhMu dj t(f trong vong. c6 tinh Mn tuong d6i dum tac dung cua nhiet hay tac nhAn oxi boo va c6 tfnh thorn b rmrc d¢ nha:t ~~nh. Ngoai ra, cac dAn xua't polihidro hay cac eha:t vong no nrong ling cua cluing cung duqc xtp vao day cac hgp chat di vong,

1.2. each gQI 16n

1.2 .1. each gqi ten thong thllbng

CiiQg nhu cac hop eha't hilu eo n6i chung, ten thong thirong clla cac hop cha:t di vong duqc blnb thanh dua tren tfnh cha:t d~ thu, phuong phap cht tao, ngu6n goc thien nhien hay xua:t sO' lich sir cua chung, OIing han, "furan" la ten di vong thorn 5 canh chua m¢t di t6 oxi. Ten goi nay dl1<;1c xuA"t pMt tit ti~ng HY-4P "furfur" nghia 18. "cam", sa eli nhu vay VI furan c6 th~ nhan dugc tu furfural rna furfural lai duqc ditu che' tit sl,l thuy phan "cam" loi ngo, vo trau, vo hat hay than cay lau sb khac,

B¢t loi ngO

rr

o . CHO

o

o

furfural

furan

Trong thuc M, ra:t nhi~u cac hgp cha:t di vong don gian khac ~u duqc goi bang ten thongtlurong nhu: Pirol, Thiophen, Indol, cacbazol. lrnidazol, Piridin, Piridazin, Quinolin, Acridin, ...

1.2.2. each g9i tin hf thdng

Cach g{Ji ten h~ th6ng cho ta quy tAc chung de goi ten m¢t each chinh xac va dt hi~u tft ca cac ki~u di vong. Ten gQi theo h¢ th6ng dtn;YC xay dung bang each ghep mt)t tit co han n6i lin s6' canh eua vong va; m~t hay nhMu tilp Mu ngu di chi sf! lll(fng va ten eele df t6' trong vong va m(il liep vi ngil n6i len muc d(i bdo hoa clla vong.

BAng dlWi dAy h¢ th6ng cho ta nhung tit co ban va cac ti~p vi ngil' trong ten goi cua cac di vong tu ba dtn mum canh,

NbUng tie'p eMu ngil' ghep vao cac tit tren d! chi ten cac di t6 la; oxa - chi oxi, thia - chi hru huynh, aza - chi nita, selena - chi selen •... Ngoai ra d~ n6i len s6 luong cac dj t6 cUng ten trong vong ngum ta con ghep them vao ti~p eMu ngil' tren cac·tit chi so lllqng nhu di-, trio, tetra-, ... d~ chi 2, 3. 4 •... dj to. Khi di vong chua hai hay nhieu d! t6 khac nhau thl tiep dAu ngil' pMi b&t ddu til di tt/ a nh6m cao nhtft trong bang tua.n hOM cac nguyen t6 va c6 s6' nguyen M nho nhtft trong nhom dy. Nhu v~y thu l1! 8Qi ten phai 18 0, S, Se, Te, N, P, As, Sb, Si, So. Ph, Hg, ...

5

S6c~ Tired Tit co ban va ti€p vingii' ..
vbng ban Yang chua nita Yang khong chtra nita
.
chua b30 hoa '" bao hoa chua bao hoa '" Baohaa
3 -IT- -irin -iridin -iren -iran
4 -et- -et -etidin -et -etan
5 -01- -01 -olidin -01 -olan
6 -10- -in ** -in -an
7 -epin ** -epin •
-ep- -epan
8 -ok- -okin ** -okin -okan
9 -00- -onin ** -on in onan
10 -ek- -ekin ** -ekin -ekan • Chua bao bOa nghia la U'ng vm s6 n6i dOl 1&1 nhit c6 th~ e6 trong vong,

··lbem "pehidroH vao tir co bin va ti6p vi ngil' cua cac hop eMI chua bio hoa luang U'ng.

Tiep vi ngii' thay d6i de chi muc dQ bao hoa ella vong, ChAng han, vong 5 canh chua nita chua bao hoa e6 duOi -01, nhung bao hoa lai c6 duOi olidin. Vong 5 canh khong chua nita neu chua bao hoa c6 duOi -01, nhung bao hoa lai e6 duOi -olan. Yang 6 canh khong chua nita, neu chua bao hoa c6 duOi -in, nhung n€u bao hoa lai co duOi -an, ... DOi khi cGng dang cac tiep dAu ngii' dihidro, tetrahidro, ... de n6i len muc d(I blio hoa cua Yang.

Ngoai ra, trong cac tiii li¢u chuyen mOD chung ta ciing thucng gap each ki hieu cac vi tri trong vong e6 n6i dOi ho~c da bao hoa hidro nhu sau: Thi du:

HN 3

4[ q

'<, .... N2 S N

I 1

H

~2 = 1,2,4- Triazolin (nghia Ill. 0 vi trf 2 c6 n6i dOi).

o

N

2H-azepin (nghia Ill. () vi trf 2 bao hoa hidro)

D6i vdi cae M ngung tl,l cua mot hay hai vong benzen v6i mot di vong thl goi ten bAng each ghep chit "benzo" hay "dibenzo" v6i ten ciia di vong. Thf du: .,.

A-u Vo)!

~ VoV

Benzo furan

Dibenzofuran

6

1.3. each danh 86

Ne'u d] vbng chi chUa ",,,t d! Id thl stIl danh cho dj td va ti~p tuc danh 56 nglri;Jc chic!u kim dOng hO. Quy tAc nay ciing duqc ap dung d6i voi h¢ vong ki~u benzo gorn rnQt vong benzen ghep v(ri mQt di vong chua rnQt di t6. ~i khi nguci ta con dung cac chit cai A~p nhu 0., p, y, ~ chi cac v~ trf trong vong, Thi du:

p' 403 P

, 5 2

0. Z a

1

4 5OJ3p 6 ~ I Z/2 ex

7 I

4 SA3 p

6l~.J 2

N ex 1

a dAy Z = 0, S, NH.

Neu m(Jt vong chUa nhilu di td gicfng nhau thi phai danh s6 nhu the' nao d~ cac di t6 c6 chi s6 nha nha:t co th! duqc va t60g cac chi s6 rna di t6 chiem la mot s6 nho nha:t. Thi du :

1,2,4·Triazol

1,2,4. Triazin

Neu vong chUa cae dj Id khde nhau thl s6 I danh cho di t6 dung tnroc trong c~ch goi ten theo h¢ th6ng va phd; danh s(f theo c:hilu nao de sao cho t60g cac chi s6 rna dj t6 chiem la ml)t s6 nba nh3:t. Thi du:

403

5 0/2 1

1,3-Thiazol (hay thiazol)

I ,2-oxazol (hay isoxazol)

D6i v&i cac hf ngung tu kilu dibenzo thi each danh s6 khong bAt d~u tir d] t6 rna b&t Mu til dinh tren cua vong bin phdi r6i ti€n theo chieu kim dOng h6 quanh M da vong. Nhung cfing c6 ngum danh s6 hdt dau til dinh dum coo vong ben phd; va tien ngtroc chieu kim dOng h6 quanh h¢ da vong (nhu d6i v(ri cacbazol va dibenzothiophen), Thi du :

~3

7~N~2;

8 9"~ 1

Dibcnzofuran

Cacbazol

Dibenzothiophen

Phenthiazin

7

1.4. each gQI ten va danh 56 cac h~ da dl vong ngung tu phiic tap

D6i vOi cac M da d] vOng ngung tu phuc tap ngutri ta thuong phai de: ra m~t sO' quy din'h chung sau day:

~ danh sO' duang vong quanh ben ngoai cua cac hop eh!'t da di vong cru, bit!u di~n cau tnic , cua chung v6i quy tAc dinh huang nhu sau:

~ S6160 ohit cua cac vong can duqc d~t thea dUOng nAm ngang, Thf du:

--00--'

---8----

Dinh huang dung

Djnh huang khOng dung

~ Khi c6 m~t met viti vong, s6160 nhlft cua chung can dtn;1C phan b6 sao cho vong cao han ben phai nAm phia tren true hoanh, Thi du:

--$

Qn---

DUng

KhOng dung

Sg danh s6 bdr d4u til vang dUlJc phan M" xa nhdt, dphia tren, ben phdi r6i theo chieu kim d6ng h6, bO qua cac di~m n6i. Thi du:

2

1 ~ 13 ::::... 4

Phenantrodin

Pteridin

~ goi ten cae h~ di vang da ngung tu cru, theo quy tik sau: - Chon vong co s6 :

+. CUog CCf mng thl vong nao chrra di to' dlb1g tnroe trong h~ th60g each got ten se d~ chon lam coso.

+ Vong 160 han duqc chon lam eo so.

+ Vong nhieu di t6 han duqc chon lam co sa.

~ Ki hi¢u chil theo canh. cua vang co sa ; con ki hieu sO' theo vi tri cua vong ghep via vm nguyen rAe ctanh theo chi&! oao ~ cac chi s6 c6 gia tri nho nhift va chir cai gan vm "a" nhal trong day a, b, c, ...

8

~ Trong ten goi chung thl ten cira vong CC/ sa diroc gill nguyen. con ten vbng ghep vao duqc dOi duoi thanh duOi "0". Thf du:

UJ 0:0
I
s
Be nzofu ran Dibenzothiophen
:0:,'. rJ 1 3' N 20 L~rj;J
e I b 0:; erE) b I
:::,.. 3' N 3
o ' f N a o 2' N 3
r:
Furan Pirazin Furan Di furoI2,3-b:2' ,3'-e]- Difuro(2,3-b:3',2'-el-
pirazin pirazin 4 5~3

6~ .. .Jl. _JJ 2

N Nt 7 I

H

4 5

3N~6

2~--Jl--)7

N N

1 8

Thieno[ 2,3-b [furan; (Khong phai furo[2,3-bJthiophen)

Pirolo-12,3-b[piridin ;

Piridor2,3-d [pirimidin

(Kh6ng phii PirimidoI5,6-e]piridin)

II ~ PHAN LOAf cAc HOP CHAT D~ VONG

- C6 ba hop char di vong thorn 5 canh chtra mot d] t6, do la furan, pirol va thiophen.

Furan

Q

I

H

Pirol

Q

Q

Thiophen

Neu trong cac di vong tren day. mot each hlnh tlnrc, ta thay the m~t nh6m -CH= bang mot d! t6 nito thl se c6 cac dj vong thorn 5 canh chua hai di t6, duoc goi m~t each luang ting 1£1. oxazol va isoxazol, thiazol va isothiazol, pirazol va imidazol:

() () ()
S
Oxazol I
H Thiazol
imidazol
eN 0 t»
N ... N
o~ I S--
H
isoxazol Pirazol isothiazol
9 - Tir pirazol neu thay the' tiep cac nh6m - CH = bang di t6 nita th'i se c6 cac triazol vA tetrazol.

4 N3 4N\3 N-N
5C~2 5 (, N2 (N)
N ...... N ......
I 1 I 1 I
H H H
1,2,1·lria/-o! I ,2,4·triazol Tetrazol - Cac di yang thorn 5 canh chira mot di t6 oxi (hay hru huynh) vOi hai di t6 nita dtn;IC goi l~ cae oxadiazol (hay thiadiazol).

c~ {~ /n\ {-j
....-N ....-N N, ....-N
0 0 0 0
! ,2,J·oxadiazol 1,2,4-oxadiazol 1.2.5-oxadiazol 1,3,4-0xadiazol
C~ (~ /n\ N-N
I()
....-N /N N N
S S 'S/ S
1,2,3-Thiadiazol I ,2,4· Thiadiazol 1,2,S-Thiadiazo\ 1.3,4- Thiadiazol - OJ Yang 6 canh thorn chua mot di t6 nito du<JC gQi 13. piridin. Neu mot, hai hoac ba nh6m

- CH ::: lrong vong piridin diroc thay the' bang cac di 16 nita thl se c6 cac di vong diazin, triazin

hoac tetrazin.

o

I

I

N

o

eN

)

N

Piridin

Piridazin (l,2-diazin)

Pirimidin (1,3-diazin)

Pirazin

( 1 ,4-<1i azin)

eN

>'~

N

I ,2,3-triazin

1 ,2,4-triazin

1,3,5-triazin

1,2,3,4-tetrazin

1,2,4,5-terrazin

(Triazin d6i xeng, xianidm)

- Nguoi ta cting da biet m~t s6 da.n xu{(t cua d! vong 6 canh chua mot di t6 oxi ho~ luu huynh, diroc gQi ill cac piran hose thiapiran tuong irng.

o

o

o

o

s

o

'S

n-piran

y -piran

u-thiapiran

y-thiapiran

Day la nhfing hop chat khong c6 cau tnic thorn.

10

- Khi mllt di vong ghep voi met hoac hai yang benzen ta co cac h¢ da vong kieu benzo- hoac dibenzo-. Th1 du:

Be nzofu ran

Benzol c [piridin (isoquinolin)

Benzopiridin (Quinolin)

~ I~N)(f

I

H

Benzo lei quinolin (Phenanthrolin)

Dibcnzopirol (Cacbazol)

Benzothiazul

H

I

(XNX)

1,& s

Dibenzol b:e Jthiazin (Phenthiazin)

- Hai di vong cling eo the ghep voi nhau thanh cac he da di vong ngirng tu:

Oy llslloll OJ
IlsJlsJ va
N N
~
Dirhiophen hay Thiophenothiophen Th ienoI2,3-b [furan Pirolo[2,3-b [piridin
N:J N N:J(N:J
~ (Jl
~ "
N N N N
I
H
Purin Pteridin - Ngoai cac di vong thorn 5 va 6 canh (; trim ra, cling con co cac di vong khong thorn loai 3 va 4 canh hoac 7 va. 8 canh chua mot hay nhieu di t6. Thf du:

\7

N I H

R'

" N R"

R ""0/-

o

o

Aziridin (etilenimin)

Oxaziridin

Oxetan

o

1,2-oxathietan

() <>
N
I
H
Azetidin Trimetylen-
sunfua 11

Azepin la mot di vong 7 canh chua mot di t6 nita. cac di vong 7 canh hoac 8 canh khac chua rnQt d] t6 oxi hay luu huynh hoac hai d] t6 gi6ng hay khac nhau ciing da duoc tOng hop.

o

N

I

H

COOH I

o:H2-»CO '<::::

\ /. Z N

P.P.A.

~

~~

(z=O, S)

(XNH2

+ NH2

3,3-Dihidrobenz- 1,5- diazepin-2,4- dion.

(XNH2

+

SH

CH3

I

O~~NO

IN 2

CI .&P

»

~N N02

~

. S

_2HZD + H2N-NH2

N-N

+

Phtaloyl peoxit

Stiben

ThI{C te' cac h~ d] yang 7 ya 8 canh nay ben vlmg hem nhieu so v6i. yang cacbon nrong ling. Ngoai ra cling con c6 cac h~ d] Yang chua cac di t6 khac nhu Si, Ge, So, Pb, P, As, Sb, Bi, Se, Te, ... rna trong d6 d*e biet duqe nghien cuu nhieu la cac dAn xuat cua selenophen.

12

III - PHUONG PHAp CHUNG TONG HQP cAc HQP CHAT DJ VONG

Trong vai chuc nam tIil lai day, nhieu phuong phap chung t6ng hop cac hcp ch!'t di vong dll duqc d~ xu!'t vA nghien cm.. kha chi til!t. Chtnh cac phuong phap nay da cho phep rna rong dang k~ pham vi dii!u cM' cac hqp chll't di vong khac nhau. C6 thi x€p cluing thuec vao ba loai: Phuong phap t:9ng htJP v()ng. phuong phdp vang h6a v()ng electron (tlk d6ng phan h6a lien kl!t h6a tri) va phudng phdp ngung II! da cdc enamin, Sau day chang ta se khao sat m~t s6 thl du cu the.

3.1. Cae phan (mg cl)ng hqp vong

Phdn Ung n'ng htJP vang 10 qua Irinh nul trong do xay ra su t:9ng hap cUa hai tdc nhdn vOi nhau dl tao ra m(JI phon til mai bin vilng. Trong qua trinh nay khong xay ra tach loai bA't kl rnQt phan nao clla phan tii chll't phan ling ding nhu cac lien k~t c chi dugc hlnh thanh chu khong bi dUt vcr. Trong da s6 cac tnreng hqp thueng hlnh thanh hai lien ke't c moi. Co ch€ cua qua trinh nay 13. s1! tao ra trang thai vong electron trung gian, Dua thea s6 nguyen til cua mOi phan tit tham gia true ti€p vao sll tao vang va kfch thu6c cua vong moi duqc tao thanh nguei ta c6 thi phan loai cac phan ling c(lng hgp vong nhu sau:

- C~ng htJP vong kilu 2 + 1 --+ 3. Thi du, phan img cua cacbetoxinitren vm xiclohexen:

o +: N-COOCzHs

~-COOC2HS

- C(Jng htJP vong kilu 2 + 2 --+ 4: Nh6m cac phan ling cong hop vong kiiu nay Iii chieu htrong phat tri~n dt nhanh ch6ng trong nhilng nam gan day, Thi du, phan ling cong hop cua cac xeten vao cac imin dAn tm s\l' tao thanh vong j3-lactam.

C6lls, c=c=o + C6Hs0I=N-C6IIs -C6lls /

ete

ete

2rfC

- C(Jng hr;p vang kilu 3 + 1--+ 4: Cho dt'n nay chua thll'y xu!'t hien mQt thi du nao v6 ki6u cong hop nay .

. C~ng hqp vang kilu 3 + 2 --+ 5: Nhom phan irng ct)ng hop vong kiiu nay rai ph6 bien va rnb ra kha nang rOng IOn t6ng hop cac d] vong 5 canh. Qua trinh a dAy diroc xem nhu phan Ung cua cac 1.3-htang c1,TC (trong d6 4 electron duqc phan b6 tren 3 nguyen tli) v(ri cac tac nhan "ai luang cue" khOng boo hoa (trong d6 chUa h~ 2 electron) va ket qua vong 5 canh duqc tao thanh, Thi du:

13

Cac nitrinilit, nitrinimin, nitrinoxit, diazoankan, azit, azometinilit, azome-tinirnin va cac nitron deu la cac 1 ,3~luCmg eire,

o ®

CHz-N=N +

(Diazornetan)

C6H:>CO, ...... H

CO B? ~~ ] 1.!""C=C'COCJ{j~. 1 H

~vC6H5 l~~"""_~~6H5 % C6HS

(Azometinilit) C6I·i:;CO - - _. H

. H COC6HS

(76%)

a

I -@ EI3N

CJis-C= N~CHz 0 -N~-o-_-20-"c""

CJisyN,ftN~ CJls1--J;'H ~ (63%)

H

CJi5C:C-CO OEt C#l5-~"":::l ~H5 EtOOCY C#ls (84%)

(Nitrinimin)

14

K co co CH:z=CH-COOEl WI ~ I

2 3 . H

(CH3hNCHO N... 0 ~ yN'N/

NH H-i-J

(Azometinimin) COO Et

(2N.)

O-CID

(DAy la mt>t tnrong hop cong hop vong nt>i phan ttt)

C6HrC-N-O _ ..... COOEt C6H5,~0 ..... COOEt

: ... (I - r~ c _

C6H1~=N-~C'NH2 N'oANH2

(Nitrinoxit)

Y6u t6 khong gian d6ng vai tro r~t quan trong trong loai phan U'ng nay. Cac olephin khong d6i xrmg co the c(tng hop vOi 1,3-luang cue theo met trong hal chieu huang khac nhau IUy thuoc vt~o ban ehai ella nh6m a ben canh n6i dOi:

- C~ng hf/p kilu 4 + J = 5:

Thf d\l dien hlnh cho loai nay la sl,I' cong hop 1,4 ella anhidrit sunfuro vao cac 1 ,3-dien:

Pirogalol

(trans, trans-hexadien)

Ch~ + S02

960C,

12gib

(cis. trans-hexadien)

I pMn

1 phAn

(san pham d6ng phan hoa)

15

Phan ling loai nay cling phu thuoc rtft nhieu van cac yeu t6 khong gian .

• Cong h9'[J Yang kilu 4 + 2 ~ 6 : Day thuc chat la phan ling c(lng hop kitu Diets-Alder, nghia la sl! cong hop cua mot dienophin ("ai dien") co lien k€t kep vao mot dien lien hop va dAn tm sl! tao thanh vong 6 canh:

........ CH3

rrH \S~H

I +

CH3-C

~H2

+

(60%)

CH3-('~-@-CH3

CH)--Z_.O (55%)

-

+

CH(COOCH3n

I~N-COOEt 01 N-COOEt

a10 tm nay phirong phap c¢ng hop vong khong cho phep tOng hop duqc di vong nhi~lI canh hon6.

3.2. Phuong phap d6ng phan hoa cac llen k€t hea trl

ve ban cM"t, co ch€ cua phuong phap nay cting gi6ng nhu phuong phap cong hop vong l:J tren, nhung chi khac 18 Sl! hlnh thanh trang thai vong electron trung gian 13. do Sl! sap xep lai h~ th6ng electron trong cung rnl)t phan tlr. Chinh VI v~y rna loai phan ling nay diroc goi la d6ng phan h6a lien ket h6a tri, 0 day khOng dy ra sir chuyen dOl cua bA't ki nguyen tit hay nh6rn nguyen tit nao, rna th\!C ch3:t chi c6 su phan b6ll;li cac electron 1t va 0" trong eA'u true cua ban than phan tit va do d6 co su thay dOi kern theo g6e h6a tri va d(l dai lien ket giita cac nguyen tir trong phan tiro Thf du:

Liel 200°c

0=C[)

(II)

(IV)

(III)

.0 day su nhiet phan hop cha:t (1) trong su c6 mat xuc tac LiQ dAn tm sl! tao thanh hOn hop trans-(II) va cis-divinyletilenoxit (III). Nhirng chi c6 d6ng phan cis khong ben nen duqc chuyen vi

16

thanh d6ng phan hoa tri luang Ung (IV), nghia Ill. dii xay ra sl! d6ng phan h6a cac lierl k~t hoa tri d~ tao thanh vong oxepin (IV), Hqp ch«t trans-(ll) hl?:n Wrig hon vi cac nhom vinyl nAm trong hai m~t phang khac nhau va khOng song song voi nhau. Vi v~y m~t trong cac di~u kien quan trong de xily ra d6ng phan h6a lien ke't h6a tri Ill. phan b6 cac nguyen tir tham gia vao sl! d6ng phan hoa lien ke't hoa tri phai 0 trong cac mat phang song song vOi nhau. Di~u nay eltn thie't de tao ra sl! phan 1>6 co 191 nhat ~ cac goc va cac dai hn;1I1g lien ket, cling nhu v~ 51! phAn b6 eo Ic;ri nh~ m~t d9 electron tren cac nguyen tu do.

Phuong phap d6ng phan hoa lien ke't h6a tri chu y€u duqc Ung dung d~ tdng hop cac di vang 7 canh chua nita hoac oxi (cac azepin ho<}.e oxepin) va c6 the eil cac vong lon han. Thi du :

- v-coaCH3

ete, if'C

3.3. Phuong phap ngung tv enamln

Enamin Ia cac amin eo chua lien k€t dOi a vi trf c, 13. Trang nhUng nam g4n dly eae enamin duQ'C sir dung ra't rong raj trong t6ng hl!P hiiu co noi.chung va t6ng hop cac di vong n6i rieng, Loai chung nhl1t ella cac phiin tmg ngung t1,l enamin 18 S\l e~ng hop vong cua cac enamin vOi nhttng hqp phan c6 kha nang pbiin tmg cao de dAn tm sl! tao tha.nh eae di vong 4,5 hoac 6 canh,

- Cac d] vong 4 canh nhan duQ'C bang sl! tirong tac cua cac enamin v&i de goc 2 nguyen tir.

Thidl,! :

(73%)

17

::t-HHCCOV

(4SI£)

- Cac di vong 5 canh dtrqc tao thanh do tuong tac eua cac enamin ¥OO. dchqpph40 l,3¥1u8ng eire (nhu da trinh bay a tren).

~s

C~S[N, ~N

N

(70%)

(99%)

0<]+

C~s

I

c

III N-O

HCllS%

Cac thi du.tren cho tathay ne-u ch€ luyen san phAm e~ trung gian vm axit thlc6 tb~ de dang loai b6 khQi san phAro phdn goc chua nita cua hop pMn enamin. Di~u nay eho ph6p rna rQng dang k~ pham vi ung dung cac enamin trong t6ng hop dj vong,

- Cac di vong 6 canh chua oxi dll'C!c t6ng hgp bang phan Ilng Clla enamin v6i '~ vii hqp eha"t . cacbonyl, thidu phan Ung cua enamin vm dixeten chAng han:

, 0 H'O FlO

~~-ctt:2-cOc~

o (64%)

Neu du xeten thl c6 th~ nhan dUQC cac u-piron :

Q) "tf" (CH3h

CH ~ D en rN(CH3n oR

~ ~N(CHY2 CH2 3~e CH3 ' 0

C + ~C_.-.. ete CH2 0 ,"

n............. =v I"' r- 0

. CH '-0=0 2~C, 4 git'l CH ~ CJis ;-)

C6H/ II \i C ·./s 'C-O . H CH2

5 CH2 IPs II

CH2

-

,CH_3D' ,0

(34%)

C-I'-I :::... 0

O"·S I

CH3

18

St,r ngung ty. cUa enamin v61 cac andehit salixylic trong dung moi tro (benzen, hexan, ... ) dAn t61 su tao thrum cac 0, Nsxetal vOi hieu suat cao. Cac xetal nay c6 the bi oxi h6a vOi S\I' tach loai cac goc chua nita va cu6i cung chuyen thanh hop chlft loai tetrahidrooxanton. V1 v~y, dAy cUng la con duong chung t60g hop cac di vong chua oxi,

o day can hru y rAng tfnh nucIeophin cao clla nguyen tll' ep trong enamin lam cho qua trlnh Csanky I h6a tro thanhuu th~ han so voi cac phan tmg khac:

-

Tfnh chat nay dugc Ung dung de rna rong cac h¢ di Yang v6i sUe cang 16'0 han nhu N-cacbankoxiaziridin ching han:

Xilen

n

~N:::COOEt

-~ (65%)

Dun sOi 4gib

Cac enamin cling dltQ'C dung lam chllt d!u de t6ng hop qua hai giai do," rn()t loat cac hqp ch«t di vong, Thi du : Tuang tac cua enamin v61 benzoylisothioxianat dan tm s\l' tao thanh trung gian dan xua:t benzoylthiocacbonyl, rna sau d6 n6 de dang dlIQ'C d6ng vong trong tetrahidrofuran thUlh dan xu4't cua pirirnidin:

r1 C6HsCON = C = s ~NH ete,Q"C

I

C~5

TIff

Dun wi

Tuang t\l'. san pharo ngung t1,l clla enamin v61 phenylisothioxianat khi tuang tAc v(ri hidrazin hay amidin se chuyen thanh cac aminopirazol hay aminopirimidin nrong tmg:

H2NNH1·HlO - EtOH

Dun wi 2gib

Et)"-"( NHC6fu

'N-N (91%)

I

H

19

· SI,r tuong tac cua ~ac enarnin b~c nMt voi cac andehit hay xeton cua day axetilen t\ID ra dc din xuat cua piridin:

~J~OOEt 0

U)H+6

Toluen

Cf)COOH Dun sOi 16 giCl

-

CXCOOBt (90%)

N CH3

CH

III -

C-CHO

HOCH:2CH20H 170-180"C, 15 giCl

(74%)

Tren d&y lit cac phuong phap chung nMt, c6 the: v~ dung d~ t60g hQP nhi~u l~i di vOOl khlic nhau, Nhung trong th1!C t€ m6i loai di vong lai c6 rf't nhieu phueng phap t6ng hqp cy th~. mil khi nghien ceu m6i loai dl vong d6 chang ta se xem xet <Uy dii va chi tie't han.

o

-

D~c tinh nucleophin cao cua nguyen tll C~ trong cac enarnin ciing duqc ang dung trong t6ng hop cac hQ'P cha:t da vong chua nita bang each axyl h6a n~i phan tir cac enamin d6. Thf dy.:

o

.......

OEt

.~

N

20

Chuang hai

NHOM DI VONG 5 CANH 1 DI TO

. . .

Nh6m di vong 5 canh 1 d, t6 baa g6m cac hop chat vong sau day:

Q (( Q Q Q
H
Furan Pirol Thiophen Selenophen Teluaphen
Q Q 0 Q
P
R/ 'R I I
H H
Silo! Gocmol PhoqxlOl Anal Thy nhien dugc nghien cliu nhi~u va ph6 bien chi III ba di vong da.u tien, Vi v~y trong chuong nay chang ta cfing chi ~p trung nghien CUu cac di vong furan, pirol va thiophen rna thOi.

I· CAU T ~O v A D!C TiNH THOM

Furan

41\.3 P S(.N)2 (l 11

H

Piroi

o

403 P 501 2 (l

Thiophen

Xiclopmtadien

Cac dj vong 5 canh chua met d] t60xi (Furan), nita (Pirol) va luu huynh.Clhiophenj.mac du ve m~t hinh thu-c cung chUa ph," cis-dien nhu phan til xiclopentadien, nhirng v! ban chA:t cau tnic va ,,*C tfnh h6a hQC lai khac hin nhau, Oting han, xiclopentadien la he dien lien hop nhung khong c6 c~u t~o thorn, trong khi d6 cac di vong furan, pirol va thiophen CI mire d¢ dang k~ d6u the hien tinh thorn, m~ dil ngay giua chang cfing c6 sl! khac nhau khli IOn.

Theo quan diem cua thuy~t obitanphan til thi cac phan tit furan, pirol va thiophen d~ mO ta nhu cac h¢ th6ng c~u tao pb!ng vOi 4 nguyen til cacbon a trang thai lai tao sp2 va m¢t d, t6oxi, nita bay luu huynh,

21

M6i nguyen tit cacbon sit dung ba obitan lai tao sp2 d~ tao lien k€t 0' v6'i hai nguyen tit cacbon ben canh (hose v6i met nguyen til cacbon va mot nguyen tl1 di t6) vA v6i nguyen tl1 hidro. D, t6 nita cting sir dung 3 obitan lai tao kitu sp2 de tao lien k€t v6i hai nguyen tir cacbon ben canh va v6'i nguyen tlt hidro. Nhu v$.y m6i nguyen tir cacbon con 1 electron p n~m cr obitan vuOng goc vOl m~t phAng vong; d6ng thoi tren di t6 nita con mot c~p electrop t1! do.·Ta:t ca 6 electron nay h9P thanh m(tt mach di~n kin, bao tram len toan ~ phan tir (xem h\nh ve). Tinh hlnh ciing urong tl! d6i v6i furan va thiophen. Chinh h¢ th6ng 6 electron 1t nay dtrqc giiii toa trong phan tit nen lam cho vong

6n dinh va thoa man cOng thuc tfnh thorn cua Hucken (L en = 4n + 2).

CAn hru y rang;' cac nguyen tir· oxi (trong furan) va hru huynh (trong thiophen) ngoai c~p electron tham gia van h¢ thorn con c6 m(Jt c~p electron nua khong tham gia van h¢ electron thorn

rna nim ;, obitan lai teo sl. nghia u.. n~m trong m~t phAng cua vong,

COn theo quan dihn clla pmrong phap set d6 h6a tri thi cac phan tit nay dU\1C xem nhu cae dang

lai tao cong huang cua m(tt day cac cau true gim han:
H H
0 - HeD - r::.~H - eb - de
X , 3 ~ X
®
(I) (II) (III) (IV) (V) Quan niem nay mO ta ro rang k!!t qua lam ma:t dinh xu clla c~p electron khOng chia xc! cr di t6 va gAn li~n vm sl! xuA"t hien di¢n tfch Am phAn tren nguyen tit cacbon cua vong (b~g di¢n tfch dUC1Jlg phan xuA"t hien tren dl t6). o dAy clfu true (I) mang sl! d6ng gop co ban. vi n6 khOng c6 su phan b6 di¢n tfch, au true (ll) va (III) quan trong hon cac clfu tnic (IV) va (V) vi chung co sl,l phan b6 di~n tich nha han. N6i cach khac, ba dang cau tnic cong huang nay phai co cac rmrc nang luong khac nhau va tft nhien sl,l d.6ng gop cua m6i m~t trong cluing van clfu tnic lai tao phai ti l¢ v6i de) dn dinh tuong d6i cua chung, rna m(Jt each tin tu"bng dm;sc phan b6 thea thu tl,l sau: I > II, III> IV, V.

Nha v$y, vOi. cA"u true electron ~c biet, cac di vong furan , pirol va thiophen d~u co tfnh thorn, tuy rAng v~ mue dQ chiing d~u nhc han so vo; benzen (phan tu benzen co th~ drrqc bi~u di~n bang hai cong thli'c rna trong d6 khong co sl,l' phan b6 dien tlch), Nhung d<> thorn giua ba di vong nay ctlng khac nhau, rna thu tl:' cO th~ x€p nhu sau: Furan < Pirol < Thiophen, Di~u nay ching nhUng dl.H;1C chung minh bCJi d4c tfnh h6a hQC rna con da<;fC the hien qua gia tri nang hrong dn dinh hoa cua chung :

22

Hop chlfl Furan Pirol Thiophen
Nbg htqng 6n dinh (kJ/mol) 92,4 109,2 130,2 o dAy ta thlfy d(l Am d:i~n cua cac di t6 thay d:6i thea day sau.O > N> S, hOi. the' cho nen furan dOng gop vao 51! t6n ~ cua cae elfu true ceng hulmg (II) - (V) nha han pirol va eiia pirol nha hon thiophen. N6i each khac oxi trong furan eho dOi electron cua mlnh tham gia VaG lien hop hoa vai. cac electron 1t nhb hon so v(ri nuo va hru huynh, do do de? thorn clla furan nho hon cua pirol va de? thorn CUa pirol nhb hon clla thiophen.

M~I khac dQ dai lien ke't trong cac phan tit furan, pirol va thiophen ciing co gia tri trung gian giii'a cac lien ttt don va dOi thong thuong.

o

1,44 A

Ql,35~

o 1,37A

o

1,43A I

tr\- 1,37A "N-\ -

I 1,38A

H

o

1,42A

6-1,37~

S 1,71A

1M" Day ding chung tb stl mlft dinh xu cia ~p eletron khOng chia xe tren di 16 va sl! dOng gop dang ke cua cac elu true eQng hucing phAn et!C VaG Sl:f t60 tai ella chang,

Nhu v~y rO rlmg ring d¢ tham cUa eac di vong nay phu thuec VaG e~p electron khOng chia xe rna di t6 dOng gop vao h~ electron 1t cua vong.

II - cAe PHUONG PHAp T6NG HQP

2.1. DUo chf troog cOng nghitp

2.1.1. Furan

Furan co the!: nh~ duqc me?t each tuong d6i don gian tir furfural, rna furfural lai duqc dieu ch€ ~ dang bAng sl! thiiy phan trong mei tnKmg axit cac polisacarit (chua trong vb trau, l6i ngO, ba mfa, than lau s~y, ... ) hay cie ch4't thien nhien khac co chira dutmg pentozo,

&! thllY phan duqc titn hanh bAng each dun soi b¢t cac phe'li¢u thuc v~ do trong dung dich axit clohidric hay axit sunfuric 12%. Trang dieu kien binh thut'1ng tir cac nguyen lieu tren co the nhan dUQIC khoing 10-13% furfural.

Ti:r furfural co the nh~ duqc furan bAng st;l nhiet phan 0 tu6n~ hoi v(ri xuc tac Ni (0 180°C) hay vOi tOi xut (03SO°C):

Phe'li~ tht;tc ~t _ Q

o CHO

Ni/280't

O +co

o

(hay vOi IOi xuV3So"q

23

TIr furfural cling cO the qua phan ling Cannizaro, ho~c t6t hon, qua st;r oxi hoa bCri oxi khong khi trong dung dich ki~m v6i d6ng (I) oxit hay bac oxit se nhan dl1qc axit furoic, rna sau do decacboxyl hea axit nay se duqc furan:

n NaOH4O% n n

'O-"CHO---- ((_O>-CH20H + 'O>--COOH

~CHO

O:zI NaOH Cu:zO/Ag20

r:>-COOH--------~

Q

2.1.2. Pirol

CO the nhan duqc pirol khi ca":t nhua than da hay nbua xuang hoac bCri tac dung cua furan vm amcniac tren nhom oxit b 400-450oC (phan ling Iurev):

Q

400"C

Q

I R

Pirol cung cO the nhan duvc mc:>t each thuan tien khi nhiet phan mu6i amoni mucat hay phan huy nhiet duang galactoza:.

H 14NOOC

Glixerin

Q

I H

(37-40%)

2.1.3. Thiophen

Trong cong nghiep thiophen dU'l;1C t6ng hop dlJa tren sl,l d6ng vong h6a but an " butadien hay buren v(jj hru huynh, cac hop ph&! duqc dun n6ng sa b¢ d~n 6O()OC r6i nhanh chong dU'l;lc chay qua 10 phin ttng. san phAro phau tmg di ra khoi 10 dU<;1c lam lanh d¢t ngt>t. Khi do thiophen dt.n;1C ngimg lai thaoh cha":t long, con hbn hop khf chua phan ling lai dU'I;IC dua van dong vong tiep thea. Cu6i cung sau khi ca":t cO the nhan duac thiophen co dt> tinh khiet t61 99%.

Thiophen ding co the duqc di~u 'ch€ bAng each dun nong h6n hop mu6i natri ella axit sucxinic v6i photphotrisunfua:

CH2COONa I CH1COONa

Q

(25·30%)

Phirong phap nay e6 the. cho 18 cac thiopben v6i nhom th€ a V! tri xac dinh neu nhu di til cac axit sucxinic thl tuong ling.

24

2.2. Tong hep Paal-Knorr

M~t trong nhirng plurong phap chung nhat d~ t6ng hop 'long furan, pirol hay thiophen la t6ng hop Paal-Knorr, Ban cha't cua plnrong phap nay 130 tac dung cua cac hop chat 1,4-dicacbony! c6 kha

nang enol h6a vci cac tac nhan dehidrat h6a c6 tfnh axit (H2SO4, P20S' P.P.A., Zn02 ... ) hoac voi amoniac hay amin b~c mot, hoac vei cac sunfua '16 ca. Thl du:

0
OjH H C6Hs C6HS
I C¢o
q\coH' P.P.A. ~H -H 0
13
H 2 (62%)
140-L'iOoC -
C=O
HI
C6Hs C6HS C6HS CH2-CH2

I I

/c;. ~C- (CH2hCOOCH3

C~s 00

.c:

C6HS S (CH2hCOOCH3

(50%)

sv 6n dinh cua cac hop chat trung gian do xu huang tao thanh di 'long thorn 13. y€u t6 quyet dinh cac phan ling nay.

2.3. Tong hqp furan thea Felst-Benarl va t60g hqp pirol theo Haotzch

Phan ling cua a-halogen xeton hay a-halogen andehit 'lUi l3-xeto este hay l3-dixeton trong s,! c6 m~t eua cac baw nhu natri hidroxit hay piridin dan t6i su tao thanh 'long furan. Phan ling nay rnang ten Feist-Benari:

Piridin

V~ co eM· e6 Ie a day xay ra qua trlnh O-ankyl h6a tnroc r6i m6i xay fa S,! d6ng 'long h6a C3 - C4 tie'p thea:

25

Neu dira vao phan lIDg loai nay cac bazo nita nlur amoniac hay amin b~c ml)t ching han thi loc d6 se nhan dugc cac pirol nrong lIDg va phan lIDg mang ten Hantzch.

N~

-

o day phan irng cua bazo nito v6i xetoeste thong thuong xay ra tnroc r6i mm tiln phin ting clla enamin trung gian v6i hop phan halogen cacbonyl va hic d6. enamin b] C-ankyl hoo. Cu6t cung

moi xay ra st! tao lien ket N-Cl d~ dong vong thanh pirol:

EtOoc.._

CH2 I C=O

CH{

-

2.4. Tong hQ'P vong plrol theo Knorr

Phan ung bao g6m sl,l' ngung tu cua cac a-aminoxeton (hay o-amino-Bcxetoeste) v6i cac xeton (hay xeto este) trong sir c6 m~t clla axit axetic (thOng thuOng han) hay kiem (thuang it han). K€t qua cac pirol dm;tc tao thanh v6i hil?u sullt cao,

o dAy cac a-aminoxeton thUCmg lai co the nh$n dU'C;'C ti:r cac (3-xetoeste hay (3-dixeton qua" giai doan nitro h6a v6i su tao thanh oxim nrong lIDg va sau d6 dU'C;'C khi't hoa tiep theo bCri kern trong axit axetic:

CH3COCH2COOEt CH3COOH

CH3nCOOEt EtOOC ~ CH3

H

(57-64%)

26

NaOH

(30%)

o

28 C, 10ngay

Tong hop nay duoc thuc hien trong mot giai doan rna khong can tach ra a-amino xeton trung gian, 00i vi cac ditu kien khir h6a ella qua trinh khong anh hueng gi d€n tac nhan thu hai, do d6 ra:t thuan ti¢n.

Co eh€ ella t6ng hop Knorr chua dU<;le nghien CUll chi ti€t, nhung c6 the: gi6i thieu rn¢t each kha tin tuem.g bang SO' do sau day:

CH3 CH2-COOFJ: ("'0 /COOEt
"' H3C,c! CH
C=O I -H2O H I'__---";U
I + C=O - -
.... C
/C~ \ /C-N/a 'CH
CH3 BOOC 1l.::J 3
EtOOC NH2 H
- 13 -~H20 H3)-{00Et
_CH COOEt
E100C EtOOC N CH3
H N.) CH3 I
H 2.5. Tong hop cac thiophen theo Hlnsberg

T6ng hop thiophen thea Hinsberg dua tren phan irng cua e-dixeton, a-halogen este hoac cac este cua axit oxalic voi dietyleste cua axit thiodiaxetic trong ditu kien cua ngung tl! Claisen (thong thuong trong s1! c6 mat ella ancolat natri trong aneol). DAy 13. phirong phap ehung t6ng h<;IP cac dan xuat cua thiophen v6i hieu sua:t cao:

COOEt 1 COOEt

EtOOC, yOOEt

+ CH2 CH

'5/ 2

27

Phuong phap nay cho phep t6ng hop de dang cac thiophen c6 hai nh6m th~ kMc nhau a vi trf 3 va 4, bOi vi cac axit dicacboxylic nhan duoc de dang bi decacboxyl h6a khi dun n6ng.

Mat khac, neu thay the' hru huynh trong phan tir cua hop phfut este bang oxi, selen hay nh6m NH thl c6 th~ nhan duqc cac dAn xuat cua furan, selenophen hay pirol nrong ling.

Ngay nay nguoi ta dii xac dinh rang monoeste cua axit dieacboxylic la san phAro trung gian d&u tien, rna co eh€ t<;10 thanh 06 nrong tu co che ngung tu Stobbe.

-

~O,

F1O~

o t~COOEt

6 5 H

-

(93%)

2.6. T6ng hop tiI este cua axit axetilen dlcacboxyUc

Cac este cua axit axetilendicacboxylic khi phAn ling v6i tile nhan nucleophin c6 1M tao thanh cac dAn xu~t cua furan, pirol va thiophen. Giai doan dgu tien cua phan ling 1~ s\l' c~ng ht1P theo ki6u Michael va tiep thea Ia S,! d6ng vong san phAm trung gian thanh san phdm eu6i cung nh" dUVC chi ra dum day:

-

28

CH3COONa CH30H,lo

o cooca, /l I

C~s-C C-H

I I _

C6Hs--c C

I <, N/ '00001

H. I )

H

(80%)

~ chwg minh cho co eM' nay, nguoi ta da tach ra duqc cac san pham hidroxidihidro trung gian va sau d6 ti~p tuc "thorn h6a" n6 met each d¢C l~p thanh cac di yang nrong img, Giai doan sau clang nlly nhAc 13 nha t61 co chI!' cua phan ling t6ng hop pirol theo Knorr b tren:

111- TiNH CHAT

ca ba di vong furan pirol va thiophen deu 16n tai a trang thai long trong cac dieu kien blnh thllbng:

o

Q

I H

o

to 320e s

d~o 0,9366

n~ 1,4216

t~ 131°e d~O 0,948 nE? 1,5035

to 84°e s

d~O 1,0644

n5° 1,5287

3.1. Phan U'ng the electrophln (SE)

Furan, pirolva thiophen c6 kha nang phan ling kha cao d6i v6i cac tac nhan electrophin, tm mac tuangduang v6i phenol va anilin,

Nhu di bitt, trong cac dj vong nay c6 SI,1' phan b6 Mt d6i xrrng dien tich, lam cho tren cac nguy~n til cacbon cua vOng tfch di~n am 16n hon tren nguyen tu cacbon cua vong henzen. Day chinh la nguyen nhan gAy ra tinh nhay cam cao cua cac di vong furan, pirol va thiophen d6i voi 81,1' tht electrophin.

Ngay trong day di vong nay ngum ta cung thA"y kha nang phan Ung th~ electrophin giarn drut tu furan den pirol r6i thiophen. Thi dl,l sau dAy clumg minh dieu do:

2. ?iridin

~rr~N02 (51%) o

29

Du6i. tac dung clla axit, thiophen to ra ben viing han furan ,va pirol. Dieu nay cho phep s\t dung rong rai cac tac nhan axit khi Iva chon di~u kien thuc hien phan ling the' electrophin a vong thiophen. Trong khi d6 d6i vm furan va pirol lai phai he't suc tranh cac tac nhan axit manh, bOi vi trong dieu kien nhu the' cluing d! dang bi polime hoa,

Cac tac nhan th€ electrophin chu yeu tAll c6ng vao vi tri 2 cua vong furan, pirol va thiophen, IXri vi trang thai chuyen tiep xuat hien trong tnrong hop nay co nang hrong tha:p han (nho su 6n dinh hoa do cong huang 160 han) so v(ri trang thai chuyen tiep dan t61 s,! th€ b vi tri 3:

{[ O:_H

o X E

X [~E

3.1.1. Sunfonic h6a

Thiophen d~ dang diroc sunfonic hoa boo axit sunfuric 95% b nhiet d~ phong voi s,! t~o thanh axit thiophen-Z-sunfonic (hieu suat 69 - 76%):

Q

Fhan ling nay xay ra d~ dang han nhieu so v6i benzen, D1Ja tren tfnh cha:t d6 nguCri ta co th~ loai thiophen ra khoi benzen ca:t tit nhira than da.

D6i voi luran va pirot khong the sunfonic h6a tnrc tiep bang axit sufuric dUQ'C. Trong tnrang hop nay nguoi ta thuong sir dung piridinsunfotrioxit tam tac nhan sunfonic h6a va khi d6 cOng nhan diroc cac dan xua:t 2-sunfoaxit nrong irng voi hieu suat cao. Thi du:

Q

+

Dicloetan

100·1 Hf'c 8-10 gic)

(90%)

(Piridinsunfotrioxit khong sunfonic h6a dU'Q'c benzen, nhirng c6 tM tac dung dUQ'C v(ri anisol va thiophen de cho dan xuat'sunfonic nrong irng v61 hieu xuat cao),

3.1.2. Halogen h6a

Halogen h6a tnrc tiep furan bAng halogen phan tu thuong di!n ra v6i t6c d~ ra:t cao, d6ng thm hidrohalogenua thoat ra lai gay OI!n sir polime h6a nhanh chong roan bQ san phdm, bbi. the' cho OI!n kh6ng the tach cluing ra duoc. Nhung trong cac dieu kien nhe nhang hon brorn c6 tM cQng hop vao vong furan de tao thanh hop chat trung gian kern ben viing nen d~ bi phan bUy bbi dung mOi thanh cac san phdm khac nhau.

30

H_D-H

CH30 0 OCH3

H,>(YH (70%)

CH3COO 0 OCOCH3

(72-76%)

Nhung t6t han ca c6 tM brom h6a furan bang phirc dioxandibromua

( Br.O GO.Br) . a cfe va khi d6 nhan duqc 2-bromfuran voi hieu suat coo.

Pirel cling d~ dang phanUng v6icac tac nhan halogen h6a, nhirng tlnrong cho cac san phAm

polihalogenua. .

Thiophen phan \lng v6i clo va boom ra't nhanh ch6ng va san phdm thuong la bOn hop rnonohalogenua ding v6i polihalogenua, rna ra't kho tach thanh timg hop cha't rieng bi~t. Nhung iOt h6a thiophen lai dien ra ra't cham. Tuy nhien c6 th~ nhan du_11C 2-Iotthiophen v6i hieu sua't cao n6u them VaG pUn Ung iot h6a mc)t luqng oxit thuy ngan trong benzen (hieu sua't 75%) hay trong mtac (70%).

3.1.3. Nitro hOa

KhOng the nitro h6a furan, piroI hay thiophen bang tac nhan va di~u kien thOng thuong nhir d6i vOl benzen, birivi de) axit cao cua mOi tnrong se gay ra su pha va phan tir va tao thanh nhua, Tac nhAn thich hep ~ nitro b6a cac di vong nay la axetylnitrat - met loai anhidrit hOn hop, nh40 duqc tir axit nitric kh6i va anhidrit axetic. Plum ung duqc thl!C hien a nhiet de) thap va cho ket qua t6t.

Q

,

H

Q-N02

II (83%)

+

rTN02 'N (5-7%)

I

H

Q

~COON02 tOe

O-N02 S (70%)

+

CSN02

S (5%)

Quacac thi du nay chang ta cling c6 th~ thay sl! khac nhau kha rO r¢t v~ xu huang va kha nang plum Ung cua cac di vOng furan, pirol va thiophen. Trong khi Sl! the electrophin a pirol va thiophen di~n ra bloh thutmg va g4n gi6ng v6i benzen thi a furan thl}'C cha't di~n ra phan irng cong va ket qua ~oth8nh cac dAn xutfr 2,5-dihidrofuran.

3.1.4. Phdn lb1g Friedel- Crafts

I>6i vOl furan va pirol khOng th~ thuc hien dU'l:1C ph3.n -ung ankyl h6a theo Friedel - Crafts vi xiic tac axit dung trong phan -ung nay d6ng thai cilng xuc tac cho ca qua trinh polime h6a cac di vong d6.

31

Thiophen do ben vilng hon voi tac dung cua axit nen co the ankyl hoa thea Friedel - Crafts diroc va k€t qua nhan duqc hOn hop cac d6ng phan 2- va 3-ankylthiophen voi ti I~ mol thay d6i tit 1 : I d€n 3 : I tuy thuoc van tac nhan va xuc tac duqc sir dung. Nguyen nhan ciia tfnh chon 19C yeu nhu v~y la do kha nang phan ling cao cua cation ankyl khi t§'n cong van di vong,

Khac voi phan ling ankyl h6a, furan r~t de dang dug<: axyl hoa theo Friedel - Crafts trong sl! c6 mat cua cac axit Li-uyt. Thf du:

~COCH:3

(75-92%)

2-Axetylpiral c6 the nhan dug<: khi dun nong tnrc tiep pirol voi anhidrit axetic ngay ca khi v~ng m*t xuc tac

Thiophen do ben vilng hon trong moi tnrong axit nen co tbe duqc axyl hoa thea FriedelCrafts voi hieu sullt cao khi sit dung cac xuc tac khac nhau:

SnC14 Henzen

!f\ (79-83%)

'S)l-...COCH3

3.1.5. Ctic phdn U'ng the electrophin khac

Furan, pirol va thiophen con c6 th~ tham gia cac phan img tM electrophin khac duqc dAn fa qua cac thi du du6i day:

* Phdn Wig thuy ngdn h6a :

Q + HgCil

CH3COONa H20,C2HSOH

~HgCI

(33,5%)

+

n

CIHg 0 HgCI

Phan irng nay cling xay ra de dang v6i thiophen, * Phdn Ung axyl h6a theo Winsmeier:

Q

I H

POC]3 + (CH3)2N-CHO -

Q-®

. CH=N(CH3}z

I e

H Cl

~CHO -iI (80%)

Furan va thiophen cho phan U'ng luang 11,1.

* Phdn ung fomyl h6a thea Gatterman (d61 voi furan va pirol):

Q

HCN

-

He]

HtJ

~CHO

32

* Phon ling clometyl h6a:

Phan tmg nay d~c bi~t dl1qc thuc hienvoi thiophen:

Q + HCHO +HCl-

Neu tren cac vi tri (l da c6 nh6m th€ thl lac nhan electrophin vAn co the! tAn cOng vao vi tri 1>:

CW:Hl~

n HCHO/HC] A_>--- (92%)

CH3 S COOCH) Zn°l' CHCI3, 25°C CH3 S COOCH3

:* Pllan irng Mannich:

Phan irng nay chung cho d furan, pirol va thiophen.

o + 'HCHO + (CH3nNH - ~o N

h

3.1.6. Quyl~t the

Nhir quy lu~t chung, chieu h11CJng cua s1,I' th€ electrophin ph", thuoc vao cac yl!'u t6 dien til nghia la dm;tc quy€t dinh hOi sl! tao thrum trang thai chuyen tiep vei muc nang lagog nM nhlft. Thi d~ :

D6i v6i cac dan xu~t chua nh6m th€ l:J ca 2 vi trf (l thl trong su th€ electrophin c6 th~ xay ra ca su thay thl!' nhom sAn c6 bang tac nhan electrophin.

33

l-HHCCOV

B)-(H3 1)HCNIHO BrnCH3
CH3 r N CHO (20%)
CH3 N COOH 2)":20
I I
H H
CH3_(")--CH3 CH)CH1Br CH3C~~CH3 - nCiI2CH3
A1a:VCS1 +
CH3 S CH3
(9·10%) (4O·SO%) Dieu nay c6 th~ giai thich bAng hai nguyen nhan: Ml)t m~t do khil nAng phau ling cao eua cac vi trf a trong cac he di vong nay dum inh hU'l1ng 6n dinh h6a cua d] t6 a cac h9P cMt trung gian. M~t khac do s\l6n dinh h6a nang hrong cua trang thai chuy&t tiep din tm sl! the' tren de vi tri (3 dlJ6i anh lurong cua nh6m the' c6 san trong nhan di vong,

D6i voi cac di vong furan, pirol va thiophen, nh6m the'dli c6 m~t trong vong d6ng vai tro quye't dinh qua trlnh the tiep tuc ; nhung di t6 cilng gay ra inh huimg dang k~ den 51! dinh hU'Oog cua nh6m the dugc dira vao tiep theo. Tuy nhien, anh hllimg dinh hlJ(mg a cua cac di t6 oxi,l1.ru hujnh va nito cling khac nhau kha rO ret,

* Nhom the' hut electron a vj trl3

Z=O,S,NH; A=nh6mMte

Truong hqp nay anh huang dinh hU'6ng a. cua di t6 va 3nh huOng dinh hU'6ng meta cUa nh6m A la cung chieu va cung guyet dinh cho nh6m the'mOi Urn cOng vao vi tri 5. Thi du :

1) HNO] I(CH3CO)z 0 2)H2504 loang

rrCHO ~NAS/

nCOOH

Br S

(69")

* N hOm the'dily electron J vi tri 3.

z s o, S.NH; A =nh6m dAye

34

Tnrf:lng hop nay 8.nh huang dinh hirong a cua di t6 quy dinh nhom tht mm vao vi tri 2 va 5. COn anh hinmg dinh huang ortho cua nhorn A quyet dinh cho nhorn th€ mm t«n cOng vao vi trf 2 va 4. Vi v~y t6ng hop ca hai anh hUCmg dan t6i. sl! th~ tiep thea uu tien hun vao vi trf 2 cUa vong. Oli trong tnrong h<;1P nay hop ch~t trung gian rnoi c6 nang IUQ1lg nhO nh~t so v6'i. cac h«;1p cUt trung gian khac c6 the d~' tao thanh trong sl.! t~n cOng electrophin b cac v! trl khac,

(Y:r

S N02 (55-60%)

Nhung trong tnrong hop khi 0 vi trf 3 co nh6m ankyi thi SI.! khac nhau trong kha nAng phan -ung gifra vi tri 2 va 5 kh6ng dang k~. Khi do ti l~ cac dong phan phu thuec mN each quytt dinh vao sl! an ngfr khOng gian do th~ tich too cua nh6m ankyl b vi tri 3 va van ban ch~t cua tac nhAn eiectrophin.

* Nh6m the hut electron J vi tri 2

Q--A

z s o. S,NH; A =nhom hut e

Nh6m Ab vi trf 2 co arm hOOng dinhhuang s1,1' tht electrophin vllo vi tri 4; con cinh huang djnh hm5ng ctia dj t6 quy dinh nh6m tM ti€p theo vao vi tn 5. Trang truOng hop nay Xliy ra sl! ~ tranh giila hai chi¢u huong va do do, c6 tM tao ra hOn hop hai dong phan, rna ti l~ giil'a chang phu thu~ vao tuang quan cua hai Anh huang canh tranh d6 va van tfnh chon h,la ella tac nhan electrophin.

Thi du :

NO@ 2

NOe ~NO-_2-

I 2

H

Qua cac thi du tren c6 the tba~y ro rang rAng a cac dan xuat cua furan thl Anh htrOng dinh huang a clla di t6 d6ng vai tm quyet dinh sl! dinh hU'6ng cua tac nhAn electrophin. Nhimg dOi v6i pirol va thiophen thl anh huOng cua nh6mth€ chiem uu th€ trong SI! dinh hU'6ng tan congcua tac nhan electrophin.

35

• Nh6tn thtdJy electron cTvj tri 2

Z=O,S,NH; A=nh6m d!ye

D~ xem xet truong hop nay c6 th~ dAn ra sa d6 phantfch nang IW1Ilg a dltCri day:

TIt Sl,l phan tich d~c tinh nang luong b tren co th~ ket luan rang sl,l the electrophin dien ra theo chieu hirong A va C c6 lqi han v~ m~t nang IW1Ilg do sl,l 6n dinh han cua hop ch~t trung gian. Nhung cling nhu tnrong hop cua cac nh6m the ankyl (nh6m A la ankyl), hieu Ung dinh hu6ng cua halogen (tv! In 2 ye'u han nhieu so v6i anh huang dinh htWng a. cua di t6. Bbi. the cho nen, trong thi dl,l neura b tren thi thuc te chi~u hu6ng Cia chU yeu va ket qua dAn xu~ 5-nitro d~ tao thAnh.

Tuy 'i1hi~ri, neu a vi trf 2 oh6m the A c6 aoh huang manh han (thi du A Itt cac nh6in -OCR3,

. .

-SCH3, -NHCOCH3, ... chang han) thl Sl,l the electrophin chu yeu xiiy ra b vi trf 3, nghia IA chi~u hu6ng A chiem uu th~ .

Ngoai ra ban cha:t cua tac nhan electrophin tlfo cOog cling gAy ra anh htdmg dmg k~ den ti I~ cac d6ng phan tao thanh,

3.2. Phin Ung thE nucleophin (SN) vtt thE' g6c (SR)

Cac phan Ung the nucleophin Va the goc d day di vong nay ra:t it duqc nghien cUu, ~ biet d6i voi pirol.

M~ du cac dAn xu!"t halogen cua furan va thiophen tirong d6i tro d6i v6i Sl,l the nucleophin (thf du: 2-brom- va 2-iodofuran khong phan Ihlg v6i CH30Na l:J lOOOC) nhung khi nang the nucIeophin l:J chung vAn cao han cac dAn xust halogen nrong ling b benzen. Di~u nay duqc gim thich rAng hi~u ling cam Ung Am cua di t6 trong cac di vong nay dil gay ra Sl,l tlng them di~n tech duoog phdn teen nguyen tit cacbon gan v6i halogen. Do v~y nguyen til halogen trong cac truemg hop nay de bi thay the nucleophin han so v6i l:J day benzen.

Tuy . nhienanh htnmg nay cling khOng dang k! lAm vi ben canh d6 con c6 hi¢u Ung lien hep nguqc l~icua halogen v6i di vong thdm (cGng nhu b day benzen) va c6 the: xiy ra sI,l va cham cua tac nhan ta.'n cOng nucleophin mang dien tfch Am v6i cac electron ptren di t6 oxi hay luu hujnh,

36

Cung nhu trong day benzen, khi dua nh6m the hut electron manh (nhir nh6m -N~ ching han) vao phan tit cac d! vang nay se lam d! dang hem cho sl,l' th~ nucIeophin. Thirong cac dAn' xuat halogen cua d] vong thorn 5 canh dU'C;IC hoathoa bCri nh6m hUt electron nhu v~y se c6 kha nang pUn Urlg the" nucleophin l6n hem rat nhieu so v(ri cac dAn xuat benzen tuong ling. V (ri tfnh chat nh6m hoat hOO ngU'Oi. ta hay dua vao di vong nh6m cacboxyl hay nhom este, vi san d6 l~ loai chang di mc)t each d! dang bAng each thiiy phan va decacboxyl hOO. Dlr(ri dAy dAn ra m~ v8.i. vi d~ :

n. CH)ONa/CH30H fi 1) NaOH 10% r\.

Br 0 COOCH3 100°C; I,S gib' CH30 0 COOCH3 2) Cu-Quinolin; '(OrOCH3

(42%) Dun sOi (36%)

Trang cac dien kien n*"g ne hem thl ngay c8. cac dAn xuat halogen cua furan va thiophen khOng chea nh6m the hut electron (nghia III khOng co nhom hoar h6a) vAn co th~ tham gia vao phlm Urlg . th~ nucleophin duqc:

n

H3C S Br Piridin; Dun sOt 8 gib'

n Quinolin

An.A + C~!iSCU

Br 0 COOH 2OCfc; 4-5 Sib'

O-S-@ (90%) o

(73%)

cac phan Urlg th~ g6c thuong xay ra a vi tri 2 cua cac di vong nay. co tht neu ra m~t s6 thi du sau dAy:

NaOH S-IO"c

Q+

,

COOEt

Q-©-cl { D6ng phan 2: 29%

o D6ngphAn3:0,7%

r:>-C~s

I

COOEt

~ (51%)

LSlN~

Nhu da bi€t, phan Urlg cUa thiophen v(ri N-Bromsucxinimit trong dieu kien nhiet dQ cao hoac chieu sang la qua trlnh th€ g6c. Nhung brom h6a 2-metylthiophen hang tac .nhan nay trong dieu ki~n nhu halogen hOO mach nMnh Clla toluen l,i dAn de~ s\l' tao thanh 5-brom-2-metylthiophen, nghia la chu yeo xay ra qua trlnh the" g6c a vong thiophen (2-brommetylthiophen duqc tao thanh v(ri luqng khOng dang kt) :

37

o ~-Br o

C04

Qua trmh nhu v~y phan aoh kha nang phan lIng Ian (so voi benzen) ella vong thiophen trong s\l th€ g6c d6ng li,

Sl,l nrong tac cua furan va thiophen voi cacben cling ditn ra thOng thirong thea kieu phan Ihlg cong hop:

Q

hv

-

H ~COOEt

{ X=O, 33% X = S, 23%

+ NzCHCOOEt

CuBr

-

{ X=O, 50% X = S, 22%

Trang khi do s,! nrong lac cua pirol v6i. cac estc cua axit diazoaxetic vaj su co mat cua xuc tac d6ng dAn. 161 S\l tao thanh san phdm blnh thirong cua su th€ electrophin. 0 da.y S\! th€ c6 the xay ra a vj trf (l va ca a vi trf 13:

Q

I

H

Cu

+ N2CHCOOEt -

(50%)

Pirol cung tham gia vao phan Ung Reirner-Tikrnann (phan irng v6i. CHC13 trong kiern manh va khi d6 t'.1O ra diclocacben) de t'.1O thanh 3-c1opiridin, hoac pirol-2-andehit, ho~c hOn h<;1P ca hai san pham do tuy thuec vao lac nhan va dieu kien sir dung. Nhung trong ca hai tnrong hqp pirol deu phan irng v6i diclocacben va t'.1O thanh hop ch~t hai vong trung gian.

Q

,

H

[ -lJI 1 HC] ~CI

C;~'CI .:__.. t. _) (12,8%)

I;:f H N

H

CHCly'KOH

ete

o CHCl3/KOH

N H20

,

H

38

~CHCI21- fl>-CHO (12.7%)

1 N

H H

3.3. Phan Ung kim ~i hoa

Furan va thiophen de dang tac dung vm n-butyllithi de cho cac dan xuat 2-furyllithi va 2-thienyllithi v6i hieu sutft eao. Khi vi tri 2 cua vong thiophen dii bi chiem thi s1,1 kim 101)1 hoa se xiiy ra a vi tri s. Di~u nay ehUng to tfnh chon IQC eao cua su t:M eOng vao vi trf a cua kim loai:

n-C4H9Li lHF.-lSoC

Khi ca hai vi tri a da hi chiem thl tfnh chon IQC hie:n nhien khong con dw;tc tuyet d6"i h6a, va We d6, s,! kim l~ hoa se phu thu()c vao bin ehtft cua cac nh6m the'da: e6 SM a cac vj tri u. GIAng han: 2~metoxi-5-metylthiophen dU'<JC metyl boa a vi tri 3 (thong qua kim loai hoa trung gian), trong khi d6 2,5 dime-tylthiophen khOng tham gia vao phan Ung nay. Ket qua nghien cuu phan ..mg kim loai hoa de din xu~ the' a vi tri 3 eua thiophen cang chi ra rAng cac nhom the' co SM co the gay HI inh hllimg dinh huang trong qua trinh nay. Thi du: Trong khi 3-metylthiophen dl1qC kim loai hoc. de dang a vi trf 5 thi phan Ung kim 1000i h6a nhu the' d6i vm 3-metoxi-, 3-metylthio- va 3-brom thiophen lai xay ra a vi trf 2. cac du kien co the dU'<JC giai thich tren co so iinh hOOng cam Ung ella cae nhOm the'd6t d¢ axit cUa cac nguyen tit hidro a vi tri 2 va 5. R6 rang rang do anh huang day electron cua nhom metyl a vi tri 3 rna hidro a vi tri 2 e6 d<) axit nha han cua hidro a vi trf 5, va nhu v.y s,! kim loai h6a i!t nhien xay ra a vi trf 5. Han nila the tich 16n cua nhom metyl a v] tri 3 cling lam han che SI! ttfn cOng cua tAc nhan kim loai vao vj trf 2. COn trong tnrong hop a vi tri 3 co nhorn the' vm hieu Ung cam Ung 1m (hut electron) thi tlnh hinh dU<;1c thtfy nguoc lai, nghia III khi do 51! kim lo,i hoa xay ra a vi to 2.

Pirol ciing de dang phan d'ng vOi tac nhan Grignard de: 1,0 thanh cac hop chat co kim. au true eua cac hop ehi"t co kim nay dU(!C xae dinh dum dang ion

o hay [0

t;l ~

MgX

-

-

Cac piryl magie halogenua khi tae dung vm cac tac nhan ankyl hoa nhir ankylhalogenua chftag han se tao ra hOn hop 2- va 3-ankylpirol (trong d6 d6ng phan 3 la chU yeu) cung v6i mot iL poliankylpirol. Nhung axyl h6a pirylmagie halogenua bAng cac axylhalogenua hay cac este lai chi tao thanh cac dan xui"t 2-axylpirol.

Pirol cflng e6 kha nang tao mu6i kim 1000i tren di t6 nita. .Ankyl h6a cac mu6i rnagie hay lithi eua pirol chu ylu nh~ duqc N-ankylpirol. Nhung ankyl h6a mu6i natri hay kali cua pirol thi hOM loan tao thanh dAn xu«t N-ankylpirol.

St! luang tae cua din xutft brom hay iOt cua furan va thiophen v61 n-butyllithi hay phenyllithi se cho cac dan xutft lithi nrong Ung eua furan hay thiophen,

39

1) n - C4H9LiJ ele 2)C02, r6i H+

D- .

HOOC S COOH

(53%)

Nhtmg chuyen hoa nay c6 y nghia quan trong, d~c bi~t d6i v6i su t6ng hop cac dAn xuat voi nh6m tht a vi trf 3 tu cac dAn xuat 3-halogen nrong tmg, bOi. vl cac dAn xua:t 3-halogen cua furan va thiophen kh6ng tM tao ra cac tac nhan Grignard.

3.4. Cac phan ung rna vong va c(tng hqp

Furan, pirol va thiophen ra't khac nhau v~ kha nang bi rnb vong. ~ rna vong furan d~t dullC bang cach sit dung cac tac nhan khac nhau nhu axit v6 00 chAng han, Trong nhi~u muc dich t6ng hop khac nhau nglIm ta dii sir-dung 2,5-diankoxi- va 2,5-diaxyloxidihidrofuran. Vi cac dAn xulit n~y dUQ'C tao ra d! dang vCri. hieu suA't cao trong cac phan lIng ceng hop ki~u 1-4 vao ¥ODg furan:

NH3JCH3COOH n (53%) N

I

H

C6HjNH2 Gt3COOH Dun s6i

o

@ (78%)

Pirol dtt6i tac dung cua axit hay haw kh6 hi YO' vong han. Nhung khi dun sOi vOi dung dich nrou cua hidroxylamin clohidrat thl pirol dUQ'C chuyen thanh sucxindiandoxim:

Q

,

H

(80%)

COn s~ khli h6a cac dAn xua:t clla pirol 00i kern trong rnOi tnrong axit dAn tm sir tao thrum ~3_pirolin :

~CH Zn/Ha MN + MN (TI 1~ 3,5 : 1) ,

CH3 ~ 3 CH3' CH3 CH3 , CH3

H H H

40

Thiophen ben vfrng han pirol va furan trong cac phan img rna vong. Mj)t tnrong hop quan trong va duy nh~t d6i voi thiophen la rna vong desunfua h6a dtJ6i tac dung cua Ni-Raney. Thi du:

Q-- NiRaney

CH(OC2H5h ---ete, Dun s6i

(50%)

Kha nang phan dng khac nhau cua furan, pirol va thiophen cling dug<: quan sat th~y qua phan ung cong h~, Khi d6 furan va cac dan xuat cua n6 duoc coi nhir phan tiI dien trong t6ng hop DielsAlder; can cac dan xua:t cua pirol tharn gia vao phan lmg nay he't sUe kh6 khan va thirc tl! lai tao ra san 'phim the!' vci anhidrit maleic:

Q

+

o

~-H

o

(95%)

(90%)

Q

I H

;.:0

+~

o

-

,()_CH-COOH

N \

I CH2-COOH H

Thiophen khOng tham gia vao phlm ..mg cong hop v6i cac tac nhan "dienophin" nhir tren,

Furan cling cong hop de dang voi dehidrobenzen d~ cho san pharn cong ben vtmg veri hieu su~t cao,

Nhimg sl! ci)ng hop tuong tl! cua piTOI the' lai dan tm su tao thanh cac dan xuat N-the cua (1- va p-naphtylamin. rna khong phai 1,4·irnin nrong ling. C6 Ie a day phan img ci)ng ki~u Diels-Alder hie dau di di~n ra va tao thanh cac imin, nhung ngay sau d6 cac imin duQ'C chuyen vi nhanh chong thrum dAn xua"t cua naphtylamin. Dieu nay hoan toan dug<: xac dinh VI thl!C te' dl1 tach fa duqc cac imin trung gian :

41

Dun sei

MgITI-lF

IV - GICU THI~U MOT vAl LO~I HOP CHAT RIENG BI~T

4.1. MQt s6 dAn xuat cua furan, plrol va. thiophen

4.1.1. Cdc andehit

* Furfural, con duqc goi u.. furfurol hay furfuraldehit, chfnh la furan-2-andehit. N6 dUVC di~u ch€ bang each thuy phan trong rnoi tnrong axil cac ph€ lieu thuc v~t chira dttOng pentozan nhu ba mfa, loi ngo, vo trau, than lau s~y •...

CHOH-CHOH -3nH20

n I I

CH20H CHOH-CHO

Q-CHO

Pentozan

Pemow(Xilow)

furfural

Thong thU'Ong thuy phan trong dung dich HO hay H2SO4 12%. Trong cong nghiep e6 th~ thuy phan bang hoi. mroc a ap suA't cao, va tuy thea thi€t bi ma eimg v6i furfural eon e6 th~ nh~ dllqC ea rnetanol, axit axetie va axeton, ...

* Pirol-2-andehit va thiophen-2-andehit (2-thenaldehit) deu c6 th~ nh*n dU"qC Mng plum tlng fomyl h6a theo Vinsmeier (nrc phan irng v6i POCl3 va dimetylfomamit hay N-metylfomanilit):

O CHl

+ <, /N-CHO

Z CJIs

0- CHl {

CHO + ?H Z=S,NH

Z CJfs

,., Rieng 3-thenaldehit (nrc thiophen-3-andehit) duqc dieu eh€ bang phan tlng cua 3-bromometylthiophen v6i urotropin (nrc hexametylentetramin) :

Cac andehit nay mang <My du tfnh ehA't cua m(lt andehit thorn, nghia la tA't ell cac phan tlng dl)c tnmg cho benzandehit. Rieng cac pirol andehit khnng tham gia vao phan tlng ngung 11,1 Perkin va phan (mg Cannizaro. Cac andehit ella cac di vong nay dUl:!C Slr dung £(Ing rai lam eMt dgu trong nhi~u t6ng bop hOU co.

4.1.2. Cd(_' dan XUGt axyl

Cac dan xuai axyl ella furan, pirol va thiophen deu nhan duqc bAng phan Ung axyl h6a thOng thuong theo Friedel-Crafts voi cac hie nhan va dieu ki~n khac nhau. Thi du :

42

9 + (CH3CO)20 BF3 ~COCH3 + CH3COOH
-
Q + (CH3COhO CH,COOH ~COCH3 + CH3COOH
..
Dun soi
, I
H H
Q + CH3COCI Alel3 Q-COCH3 + HCI
-_ Cac dan xuat axyl cua furan, pirol va thiophen la nhimg hop chat ben viIng, khong bi polime hoa va khong nr oxi boa. Chung co th~ de dang daqc khir hoa den ankyl nrong U'ng va hi oxi hoa thanh axit cacboxylic, Ngoai ra chung con <.:0 day dli tinh chat ella cac xeton beo thorn hay xeton thorn.

4.1.3. Cae axil cacboxylic

* Axit furoic, tire Iii axit.furan-z-cacboxylic, co the nhan duoc bang each nhiet phan axit muxic, hoac di til furfural qua su oxi hoa hay qua phan irng cannizaro,

CHOH-CHOH to

I I --iO

HOOC-CHOH CHOH-CHOOH

axit rnuxic

~ + C02 + H20

I(O'>-COOH

r;)-CHO

\OJ

~COOH

KOH

* Cac axit pirol cacboxylic e6 th~ nh~n duoc bang su oxi hoa cac dan xuat axyl nrong dng hoac qua eon duemg co kim.

10j

~COOH

I

H

~COOH

\

H

Q

I

MgI

* Axit thiophen-2-eacboxylie duoc ditu che tu cac dan xua:t axyl nrong irng qua eon duong oxi hoa hoac di tu cac hop eha::t co - kim ella thiophen :

\OJ

Q-COOH

NaOel hay KMn04

43

Q

Na-Hg

Q-Na

~COOH

*Rit'!ng axit thiophen-3-cacboxylic c6 the nhan dtn;*: ti:r 3-iodothiophen qua ph3n ling the' nueleophin vci xianua r6i thuy phan tiep thea:

KCN+CuCN 6nghAn kin

2H20 MOO!

Cac axit loai nay mang d~y dO. tinh cM:! cua met axit thom, Cluing c6 the de dang dll'qC este h6a, decacboxyl h6a va tao mu6i vOi. cac ion kim loai,

Ml'?t dieu dang chu y la trong cac phan -ung the electrophin nh6m cacboxyl thuong dll'qC thay the bffi chrnh tac nhan electrophin nhu nh6m nitro hay brom chAng han,

4.2. M~t viti d] vong no 5 c;,tnh 1 d] to tuong Ung

- Khi hidro hOO xuc tac furan va pirol de dang nh~ duqc tetrahidrofuran (THF) va pirolidin nrong ung:

Q

Q

Furan

1HF

Q

I

H .14

Pirol (Kb = 10 )

H2/Ni

y

H -3

Pirolidin(Kt, = 10 )

200-250"C

VI thiophen dau d¢C da s6 cac loai xuc lac nen khOng the khli h6a thiophen nhu ~n thanh tetrahidrothiophen dugc. Mu6n t6ng hop n6 phai d6ng vong tit cac hcp cMt mach thAng, thi du :

BrCH2CH2CH2CH2Br + Na2S - Q + 2NaBr Ngoai ra cling c6 th~ thirc hien su chuyen h6a thea lurep:

Q

Q

{ Z=S,NH

. Car' hop ch~t d] vong no nay khOng con tfnh thorn va vt m~t h6a hQC chdng tUCMg tt,l nbu ete, amin bee bac hai va diankylsunfua. Chinh vi v~y rna pirolidin co dQ bazo 100 hon nhltu so v6i pirol.

- Tetrahidrofuran dugc sir dung r()ng rai lam dung mOi trong t6ng hop huu co, dq.c biet dung mOi phan -ung Grignard va trong pMn -ung khir hOO nb6m cacbonyl bang LiAlH4" Tetrahidrofuran con dltgc dung trong cong nghiep IQC db va lam nguyen H¢u san xu~t SQi t6ng hop nhu nilon-66 ch~ng han :

Tetrametylen sunfon (con goi la sunfolan) - san pharo oxi boo Tetrahidrothiophen - ciing duqc sir dung lam dung mei trong t6ng hop huu ca.

44

4.3. Cae d, yang 5 ~nh 1 dt t6 trong thlen nhlen

43.1. C ac h{fp chat chiia ~ khung porphin

Nhu di bilt porphin IA h~ phan tlr bao 86m 4 vong pirol dllgc lien k€t vOi nhau IXri cac c4u n6i metin. N6 c6 clfu tao phing va co tfnh thorn

Porphin c6 chUa cac nh6m the' kMc nhau thi dlllj1C goi la cac porphirin, Chfnh porphirin la b¢ khung co ban cua nhieu phan tit hQ'P chlft thien nhien duOi dang ph1k v6i cac ion kim loai khac nhau, Nhung trong cac hop chat nay, chfnh ban than kim loai quye't djnh y nghia hoat tinh sinh hoc clia chung, Du6i. dAy cluing ta xem xet mt')t s6 hop chl(t d6.

• HEMOGLOBIN

Porphin

Hemoglobin la mt')t mu6i phrrc clla porphirin vm ion sAt. N6 chfnh 13. thanh phAn co ban tao nen h6ng cAu trong mall vA lam nhi~m V\I chuyen ehb oxi tir ph6i d€n cac t€ bao, au tao ella hemin (tIi'c IA porphirin tao ra hemoglobin VOl ion sAt) duqc xac dinh ehinh xac b~ng con duong t6ng hop toan pMn n6 vao nam 1929.

+

cr

*CLOROPHIN

{ R =CH3 : cbropbin A R = CRO : cbrophn B

CHl CH) CH) CH)

C2oH39

Clorophin chinh la hop chat phtrc cua mot loai porphirin voi ion magie. N6 ia ehlft tao ra rnau xanh trong la cay (diep luc t6), d6ng vai trO quan trong trong qua trinh quang hoa, nghia 1ft chuyen nang lw;tng anh sang m~t trOi. thanh dang hOO nang (t6ng hop tinh b¢t hoac xenlulozo tu nuac va khf cacbonic dum lac dung cua snh sang m~t troi), T6ng hQ'P toan phan clorophin A va B duqc thuc bien vao nam 1960.

45

* VITAMIN B12

CH3

L-CH2CONH2

"">CH2CH2CONH2

Vitamin BJ2

Phan IU vitamin B12 g6m hai phan co ban:

Phlin nucleotit va phan mang mall. Chinh phan mang mall nay diroc xay dung tir mot vong porphirin dli dl1Q'c khir hoa met pMn va trong do thieu mot cau rnetin. Cac nguyen tu nito cua cac vong pirol trong porphirin lien ket phirc voi ion coban, d6ng thoi ion coban lai lien k€t voi m(lt

nh6m xianua. Do do vitamin BI2 con diroc goi la xiancobanamin.

~u tao cua phAn tit vitamin B12 diroc xac dinh vao narn 1955 dira tren co so nghien cUll cac san phAro phan huy no va cac dil kien nghien CU"u tinh the hoc, Sau d6 vitamin B12 dli dU'qc Woudwoad t6ng hop roan phlin, va chinh nhb' thanh cong nay cung voi cac thanh tfch vi dai khac trong linh Vl!c t6ng hop hilu C(1 rna nam 1965 Woudwoad da dlT<;JC nhan giai thuong Noben v~ hoa hQC.

Vitamin BI2 dong vai tro quan trong trong qua tr'inh trao dOi cha't trong C(1 th~ con nguoi, d~c biet trong qua trinh sinh t6ng hop axit nucleic trong co 1M.

4.3.2. Cal' hop chdt chua vong pirolidin WI br) khung tropan.

Nh6m cac hop eha:t nay phAn 160 III cac ancaloit co trong thirc v~t. Milt 56 chat di~n hinh duQ'C gioi thieu dum day:

* GIGRIN

DAy Iii. m(lt trong nhimg ancaloit don gian nML N6 duqc tach ra ttt ta cay "Coca" a Nam My. Gigrin la mot dAn xuat cua vong pirolidin. 0 lieu eao n6 ra:t d(lc, nhung VOl lieu nho thich hop no co tac dung kich thlch hoat d¢ng cua toan co th~ noi chung.

46

Ngoai ra cung c6 th~ xtp nicotin vao nh6m nay (se giOi thieu 0 chtrong piridin).

Tropan la rn~t hop ch6t vong c4u rna chinh nguyen tit nita gilt V! tri c~u n6i gifi'a hai vong: pirolidin va piperidin. Nhiing ch6t di~n hinh cua nh6m nay la atropin va cocain,

~~

~COCt.Hs

Tropan

Cocain

,.. ATROPIN

N6 III din xua't clla tropan, c6 d~ tinh cao, nhung viln dllt;1C sit dung trong y hQC lam thu6c giam dau (gAy te cue 1>(», va d*c biet du'!C dung trong khoa mdt vi n6 co tac dung lam mo rf;Jng con nguoi mat.

,.. COCAIN

Cocain la mt)l ancaloit chll ytu c6 trong cay "coca" va ctlng ta met diln xu6t cua tropan. N6 dUf;IC Niemann tach ra :1n d4u tien vao nam 1860 tu la cay "coca" lJ Nam My. N6 dllt;1C sir dung trong y h9C lam thu&: ngu, :~ ... &: gay me va gay te cue bQ. Nhuoc di~m cua cocain la gay nghien va do d6 n6 la m~t trong nhiing ch6t rna tuy manh. 0 lieu cao n6 dQc va gay tac dung manh dtn h¢ thM kinh trung lWI1.g.

4.3.3. Cdc hCJP challhien nhien co chu-a vong furan

Vong furan ding thllimg g~p trong phan tir cua mot s6 chi't thien nhien, chAng han 2·rnetylfuran c6 trong dS.u thOng, 5·metylfurfural va ancol furylic c6 trong ca pM rang, ... D*c biet cac din xust cua furan trong thien nhien th110ng t6n tai a dang lacton. cac hop chat phUc tap han chiia Yang furan cung dm;Jc 11m th6y trong mt)t s6lo~i qua, hat va boa.

4.3.4. Cac ht;1P chat thien nhien co chu-a vang thiophen

cae dAn xu6t ella thiophen thllimg it g~p trong thien nhien, Tuy nhien nguOi ta cilng tim th6y trong rnt)t s61~i hoa cac ch6t a,a..trithienyl va metyl (2-fomylthienyl-5) axetilen,

a,a- trithienyl

H3C-C=:C()-CHO Metyl(2.fomy lthienyl- 5)axetilen

HN~H

t:i-(CH214COOH Vitamin H (Biotin)

Vitamin H (hay con SQi 1.1. biotin) lil mt)t hop chat thien nhien co chua vong tetrahidrothiophen.

Vitamin H duqc tao fa ngay trong co the con ng110i va. n6 giG' vai tro 100 trong qua trinh t60g hop purin. Vl v4y n6 c6 y nghia 100 trong qua trinh hoat dt>ng s6ng.

47

Chuang ba

A,. ."..... A'

HE NGlING TU CUA CAC 01 VONG THOM 5 CANH 1 01 TO

• • III II 'l1li

H¢ ngung tu cua cac d! vong thorn 5 canh 1 di t6 bao g6m: Benzofuran, indol, benzothiophen va cac dibenzo nrong ling:

4 4 4
:co~ 0J~ DJ~
7 P 7 li"t '7 SI
H
Benzofuran lndol Benzothiophen
M2 5 4 M
6a:D3
6 3
? 4 3 7 N 2 7 89S 12
8 9 I 1
H
Dibenzofuran Cacbazol Dibenzothiophen 1- vAl NET vf CAU TAO CUA BENZOFURAN, INDOL V A BENZOTHIOPHEN

V~ m~t hlnh tlnrc nlu a cac vi tri 2 va 3 cua vong furan, pirol va thiophen duqc gh6p li~n v6i m"t vong benzen thlta Se c6 cAc h¢ di vong ki~u benzo cua cac dt vong thorn 5 canh 1 di t6:

Benzofuran, indol va benzothiophen.

ve m~t tfnh chllt h6a hoc cac h<;1P chllt ki~u benzo nay cfing c6 mot vai ditm khac vm cac dan di vong nrong ling. Dieu nay do cau tnic cua chung quy4!"t dinh.

Theo thuyet obitan phan tit (MO) thi cau t~o cua benzofuran, indol va benzothiophen ra:t gi6ng vm cac cau tao cua dan di vong nrong ling va ctlng rllt gi6ng v6i naphtalen. Trang cac h¢ ngung t1,1 kitu benzo nay co 10 en, nghia la thoa man cling thuc Hucken ve tfnh thorn.

f.
l)Ct;»
H
5
10 2)(0
trong EtOH
104 Hlnh ve dum day cting cho tha:y dang phO tit ngoai cua indol vtl naphtalen rli't gi6ng nhau, Dieu d6 phan gi6ng nhau v~ cllu tnic electron giUa chang.

2400

2800

A.A

48

Theo quan diem cua phuong phap cap h6a tri thl cac h¢ di yang kieu benzo nay c6 the duqc mO tii bang su lai t1,\O cong huong cua cac c~u tnic gioi han dum day:

co - w - w -
(i) e ®
(I) (II) (III)
e 0Co
- W - -
~ "'"
~ &
(IV) (V)
(X= 0, NH, S) Trang s6 nay su d6ng g6p cua cac Ca'll tnic I va II la quan trong nhat, bOi vi a cac cau tnic can lai (III, IV va V) su cong hUCmg cua vong thorn henzen bi pha va va c6 su phan b6 di¢n tich Ian han.

Tir so do tren day c6 the thay rAng su tang m~t d~ electron a vi tri 3 dirong nhir rnau thuan v61 su tang di!-c tinh 'Am dien d vi tri 2 trang cac dan di vong nrong img va cho phep cac tac nhan electrophin tan cOng vao vi trl 3 Ia cM yeu (trir benzofuran). Nhung dieu nay dugc giai thich clog c6 nhu v~y thi ca'u tnic thorn cua vong benzen m6i duqc bao toan va trang thai chuyen ti€p trung gian trong str th€ electrophin rnoi t6n tai a rmrc nang hrong thap han.

Mat khac, cling nrong tu cac dan vi vong thorn 5 canh 1 di t6, d~ thorn, va do d6 cii d~ ben ciia benzofuran, indol va benzothiophen con phu thuoc ca vao su d6ng g6p cuacap electron tren di t6 vao h~ electron 1t trong toan phan tir, nghia la phu thuoc vao rmrc d~ cua cf.t1ng tham gia vao Sl! thorn hoa cua roan M di vong. Chfnh dieu nay se giiii thfch Vi sao benzofuran cho sl! the electrophin a vi tri 21a chu yeu,

Rieng voi indol c6 the n6i them rAng ca'u tnic electron cua n6 la su t~p hop :ci'Ia hai vong benzen va pirol, rna sir t~p hop nay lam cho indol 6n dinh hem ve mat phan b6 di¢n tich va kha nang phan tlng nho hem mot chiit so v6i pirol. Cau true cong hueng va sir phan b6 electron ciia vong indol c6 tM dug<: gioi thieu nhir sau (trong dieu kien gioi han bao toan tinh thorn cua vong benzen):

-0,023

~ _ ~e_ r"r====; +{J,Q3~.70:623·~·~,S730,508 ~:~~

~NJ ~N~ ~N~e

I I I

H H H

(VI) (VII) (VIII)

cau tnic (VIII) it tin nrong hem, bOi vi a d6 h~ lien hop thorn bi pha hUY. Cau tnic VU cho phep giai thfch ro rang Sl! ta.n cong electrophin vao vi tri 3 cua vong indol.

Tir sl,f phan b6 mat d~ electron va me hinh phan nr cdn thay rang vong pirol bieu thi d~c tinh cho electron: Da s6 nguyen tir cacbon cua vong benzen diroc d~ tnmg bOi su du electron, con trong vong pirol thi dieu d6 chi the: hien a cacbon vi tri 3.

Nhung day chi la trang thai co ban, N6 khac xa voi su phan b6 mat d~ electron trong trang thai chuyen tiep xuat hien trong qua trlnh phan tlng. Cho nen sir phan b6 m~t d~ electron du'lC tfnh toan

49

4-HHCCDV

i:J tren dii khong duoc xac nhan bang can duong thirc nghiern. Nhirng du sao no cung cho thay su phu hop voi thuc t€ la die tic nhan electrophin chu yeu tflll cong vao vi trf 3 elm indol,

,II - cAe. PHUONG pHAP T6NG HOP BENZOFlIRA_,~, I]\jTJOL V A BENZOTHIOrHEN

~ 1m ta co the lay benzofuran, indol va benzothiophen tCr nhua than da, Trang so cac di vong nay tnt indol dUQ'c nghien ciru nhieu hon ca VI SI! phd bien ella no va dan xuat trong thien nhien, ding nhu sir co mat cua no trong nhieu hop chat co hoat tinh sinh hoc, Chinh VI vay trong phan nay chu yeu cluing ta khao sat cac phirong phap Icing hop vong indo!.

2.1. T6ng hop indol thea Fischer

M~t trong nhirng phuong phap tOng hop indol quan rrong va phd bien nhilt III SI! chuyen hoa arylhidrazon cua cac andehit hay xeton thanh dful xuat cua indol bang each dun nong dc

arylhidrazon nay trong sir co mat cac xiic tac axit nhir ZnC12, BF3.(C2HshO, axit poliphotphoric (PPA), ... Phuong phap nay mang ten Fischer. Y€ mat hinh thirc tong hO')1 indol thea Fischer baa g6m sir chuyen vi phenylhidrazon kern thea su dong vong va tach loai phan nr amoniac, Thi du:

WCH

I 6 5

H

~C3Hi ~NACH3

I

H

Co che ella phan irng nay dii dUQ'C nghien ciru nhieu Nhtmg truoc day da so y kien nt;hi6ng ve co che thea kieu chuyen vi o-benzidin:

O~-

I I

H H

~-~

BF). (C2Hs)zO CH3COOH,65t

I

H

P.PA

OCHhC-CH C H CuC]

II 2 3 7 0

NH- N 200-250 C

-

50

OJ:)

I

H

(93%)

(73%)

(31.4%)

~-__(j ~-~

-NH3

0:0

I

H

Co ch€ nay dircc xac nhan bOi. cac If do sau day:

- Phan ..mg duqc xiic tac bffi cac tac nhan axit (nghia la nrong tl,l' xuc tac chuyen vi benzidin).

- Phan irng dien ra binh tlnrong khi them cac amin thorn khac vao bOn hop phan img.

- Xeton cang d€ dang enol h6a thi su chuyen h6a phenylhidrazon cua no thanh indol ding cang

de dang.

- Trang qua trinh phan img nguyen tit nita xa vbng thorn hem trong arylhidrazon bi tach ra a dang amoniac,

-

+

- Trang mot vai tnrong hop nguoi ta tach ra dtroc hop chat trung gian trong qua trinh chuyen hoa thea co ch€ tren.

Ngay nay voi phuong tien hien dai ngiroi ta chirng minh rang sl,l tao vong pirol trong indol theo phuong phap Fischer gAn lien voi SI! chuyen dich 0" cua lien k€t 0" va sl!. xuat hien csu true trung gian b6n trung tarn dang ghe:

Chuyen dich 0" [3,3] trong tnrong hop nay baa g6m SI,l' ddt vo d6ng thoi lien k~t 0" 3,4 va SI! t .... o thanh lien k€t 0" a vi tri 1,6 kern thea ca S1! chuyen dich lien k€t 1t.

V 6i each giai thich sl,l tao yang nhu v~y thl sl! phan b6 m~t d¢ electron trong h¢ th6ng khOng co y nghia rna gia tri co ban cua co ch€ phan irng baa g6m a su bao ve tfnh d6i xrrng obitan.

51

2.2. T6ngh1?P lndol theo Madelung

Phuong phap nay baa gem sir dong vong loai mroc cac Nsaxyl-o-roludin bang tac dung cua cac bazo manh a nhiet d<> eao. Phuong phap nay quy gia a ehb d~ dang co dtroc cac chat dau.

(XCH3

NH-CHO

~ll (79%) ~N)l

I

H

350-3600C, 20 ph

NaNH2

~Jl (XO-X3'10) ~"'NJ CH

, 3

H

Co eh€ cua phan irng nay vAn can nhieu van d~ can nghien ciru. Mac du eo th~ hieu vai tro cua bazo a day Iii de tach proton fa khoi nhom metyl va chuyen no thanh cacbanion d~ di van ngung tu vci nh6m eacbonyl theo kieu Claisen. Nhung thirc te cac giai doan tnroc va sau khi tach proton dien fa phirc tap hon nhieu, Dieu nay duqc xac nhan bCti cac su that san day:

- Mot nira s6 N-axyl-o-toluidin thtrong diroc tach ra 6 dang o-toluidin (nghia la xay ra deaxyl h6a hay thuy phan nhorn anilit).

- Trong qua trinh phan irng co tach ra ox it eacbon (CO). Nhirng neu them vao bOn hop phan irng mu6i kali fomiat (HCOOK) thi sir tach oxit eacbon giam di dang kE.

- Neu nhu N-axyl-o-toluidin khoi da:u co nhorn the a nguyen nr N (thf du nhom ankyl chang han) thl hieu suit cua indol tao thanh rat thap.

Ga:n day co thong baa vt sl! 'ciii tien phtrong phap t6ng hop indol thea Madelung bang each d6ng vong cac fomamidin trong N-metylanilin dun soi voi sir co mat cua natrimetylanilin. Phan irng co th~ diroc gioi thieu bang so d6 sau day:

C6HSN(CH3)Na C6HsNHCH3

H¥"0 bam

_~H H~

~"""rd

UJ

I

H

(76,5%)

2.3. T6ng hop indol thea Reisert

Ban chat cua phuong phap la sl! khir hoa dong vong axit a-nitro phenylpiruvic va cac dan xuat cua no bang cac tac nhan nhu kern trong axit axetie chang han, hoac siit sunfat trong dung dich amoniac hay natrihidrosunfit. a day qua trinh khir hoa kern thea st,( loai mroc dong vong axit

52

o-aminophenylpiruvic trung gian thanh de axit indol-z-cacboxylic, rna sau do de dang decacboxyl hoa d~ cho indol :

CH 0 CH2COCOOH CH)0Y'u---T CH30

_J I --- ~J,,,J, -C02. . I I

CHPNH, Clh ~ coon 250-260"c C113D:Jl

~ I

H - H

(71%)

Phuong phap nay d~e biet thuan tien doi voi sl! dieu che' cac indol co nhorn the a vong benzen, bci VI cac axit phenylpiruvic nrong ling de dang nhan diroc khi ngung tu cac o-nitrotoluen vOi dietyloxalat trong sir co mat cua xiic tac bazo.

2.4. T6ng hop indol thea Nhenhixescu

Phuong phap nay dua tren SI! ngirng tu enamin cua l,4-benzoquinon voi cac este cua axit p. aminoerotonie. Phan rrng dtroc thuc hien bang each dun soi hOn hop cac ch~t dau trong cac dung rnoi nhtr axeton chang han, Cac este tao thanh co th~ de dang dircc thuy phan va decacboxyl hoa khi dun soi trong axit clohidrie 20%.

°

CH3it)1 ~'rr/COOEt AXetoll HO~COOEtHOWJCCOOEt

C Dunsoi M .. ,A + I

CHi 'NHGb CH3 N CH3 . 'N CH3

o I I

CH3 (22%) CH] CH3 (10%)

CH3COCH3 Dun soi

(63%)

Trong tnrong h9P cac 1 ,4-benzoquinon co chua nhorn the a vj tri 2 (nhir a cac thi du tren) thl ve mat If thuyet phan img co th€ cho 3 dong phan (nrong irng voi nhorn the 6 V! trf 4,6 va 7 cua yang indol tao rhanh). Nhirng thuc t€ phan irng dien fa mot each d~c biet, tao thanh chu yeu d6ng phan voi nhom the a vi tri 6, va co the voi mot hrong nho dong phan c6 nhom the a vi tri 7. Ti l¢ gili"a hai dong phan nay phu thuoc th€ tich nh6m the trong yang benzoquinon. Rieng d6ng phan voi nhom the a vi trf 4 thirc te khong dircc tao thanh,

Su quan sat nay cling nhu cac dfr kien thirc nghiem khac de nhan mot CO ch€ cho rang trong giai doan dau cua phan rmg xay ra sir cong hop cua nguyen til' Cp co doh nucleophin cao trong hop phan enamin vao benzoquinon thea ki€u cong hop Michael. a day do iU.h huang djy electron cua

53

nh6m the trong benzoquinon (nh6m CH3 hay CH30- iJ tren chang han) nen sl! cong hop tnrc tiep ella hop phan enamin m¢t each thich hop ban sf: xay ra a phia d6i dien vm nh6m the' trong phan til benzoquinon. Vi v~y c6 th~ bi~u dieD nhu sau:

R~~rax: Xt:1COOIi _ H~CO~R

Iy R'''''''C('NHR_'' R ~f?C'R' R~o ~R'

° ~ RIO

RIO

_ H:w:H COOFt

R '

(.;0 RIO

H~COOEt R~R'

R"

CC1 che' nrong tl! d6i voi sl! tao thanh d6ng phan vei nh6m the' CJ vi trf 7 cua vong indol.

M¢t each tin tuong ti l¢ giita cac d6ng phan voi nh6m the' R CJ vi tri 6 va 7 diroc quyet dinh bbi yeu 16 khong gian trong giai doan eu6i cung ella Sl! tao thanh vong indol.

Phuong phap nay c6 I1U di~m iJ chO cbo ta cac vong indol e6 nh6m hidroxi iJ vi tri 5 (M nghien cuu cac hop chat indol co hoat tfnh sinh hQC) nhirng co nhiroc di~m la cho san phAro voi hieu suat thap,

2.5. T6ng hqp indol theo Risler

Phirong phap t6ng hop indo! theo Bisler dua tren Sl! tirong tac cua cac arylamin vOi cac a-halogen- hay a-hidroxieaebonyl trong di~u ki¢n ella xiic tac axil.

C6Hs-.C=O

I +

C6H{CH-OH

54

Trong tJUOTig hop cua cac xeton khong doi ximg phan trng co th~ tao ra h6n hop hai d6ng phan:

San pham trung gian dau rien cua phan irng nay rna co th~ tach ra diroc a nhiet d~ thap tii cc-xctoamin. Nhirng do sir chuyen hoa nrong h6 nhanh chong sua cac xetoamin dum tac dung ciia axil hay nhiet nen thuc te da tao thanh hon hop de xetoamin. Ngiroi ta cilng thay toe dt) cua nhiIng chuyen vi nhu the phu thuoc rat dang k6 vao cau tao cua cac chat tham gia phan irng. Otinh VI vay rna cau tao thirc cua cac anilinxeton khong th~ xac dinh chinh xac duoc:

C6HsCH2~ CH- Br

- I -

C6H5-C=O

SlJ chuyen hoa nrong h6 nhanh chong nay iii nguyen nhan dAn tOi sLJ tao thanh h6n hop hai d6ng phan,

2.6. Tong hQP benzofuran va benzothiophen

* Phuong phap t6ng hop benzofuran kinh dien nhirng rfft thuan tien va diroc irng dung rong raj la di tir cumarin. Theo phirong phap nay nguoi ra brorn hoa cumarin roi che bien tiep thea san pham dibrom cumarin bang kiem va cuoi cling decacboxyl hoa axit cumaric tao thanh:

cxt_Br

O~O

-HBr

KOHjEtOH

70%

CaO

-to

co

o

(82-88%)

* Phuong phap tong hop benzothiophen trong cong nghiep r:'lt dan gian, dua tren SlJ phong h6n hop cua Stiren va hidrosunfua qua xuc tac (FeS + AI2S3) o600oe

00

S

Tuy nhien phirong phap dong vong dehidro hoa cac o-ankylthiophenol 0 4450C tren xuc tac oxit d6ng va oxit crom la con dtrong chung nhat cua su t6ng hop cac benzothiophen:

55

* Ngoai ra ciing con nhieu phuong phap khac diroc sir dung de t6ng h9'P benzofuran va benzothiopben. Thi du: d6ng yang cac h9'P chat cc-phenoxi- hay e-thiophenoxicacbonyl trong cac dieu kien nhe nhang cua phan img Friedel-Crafts:

1) SOCl CH3Y'lr--fO CH3Ylr-----tr-OH

CHr-@--OCH2COOH 2) Ala: ~O) ~ ~o)l

T6ng h9'P benzothiophen bao g6m si! tao thanh lien k€t 2-3 duoc coi nhu cac thi du cua phan irng ngung tu Claisen hay andol noi phan tu cua cac xeton hay andebit the,

Phuong phap nay tim tba:y su ling dung rong rai d6i voi su t6ng hop benzofuran va benzothiophen. Nhung nhuoc diem duy nha:t cua n6 la phai di til cac chat diu r{lt kh6 kiem.

~CHO 1)NaOH,aCH2cooH ~ ca(OH)2001 \

~SH 2) H+ ~S.....lCOOH to :::::... S

III ~ TiNH CHAT

CD

o

Ct:J

,

H

.O:J

S

Nhu da n6i 0 tren, cac di yang ngimg tu benzofuran, indol va benzothiophen e6 kha nang phan irng thap ban cac dan di vong wang ling. Mat khac trong cung mQt dieu kien, ban than cac di yang ngung tu kitu benzo nay cling bieu IQ tinh cha:t h6a hoc rat khac nhau. Ching han, benzofuran tuy v~ rmrc d€> phan (tog e6 kern hon furan, nhung van the hien nhiing tinb chat d~c tnmg d6i VO; mQt vinylete, trong khi do indol khOng c6 tinh cha:t nay va con r{lt d~ tham gia van phan ung th€ electrophin; con benzothiophen, trong su khac vOi thiophen, da: khong ducc fomyl h6a thea Winsrneier va ciing khong ti€p nhan phan img Mannich,

56

Ngoai ra de di vong nay cting kern ben vU'ng trang moi tnrong axit manh, Thi du, dum tac dung cua hidro clorua trong dung moi khong praton h6a indol de dang duqc chuyen thanh dang dime:

20:J

I

H

He!

---

3.1. Phan ling the electrophin (SE)

BAng phirong phap phO tir ngoai va pM cong huang tir nhan, ciing nhu bang SI,i' trao d6i dotori n3uo; ta da xac nhan fling su lien ket cua axit diroc quyet dinh boi sir proton h6a chu yeu 0 vi trf 3 cua vong indol:

Tu d6 can thay rang sl! the e!eetraphin 0 indol xay ra tren vi tri 3 nhtr dieu nay da: diroc tien doan mot each If thuyet. Benzothiophen trong cac di~u kien nay cimg bi€u I¢ tinh chat nrong nr indol, nghia Ia ding eho cac dan xufi't tM 0 vj tri 3 Ia chit yeu: d6ng thai e6 tao thanh m¢t hrong nho d6ng phan the' 0 vi trf 2. Rieng doi voi benzofuran sir the' eleetrophin xay ra mot each d<).e biet o vi trf 2. C6 Ie yeu to chu yeu quyet dinh sir dinh hu6ng khac nhau trong cac phan irng the' eleetraphin cua cac di vong nay ehinh Ia rmrc d<) am dien khac.nhau giira 0, S va N. Mot so thf dl,l ve pharr irng the' eIeetrophin diroc dan ra duoi day:

OJ + (CH3)2N -CHO POct) N

I

H

UJ + HCRO + HC!

S

(40%)

~CHO N

I

H

(97%)

~CH2N(CH3h

l0--.".) (40%)

N .

I

H

c::::cJCH2Cl S

(56%)

Neu nhu vi trf eo kha nang phan rmg eao nhat trong cac qua trinh the electrophin cua cac di vong nay dii bi chiem bbi mot nhorn day eleetron thl phan img van e6 the xay ra 0 vi tri khac :

57

HC] d~c to < 3UoC

WCH3+

,

H

o

~~-Br

o

()::)NHCOC; S

(69%)

(45%)

SI;l' co mat nhom the' hut electron trong phan di yang se lam.mat hoat tfnh Ct nhan di yang va khi do 51;l' the' electrophin se xdy ra Ct ben yang ben zen cua phan tu:

~CHO

~NJ + HN03

,

H

OcrCOOC2HS

+ Br2 N

,

H

~CHO ON~NJ

2 ,

H

(2&%)

~COOC2H5 Br~NJ

,

H

N02

fuN02+ ~N02

's 02N~S)

cling chi xay ra 0 ben yang benzen rna thoi:

Neu nhu ben yang di Yang c6 2 vi tri bi chiem boi cac nh6m the thl SI! the' electrophin tiep tuc

"'

H Br2/CH1COOH - ~CH3

. 0 +

Xiclohexan, U C N C6HS

,

Br

(78%)

(47%)

Cling nhu 0 furan, pirol va thiophen, trong mot vai tnrong hop cua su the' electrophin (d~c bier nitro h6a) da xay ra 51! thay the' nhom the' co san trong cac di Yang nay bang tac nhan electrophin, Thi du :

58

(32%)

(270/0)

(12%)

Khi co mat nh6m amino hay hidroxi ben vong benzen cua phan til thi S\1' the' electrophin cung chi xay ra b ben vong benzen, ngay d. trong tnrong h<;1P ben vong di vong con co cac trung Him philo irng cao khac dircc t\1' do:

1) ZnC12 2)HzO

C6HSC°'QTCH3 HO °

H2NUJ

i ,

""" S

(63%)

HOUJ

I I

...... s

Br2/CHFOOH CH3COONa

HOXbBr I . I

Br S

(52-75'k)

Sau day ta nghien ctru chi tiet hon hai phan img the electrophin: Nitro hoa va halogen hoa indol, benzofuran va benzothiophen,

* Nitro hoa

Nitro hoa benzofuran bang axit nitric d~c trong axit axetic dAn t61 sir tao thanh 2-nitro, trong khi do tit benzothiophen ta lai nhan diroc d6ng phan 3-nitro-. D6i voi indol, chieu huang cua qua trinh nitro h6a phu thuoc nhieu vao rnoi tnrong phan irng, C11~ng han, khi nitro hoa trong axit nitric d~m dac hay trong axit axetic ket tinh thi S\1' th~ xiy ra b vi tri 3 va 6, nhung khi nitro hoa trong axit sunfuric thl hau nhu chi tao thanh dftn xullt 5-nitroindol:

~N02 02N~N~CH3

I

H

(39%)

59

Ngiroi ta giA thiet fling 0 giai doan dfiu xay ra sir cong hop cua axit (tuc proton hoa) vao vi trf 3 va trang hop chat tao thanh trung gian nay sl! th€ electrophin co th~ xay ra iJ v] tri 5 mac du rA't kh6 khan. Nhirng dieu kh6ng the hieu diroc la tai sao iJ giai doan cu6i sl! tA'n c6ng cua ion nitro lai xay ra 0 vi tri para- d6i v61 nguyen tir nita bac b6n mang dien tich dirong?

~ ~N)\CH

, 3

H

H H

r"Ir--+ H ~2N Y)-----+- H

~N~CH ~N~CH

,3 ,3

R R

>I< Halogen hoa

Halogen hoa tnrc tiep benzofuran bang clo hay brom thuong dan t61 su cong hop chung van lien ket CTC3 va sau d6 diroi tac dung cua bazo hay nhiet, san pham diroc tao thanh trung gian nay co thl! tach 10<;1i hidrohalogenua de chuyen thanh hon hop 2- va 3-ha!ogen benzofuran. Nhung khi brorn hoa hay iot hoa benzothiophen thi chi co dan xuat 3-halogen dircc t<;10 thanh.

D6i voi indol qua trlnh bram hoa phu thuoc nhieu van ban chat dung moi, Chang han, khi sir dung axit axetic k€t tinh hay dioxan lam dung rnoi co the xay fa su the thong thuong ; nhung trang cac phan irng halogen hoa indo! v61 dung rnoi co tfnh nucleophin cao nhu ruroc hay tert-butylancol tht lai dien ra ca qua trinh oxi 110a va ket qua oxindol diroc t<:LO thanh. Thf du :

o

C:~N-Br

o

Ngiroi ta gia thiet rang trong ta't d cac tnrong hop san pharn trung gian deu la dan xust 3-bromindolenin. Nhung khi co mat rnroc hay cac lac nhan nuc1eophin thi chfnh 3-brom indolenin co the chuyen thanh dan xuat oxindol:

Bt

(Jc:tN-Y R Dung m6i kh6ng pMn c~ (R '" H)

H

-H+1H20 (hay dung mol nucleophin)

w~

I OH 'H

Br

~H

~~

OJrBr

N

,

H

-HBr

H

0:tR

N 0

I

H

Ngoai cac phan irng the electrophin d1'l diroc nell a tren, indo! co kha nang phan ling cao, con co the tac dung v6i cac tac nhan electrophin yeu nhu nitroetilen, chi tetraaxetat..., va cling nhu de dang bi oxi hoa :

60

25"c

Benzen

°2

(75%)

ete dau hoa

3.2. Phan itng the nucleophin (SN) va the g6c (SR)

Cling nhir iJ cac dan di yang tuong ung, cac phan irng the' nucleophin va the' g6c iJ benzofuran, indol va benzothiophen n'ft it duqc nghien cuu, Ngtroi ta biet dng neu iJ trong nhan cua cac di Yang benzo nay khong co nhom hut electron lam hoat hoa thl sir the' nuc1eophin tnrc tiep cac nguyen tu halogen dien ra ra:t kho khan. D6i khi ngoai phan irng the' nucleophin con ken~ theo ca nhirng chuyen hoa phirc tap.

~Br + Cll2(CN)2 ~c!'N02

Piridin

~CN ~O)l.N02

(76%)

22()'23fc, 12 gio

-

Ocr,Br

+

o N02

o

I

H

KOIfC2HsOH 220-250'1::, 50alm

W

(62,5%)

+

Benzofuran co th~ phan irng voi diclocacben trong hexan, nhirng benzothiophen lai khong tham gia phan irng nay. Ciing trong dieu kien cua phan -ung Reimer-Timan (tuc phan img vci diclocacben hinh thanh tit c1oroforn trong kiem manh) indol co the cho cac san pham indol-3-andehit hoac 3-cloquinolin (tirong tt;( nhu phan -ung eua pirol voi clorofom trong kiem),

QJC-COOEt/CH30Na hexan,O't

Cl CCXC1

Cl ..!:!t2. (15%)

o "%. 0 CI

61

co

L

H

~CHO ~N)

L

H

Mac du phan (eng ella benzofuran, indol va benzothiophen voi este ella ax-it diazoaxetie (N2CHCOOEt) dii dtroc thirc hien, nhung CC1 eh€ ella no chua ro rang nen doi hoi phai eo su nghien CUu tiep tuc va chi tiet hon.

3.3. Phan (rug kim loai hoa

Phan irng kim loai hoa benzofuran, Nvankylindol va benzothiophen dien ra rllt d~ dang. Otfulg han, khi tac dung voi n-butyllithi, cluing tao ra cac dfin xuat 2-lithi nrong img, rna tir do co th€ chuyen h6a tiep tuc thanh nhieu loai dan xuat khac nhau:

~ ~o)l

ete, dun s(")i

CH3(CH2)3Li ete, dun soi

CH3lCH2)3Li ete, dun sci

Bang phan irng nay e6 tM d~ dang dua cac nh6rn the khac nhau van vi trf 2 cua vong indol hay benzothiophen, rna 0 do neu dung phan irng the electrophin thi thong tlurong chi co th~ nhan duoc san pham voi nh6rn the 0 V! tri 3.

D1) linh dong kha eao (tinh axit) ella hidro trong nh6m NH trong vong indol eho phep M dang thay the n6 bang kim loai kiem (khi tac dung 0 nhiet d¢ eao voi Na hay K hoac khi phan ffilg vci

NaOH hay KOH) ding nhu khi phan irng voi n-C4H9Li hay tao thanh thu6e thir Grignard. Chien huang ella cac phan irng nay phu thuoc nhieu van ban chat kim loai, ding nhir di~u kien phan crng va di;le tfnh cua cac tac nhan, Nhung thuc ra cho den nay y nghia va anh huang ella de yeu t6 nay van chua diroc giai thich ro rang. Tuy nhien voi su giup do ella phuong phap ph6 cong huong tu nhan ngiroi ta da xac dinh hop chllt co-magie ella indol t6n tai duoi dang ellu true ion;

co

I

MgX

Chinh vi vay rna khac v61 pirol, phan ling cua hop ehAt co-magie ella indol thuong ddn 161 sir tao thanh cac dan xuat (j vi trf 1 va 3. Tir cac dfr kien thuc nghiern e6 th€ ket luan rang cac mu6i natri,

62

kali hay lithi cua indol khi ankyl h6a se cho san phdm Nsankylindol, trong khi d6 mu6i magie lai tao ra da.n xuat 3-ankylindol. Tuy nhien trong thuc te va.n t6n tai mot 10<;1t nhirng tnrong hop ngoai I¢ :

00

N

I

H

n-C4H9Li ete, dun sOi

[00 1 I) CO2 00

I I - I I (61%)

N 2)H]O+ N

I I

u COOH

00

N

I

MgX

o

+ C:~

o

anisol

00 - C2HsMgBr [0-r

N ete ~N}

I I

H MgBr

Trang khi cac dan xUlit halogen cua benzothiophen dii dang tao ra thu6e thir Grignard thi cac dan xua:t 2- va 3-brombenzofuran lai khOng tham gia vao loai phan ung nay. Rieng cac dAn xuat 2- va 3-halogenindol vi rlit khong ben nen ciing khong diroc sit dung lam tac nhan tao ra thu6c thit Grignard.

H2<°Y)-.J_ ~rH2<O~~ 11~ H2~°Y')--p

o~s Br l o~s MgBr 2) HO O~S)l._OX>H

(63%)

0c:J?

S (69,5%)

N6i chung cac dAn xuat halogen cua cac h¢ di vong ngung tu nay phan irng d~ dang v6i cac hop chat co-kim, va sl! chuyen h6a tiep theo cac hop chat trung gian di~n ra rlit tot, dong thOi c6 th~ cho nhieu loai hop chat hiiu co khac nhau voi hieu suat cao.

~ (86%)

~OY--COOH

63

[OcxLi] (X:(COOH

I I I)C02 I I (55%)

S/ F 2)HCI S F

3-Benzofuryllithi (nhan diroc tu phan irng cua 3-brornbenzofuran vci n-butyllithi) (rang dieu kien nhiet d~ thap va thai gian rat ngan co th~ chuyen thanh cac dan xuat the- 0 vj tri 3 cua benzofuran. Ne'u khong tlurc hien nghiern ng*t dieu kien nhu v~y thi se xay fa su mo yang d, yang va tao thanh cac phenol axetilen :

I) C02 .70oC 2 h (C(COOH

, ,p I I

2)H30+ % 0 (14%)

° CXC=CH

1) I gio~ 25 C I

2)HP OH

1) G13(G12)3Li/ete

2) H30+

IV - GIOI THI~U MOT s6 HOP CHAT RIENG BI~T CVA INDOL

4.1. MQt s6 dAn xuat cua indol

* Indol-3-andehit

Indol-3-andehit diroc t6ng hop chit yeu bang phan img Winsmeier, nghia la tac dung tnrc tiep cua indol vci dirnetylfomamit va photpho oxiclorua.

~CHO

~"'l"J (97%)

N

,

H

Ngoai ra cling c6 th~ di tir indol qua phan img Reimer-Timan, nghia Iii phan irng cua indo! vo; clorofom trong moi tnrong kiem manh (tao ra dicloeaeben). Nhung plurong phap nay eho hieu suat thap hon (31 %).

Nhom fomyl trang indol-3-andehit rnang kha d:1y dii tinh chat cua mot andehit thorn, e6 th~ diroc khir h6a thanh nhom metyl ho*e oxi hoa thanh nh6rn axit cacboxylic,

64

[HI

-

Indol-3-andehit

3-Metylindol (Scatol)

Nhimg indol-3-andehit khOng tham gia phan irng ngung tu Perkin va phan Urig Cannizaro. * Cdc axyUndol

Cac axylindol du((C t60g hop b~g nhieu coo dU'ang khac nhau: +) Qua hop chat co-magic cua indol:

r"'ir-u ~COCH}

~N)J + CH)COCI hay(CH3COhO-0N}

I I

M~r H

+) Axyl h6a bang anhidrit axit vo; sl! e6 m*t cua axit pecloric:

OcrCOCH} \

N R

t

H

+) BAng phan tIng Winsmeier:

Q:rCO-R

N R

t

H

3-axylindol phdn nao mang d*e tinh amit do sl! lien hop cua dOi electron nr do tren d! t6 nito vo; nh6m eaebonyl b vi tri 3 nen kh! nang phan irng kern hon o cac axylbenzen tuong U'ng. Tuy nhien chiing vAn tham gia d1.1((C vito cac phan trng d*e tnmg cho cac xeton thorn hay beo thom. Thi du : 3-axetylindol e6 th~ phan img blnh thuong vo; isatin trong mei tnrong kiem rnanh d~ cho axit quinolin-4-cacboxylic (PMn I1ng Pfitzinger):

COOH

r"Ir-rCOCH3 r"jr---?'0 _K_O_H_33_% ...

~N)J + ~N~O

t I

H H

* Cdc axit indolylankan cacboxylic

Phuong phap don gian d~ dieu ch€ cac axit indolyl-3-ankaneacboxylic la phan img t11fC ti€p cua indo 1 voi axit ro-halogenankancacboxylie b nhiet d(t va ap suat eao :

65

5-HHCCDV

W +Cl(CIJ;z)"COOH

,

H

Ca- axit ;,ay ding co tM nhan duqc bang phan irng Wil'gerodt-Kindler, nghia 1a bang sl;l' dun nong -xylindol voi luu huynh va rnopholin r6i tiep thea thu), phan thiomopholit trung gian:

I) NaOH 2)HCI

~l' N°! (CH2)nCOOH

~lI.T) n= 1-5

\

H

Phuong phap nay co nhuoc diemtlurong cho hieu suat thap va khi mach ankan cang dai (nrc 13. n cang Ian) thl phan irng thuc hien cang kh6 khan va hieu suat san pham cang thap.

Rieng axit indolyl-3-axetic (tire la Heteroauxin) c6 thfi nh~ dU'qc dt! dang bang con dirong kinh di~n qua sl! tao thanh truf!g gian gram in (tuc dimetylarninometylindol) :

Q:J

,

H

-H 0 + HCHO + (CH3hNH __..l__..

WCIJ;zN(CH3l2

,

H

Cac axit indolyl-3-ankancacboxylic (d~c biet axit indolyl-3-axetie va axit indolyl-3-butyrie nrc IAA v~tIBA) III nhUng chat kfch thfeh su phat trien cua thuc v~t, d~e bi~t kfeh thfch qua trlnh ra rt nen co trng dung nhieu trong Iinh Vl,!e cay trong.

* Triptophan

Triptophan hay axit tt-amino-I3-(indolyl-3)propionic 13. ffi¢t axit amin khong thay the'. No khong th! duqe tao ra trong co' thi con ngiroiva dl)ng v~t nhung Iai lA m!)t pMn quan trong xay dung protein. C6 the t60g hop triptophan tir indol-Jvandehit thea cac phuong phap sau:

+) Ttl indol-3-andehit vOi axit hipuric:

o

~CHO "

~N) +CtJls-C-NH-CH:zCOOH

,

H

(CH3CO)zO CH>COONa

6.6

+) Tir indol-3-andehit vui hidantoin:

Piperidin

CH=C-CQ __

! .,..>NH-

N HN-CO

I

H

* Serotorin va cac trtptamin

Serotonin chfnh Iii. J3-(5-Hidroxiindolyl-3)etylamin. COn khi thay cac nguyen tir hidro trong nhom -NH2 cua Serotonin se duQ'C cac triptamin.

Serotonin noi rieng va cac triptamin n6i chung duqc t6ng hop de dang bang SI! agung t1,1 ella indol nrong U'ng vm oxalyl clorua r6i sau d6 cho tac dung cua hop ch~t trung gian nay v6i amoniac hoac amin bac ml)t hay bac hai va cu6i ding khir h6a tiep theo bCri lithi nhom hidrua trong tetrahidrofuran (THF):

H0'(XJ H00:1COCOCI H0'Cc1colo

I I + (COClh ~ I I NH~ ! NHz-

N (-Hen N (-Hel) N

I \ I

H H H

[HI HO~CHzCHzNHz

(LiAIH4trHF) ~N)

I

H

CUng co th~ nhan duqc Serotonin tU phim U'ng ciia 5-hidroxi indol vei nitroetilen r6i ti€p thee khir hoa nhom nitro thanh nhom amino:

H0'(t:J H0-CO- H00Jr

I I I I C1i2CHzNOz [H] I I CH.!CH2

+CHz=CH-N02 - - I

N N N NHz

\ I I

H H H

67

Serotonin d6ng vai tro quan trong trong qua trlnh hoat dong tarn li va than kinh cua con ngiroi.

Neu thay deli dang k~ n6ng d¢ Serotonin trong vo nao thi l~p tuc xay ra su r6i loan tam tMn.

* lsatin

C6 th~ nhan diroc isatin bang phan ling oxi hoa indigo: o O~

....,__-v ..... -_

2~O ~NAO

I

H

Nhung phirong phap t6t nhat t6ng hop isatin la dun n6ng h6n hop anilin, axit clohidric d~c, hidroxylamin, cloralhidrat va natrisunfat khan r6i sau do dong vong san phdm isonitrosoaxetanilit trung gian dum tac dung cua axit sunfuric d*c (Phuong phap SAng-may-e):

(a]

O Hel

+ CbC-CHO.H20 + NH20H Na so NH2 2 4

~O ~Nko

I

H

o -

NH- co - CH=N- OH

Isatin c6 tM diroc axyl h6a tren di t6 nita va tham gia cac phan ling ngung tu tren nh6m cachonyl, duqc sir dung lam thu6c thll trong phan tfch hiru eel va tac nhan trong nhieu 16ng hop hiru co, d~e biet trong phan ling Pfitzinger (M¢t trong cac phtrong phap t6ng hop vong quinolin).

4.2. MQt so hop chat thien nhien chua vong indol co hoat tinh sinh hQC

Ngoai cac hop eh~t chua vong indol c6 trong th€ gioi d¢ng vat nhu triptophan, Serotonin, bufotonin va cac triptamin khac, ... eon e6 nhieu ancaloit chua vong indol a trong th€ gioi thirc v~t. Di~n hlnh la cac chat dum day:

* Rezecpin

Rezecpin la m¢t ancaloit chua vong indol va r~t phirc tap, Cau tao ella n6 ducc Slitter xac dinh; eon t6ng hop dinh huong l~p th~ toan ph~n diroc Woodwoad thuc hien vao nam 1960. Phan tir rezecpin c6 chua 6 nguyen tli cachon bat d6i, do d6 c6 t61 64 d6ng phan quang hQC. Nhung trong s6 d6 chi c6 m¢t d6ng phan co diroc tfnh va diroc dung lam thu6c chua benh cao huyet ap, cling nhir chua mot s6 dang benh tam than, V~ ditu nay, c61E, do no lam tang n6ng d¢ Serotonin trong nao hi? qua eon duoog chuyen h6a sinh hQC trong co th~ can ngiroi,

68

* Stricnin va Bruxin

Stricnin

Bruxin

Stricnin va bruxin cling la nhtmg ancaloit chua vong indol. Chung la nhirng chat ket tinh va co hoar tfnh quang hoc, Rieng bruxin ducc sir dung nhu mot thu6c thi'r de phan tach h6n hop raxernic. Stricnin la milt trong nhUng thu6c v~ dQ doc duoc xep bang B, nhirng trong y duoc n6 diroc dung lam thu6c tro tim va kfch thich toan co th~ hoar dong. TOng hop toan phan stricnin g6m 25 giai doan cling diroc Wood woad thirc hien vao flam 1954.

v - cAc H~ NGUNG 'ru KIEU IJIBENZO CVA cAe DJ VONG THOM

5 C~NH 1 DJ T6 : DIBENZOFURAN, CACBAZOL V A DIBENZOTHIOPHEN

Cac h¢ ngirng tu ki~u dibenzo cua cac di vong thorn 5 canh 1 d] t6 ph6 bien la dibenzofuran, cacbazol va dibenwthiophen.

9 1

8CXJ02

I I 3

7 0 0

654

5 4

6CCQ3

I I

7 S ....... &2

8 9 1

Dibenzofuran tOne = 87°C

Cacbazol tOne = 2460C

Dibenzothiophen. tOne = {noc

Cung nhu cac hop chllt' h~ ngung tu kieu benzo wong Ung, n6i chung cac he di vong ki~u dibenzo nay rllt it diroc nghien ciru. Rieng cacbazol vi co milt s6 dan xua't dUqc 6ng dung trong dtroc pham va pharn nhuorn nen diroc nghien ceu nhieu hem.

5.1. Cac phirong phap t6ng hop

Ca ba hop chat dibenzofuran, cacbazol va dibenzothiophen d~u co tM tach ra tu nhua than da.

Tuy nhien cac he di vong nay cling c6 tM duoc t6ng hop bang cac phirong phap khac nhau.

5.1.1. Dibenzofuran

Dibenzofuran co th€ nh~ diroc bang each nhiet phan voi xuc tac thich hop cac phenol, dihidroxidiphenyl hay diphenyl ete:

0:1) + H,O + H,

69

~I ~o~

~I ~o~

5.1.2. Cacbazol

Cacbazol d~ t6ng hop tuong nr ti.r diphenylamin, 2, 2'-diamino di-phenyl hay o-aminodiphenylamin hoac bang su nhiet phan phenthiazin khi co mat d6ng kim loai.

QNH_D -H2 0c0
to
N
I
H
Ct::-::D HO CO) + NH4Cl
I to
NH2 H2N U N
,
H (XNH2 r"I HONO NH~ (-2H20)

ex»)

I

H

~ +.CuS

VN.-Z/

,

H

5.1.3. Dibenzothiophen

Dibenzothiophen dl1~ t6ng hop bAng each dun nong cac hop chA't hidroxi cua diphenyl voi P2SS' hoac dun nong diphenyl v6i luu huynh trong su c6 mat cua AICl3 khan, hoac tir benzen voi thionylclorua hay tir mu6i diazoni cua 2-aminodiphenylthioete :

5.2. Tinh ch{ft

5.2.1. Phdn zmg the electrophin (8£)

So voi cac don di yang tuong U'ng thl cac hcp chA't di vong nglIDg tu kitu dibenzo nay co kha nang phan irng kern hen, nhung ben vilng hon trong mOi tnrong axit. Trong ba di yang nay thi

70

dibenzofuran tham gia cac phan irng the' electrophin voi sl! tao ra cac san phdm rat tha:t thtrong tuy thuoc vao tac nhan ta:n cong va dieu kien phan irng. ChAng han: nitro h6a dibenzofuran da nhan dtroc 3-nitro- va 3,8-dinitnxlibenzofuran:

CeO HN03!H2S04 CeO N02'(JcO

I I + I I

o hay HNOyCH3COOH 0 h· N02 0 h N02

Nhirng khi thuy ngan clorua h6a thl lai nhan dtroc cac san pham the' 0 vi tri 4 va 4, 6:

Cc0

o

HgCIz

rIr--1\\

~oy

HgCI

+

Q::1?

HgCI HgCI

Cac phan irng the' electrophin khac nhu halogen h6a, sunfonic h6a, axyl h6a, clometyl h6a hay fomyl hoa noi chung deu cho cac dan xuat the' a V! tri 2 va 2, 8 nghia la a cac vi tri para d6i vai. di t6. Mot vai thi du du(_1C dan ra diroi day:

O:;P + HCHO + HCl -H2O

Cc0 + HCN + Hel Alel3

0 ~CHO ~O~

OJ)

N

I

H

OcCrN02

+ N

I

H

CeO

s

5.2 .2, P han ung kim loai h6a

Cacbazol co the phan ung vai. kali kim loai hay kalihidroxit nong chay de cho rnu6i tren d] t6 nito, rna tir d6 co th~ chuyen tiep thanh cac dAn xua:t ankyl hoac axit cacboxylic :

71

Dibenzothiophen cung c6 the tac dung voi n-butyllithi d~ cho cac dAn xuat the' a V! trf 4. Cac san pham trung gian nay d~ dang dU'<;Ic chuyen thanh dan xuat ankyl h6a :

5.2.3. P han ,mg oxi h6a va vo vang

Khi dun n6ng v6i kiem hay AI03 dibenzofuran se bi vo yang furan a giila d~ tao thanh dAn xuat hidroxidipheny 1:

l)NaOH, to 2)HCl

~ ~OH ~

Dibenzothiophen khi bi oxi h6a se chuyen thanh sunfon:

~ ~S~

tOJ

Cacbazol nrong d6i ~n viing d6i v6i tac nhan oxi h6a ctlng nhu tac dung ciia nhiet nen khOng bi vovang.

72

Chuang bon

cAc 01 VONG 5 C~NH CHUA 2 HAY NHIEU 01 TO (CAC AZOl)

Azol la ten goi chung cac di vong thorn 5 canh chua 2 hay nhieu di t6, trong d6 it nhA't e6 mot di t6 nita. Nhu vay, cac azol chlnh co thi diroc gioi thieu du6i day :

N N Q } 1,3-azol
fa> (j
I
H
oxazol imidazol thiazol
t~ 69°C t?x: 96°C t~ 116°C
to 256°C
s
c» r» eN } 1,2-azol
<Y N' s'
I
H
lsoxazol pirazol isothiazol
t~ 95°C tric 69°C t~ 114°C
,0 1l!7oC
s
(~~ Z~ N-N N-N N-N
I() Z) Z 'k
N/ N/ 0 S N/
I I I
H H H
1.2.3-triazol 1,2,4-triazol 1,3.4-oxadiazol 1,3,4"thiadiazol Tetrazol
tric 23°C t~ 121°C .
,~ 204°C t~ 2600C Sau day chung ta chi xet mot s6 hop eMit chfnh rna chu yeu Ill. cac 1,3- va 1,2-azol.

Neu so sanh vOi cac don di vong nrong irng chira mot di t6 thi cac azol nay Mn vtrng hon nhirng kha nang phan irng lai kern hon. Mat khac nhieu tfnh chat b cac di Yang nay cling r:ft khac nhau. Thf du, trong khi thiazol kern ben d6i vci tae dung oxi hoa cua KMn04 thi isothiazol lai ben viing han nhieu, trong khi oxazol ben viing d6i voi hie dung cua kiern thi isoxazol lai rat d~ bi vcr yang bOi tac dung cua bazo hay tac nhan nuc1eophin khac,

73

I· vxr NET vf CAU TA.O

Theo thuyet obitan phan tlt thi cac phan nr di vong nay deu co diu tao phang va trong vong chua he th6ng 6 electron 1t do m8i nguyen tu cacbon va di t6 nita thu hai dong gop 1 en' con di t6 tlur nhat d6ng g6p 2 en' Trong tnrong hop vong chua 3 hay 4 di t6 thl he th6ng 6 en cfing duoc KAy dung nhu vay (xern hlnh ve) :

~~---------~. ~fI :'I~--------- ... \

~~~ ..

i1 day X = O, Shay NH

Tinh ben vtrng cua cac azol nay duoc quyet dinh chinh boi SI! c6 m~t h~ 6en giai toa trang roan phan tir. Tir su mo ta tren ta cling thf1y r6 rang nguyen tir nita cua vong con c6 cap electron tu do duoc phan b6 tren mat phang obitan vuong goc voi mat phing cua h~ obitan 1t cua vong. Chinh cap electron tt! do nay lam cho cac azol c6 tinh bazo va quyet dinh d~c tfnh nuc1eophin cua cluing.

V 6i quan di~m cua phuong phap c~p hoa tri, cau true cua cac awl nay phai duoc xem nhu SI! lai t<;10 cong hirong cua mot day cac cau tnic gi6i han, Thf du:

-

-

Quan di€m nay cho thay ro rang y nghia cua c~p electron tl! do tren dj t6 nita trong cac phan img hoa hoc khae nhau, M~t khac cling cho thay su dong g6p khong d6ng deu ciia mlli cau true gioi han vao su lai tao cong hirong cua azol, va hOi the' cho nen su phan b6 mat dQ electron tren cac nguyen tiI vong azol cling khong d6ng deu, Dieu nay con dtroc phan anh qua tfnh chilt hoa hoc ciia cluing.

Duoi day dua ra cac dfr kien ve su phan b6 mat dQ electron va dQ dai lien ke't trong cac phan nr azol :

0,529 -0287

-0068CN'

, 0,759

.{),037 +0 094

0.396 NJ.48i 1+0,298

H

0,581 .{),017CN +0,025

0,770 I 0,765

-0,051 ~,269

0,441 N 0,396

I +0,300

H

(Theo Braun-1955)

74

2'1-----,-0,312

0,636 0,7!l3

-0,021 ,357 +0,017;

0,688 +0,001 N 0,462

..0,029 1+0,256

H

_0'1~0'580 N-O,GI9

0,776 I

+0,032 N -0,189

0,45 0/0,412 +0,2&1

0,434

0,569 N 0409

+0,059 - ,

0,729 1°,647

+{l,043 ~ 122

0,401 0,60 S 0,642 0,443 +0,1&5

_0'10~0'569 N -0,328 +o,1440°,634 -0,050 N 0,584 N -0,142 -0,181N--N -0,075

0756 J ° 697 0,707 0,705 0,73°1 I 1 1

, , _. +0 099 -0 027

..o,Q70 ,590 +0,023 ;+0,016 _.,..-;:N 0,281, C::-"._ _.......C ' +0,167C .... NH/N'

S 0589 0,594 S 0,502 0,571 ~S

+0,478 +0,491 +0,086 +0,116

Tit cac cau true duoc gioi thieu ta tha'y tren di t6 nita ella vong (0 vi trf 3 hoac 2 trong cac 1,3- azol hay 1,2-azol) con c6 c~p electron nr do khong tham gia vao sir 6n dinh hoa vong thorn, nhung co kha nang the hien tinh bazo va tao ra cac lien ket moi, Tuy nhien tinh bazo ella cac azol nay ra't khac nhau, Thi du :

Chat Irnidazol Thiazol Pirazol Isoxazol Amoniac Piridin
pKa 7 2,5 2,5 1,3 9,2 5,2 VI v~y rna trong khi imidazol co the tao rnu6i k€t tinh ben vimg voi nhieu axit khac nhau thl cac azol khac co tfnh bazo yeu han, mac du cling co th~ duoc proton hoa nhung rnu6i cua cluing rhuong bi phan li rnanh, nghia la kern ben vtrng.

Mat khac ding can thay dng khi tac dung voi cac tac nhan ankyl hoa ta't Cll cac azol nay deu c6 . the chuyen thanh rnu6i bazo nita bac bon, Rieng cation irnidazol c6 tfnh ben vtlng d<,!-c biet so v6i cation cua cac azol khac, Dieu nay diroc giai thich dog cation irnidazol co tinh d6i ximg cao rna 0 cation cua cac azol khac khOng co :

@

C;-H

N

I

H

-

~N-H

~i)

N

I

H

Ben canh tfnh haw, a irnidazol va pirazol con c6 proton axit, va cfing nrong 1\! pirol, cluing de dang tao rnu6i voi cac ion kim loai, Tuy nhien tfnh axit cua imidazol va pirazol lon hon pirol rnt)t chut do anh huong hut electron cua di t6 nita thu hai trong vong.

S\! nghien ciru tinh cha't v~t li chi ra rang irnidazol va pirazol con e6 kha nang tao lien k€t hidro giira cac phan tir, VI v~y rna cluing eo nhiet dQ soi kha cao (2560C va 1870c nrcng img) so voi cac hop chat cung co kh6i hrong phan tll'. Trong khi d6 cac dan xuat Nvankyl hoa, rna 0 dft'ykha nang tao lien k€t hidro da hi loai trir, thirc t€ co nhiet dQ soi thap hon nhieu, Dieu nay diroc giai thich rang 0 trang thai long imidazol t6n tai a dang t~p hop khoang 20 don phan tit voi nhau thOng qua lien k€t hidro, con pirazol tlnrong " dang dime :

75

TI'r nhling dieu m6 ta (j tren c6 th~ hi~u rang cac imidazol va pirazol neu kh6ng c6 nh6m the (j di t6 nita s6 1 (nghia la can H axit) c6 th~ tao thanh him hop hai dang tautome. Cac dang tautorne nay d~ dang d6ng phan hoa IAn nhau mot each nhanh chong do str co mat cua cac lien ket hidro, Thi du:

4 5 1

CH3TN3 CH3TN-H

5 z. .. ) 2 - 41!...._ _ 12

t;:ll Nf

H (1)

4 3

~II\

; CH X. __ .... N2

3 t;'ll

H

4 5

~ CH3~~-H

(II) 2

Nlnr vay cac nguyen tlr nita trong imidazol va pirazol thuc te co thi! dong vai tro nhu nhau va trong SI! the khong d6i ximg co kha nang t6n tai hai cau true tautome hoa, Chinh VI the trong cac phan irng hoa hoc cac hQV chat (I) va (II) duoc xem nhir la h6n hop cua hai d6ng phan: d6ng thoi co tM coi 4-metylimidazol va 5-metylimidazol chi la mot, va nrong tu, 5-metyl pirazol cling hOM roan giong voi 3-metylpirazol. Do d6, d6i voi cac tnrong hQV nhu vay, nguoi ta phai dung each danh s6 kep trong ten goi cua chiing. Chang han: hQV cha-t (1) dUIfC goi la 4(5)-metylimidazol va hop chat (II) la 3(5)-metylpirazol.

, , .:l

II· CAC PHUONG PHAP TONG HQP

2.1. Tting hop cac 1,2-azol

- Phuong phap chung nhat va duqc Slr dung rong rai nhat d~ t6ng hop vong isoxazol va pirazol la SI! cong hop cua hidroxylarnin hay hidrazin van hop chat 1,3-dicaebonyl. Phan irng tao thanh trung gian cac oxim hay hidrazon va sau d6 duoc dong vong tiep thea:

r-r-CH3

A_ ..... N (73-77%)

CH3 N ....

I

H

(84%)

76

Nhtroc dit~m cua phirong phap nay la khi sir dung hop chAt dicacbonyl khong d6i xirng va hidroxylamin hay hidrazin mot h'in th€ thi thuong nh~ duqc hOn hop hai san pMm. Tuy nhien phirong phap nay van diroc irng dung rong rai d~ t6ng hop 1,2-azol.

- Isoxazol va pirazoi ci1ng c6 th~ nhan duqc bang su ngung tu cua hidroxy1amin hay hidrazin voi cac hop chat cacbonyl a,~-kh6ng no (chua n6i d6i hay n6i ba).'

o

CH3CH2-~-CH=CHCl + H2N -OHHCI CHpH Dun sol

CH3COOH H2S04, Dun sbi

(93%)

CIO

C6H5-CH=t-~-C6H5 + C6HSNHNH2 ~H50H Dun sol

Nhtroc diem cua phuong phap nay cfing ill. trong mot vai tnrong hop tao thanh hOn hop cac d6ng phan. sa di nhu vay VI phan ling dien ra c6 th~ thea hai chieu hu6ng: Hoac xay ra su ngimg W d~ tao thanh oxim hay hidrazon tnroc r6i moi d6ng vong tiep thea; hoac nguoc lai, xa.y ra sl! cong hop cua hidroxylamin hay hidrazin van lien ket kep tnroc roi rnoi d6ng vong tiep thea vm su tham gia cua nhom eacbonyl. Tft:t nhien tuy thuoc vao ban chat tac nhan, dung moi va nhiet d¢ phan irng rna chieu huang nao se chiem uu the.

- S\! cong hop vong kieu 1 ,3-luemg eire cua cac nitrin-oxit hay diazo-ankan vao axetilen rna lien ket ba cua n6 diroc hoat hoa bbi S\! c6 mat nh6rn hut electron ben canh cling dan t61 su tao thanh de dan xuat cua isoxazol va pirazol:

ete -

ot

r1CHO ~ N ....

H (&4%)

77

, v~ co ch€ c6 th~ xern phan ung nay nhu 13. su cong hop theo kitu Michael dAn t61 hop chat hrong cue r6i sau d6 san pham trung gian nay diroc phan huy va d6ng vong thanh dAn xuat cua isoxazol:

- Ve nguyen tic cac phuong phap duoc neu ra b tren cling co the van dung de tOng hop isothiazol neu di tu thiohidroxylamin (H2N-SH) hay nitrin sunfit (~HsC=N--)- S). Nhung trong thirc t6' thiohidroxylamin rat khong ben can nitrin sunfit cho de'n nay van chira dtroc biet, VI vay viec tdng hop isothiazol phai di bang con dirong khac, chang han, phai sir dung cac chat dau rna trong phan tii da co san lien ket S-N. Mot viti thi du dl1qc dan ra duoi day:

Al203 holt! hml 20rfC

3 O~ + 8H20 + H2S S""

nCH)

l(_ .... N (25%)

S

2.2. T6ng hcp cac 1,3-3zol

D6i v61 cac 1 ,3-azol thuong khong co mot phuong phap chung va tong quat nao de t6ng hop nhu trong tnrong hop cua 1,2-azol. Tuy nhien cling co the dan ra mot s6 phirong phap chung sau dAy:

- Dong vong hoa cac hop chat l,4-dicacbonyi, rna giira hai nhom cacbonyl do co met di t6, nghia ia ve mat nguyen tk phuong phap nay tirong tt,r tong hop cac dan di yang 5 canh 1 di t6 theo Paal-Knorr.

78

(93%)

S,! dong vong dehidrat hoa cac o-axylaminoxeton (I) la milt trong nhimg phuong phap hi vong di! t6ng hop vong oxazol. Nhung phuong phap nay co nhiroc diem la chi tao ra cac oxazol eo chua hai nhorn th€ a cac vi tri 2 va 5.

Tuy nhien phuong phap nay eilng duoc sit dung M t6ng hop ca vong thiazol. Thi du:

CHCI3. dun sOi

- SI,l' nrong tac cua cac a-halogen eaebonyi v6i amidin va cac thioarnit eo tM dung lam phirong phap t6ng hop cac imidazol va thiazoi nrong ling:

CH3 1 CH3t

CH3-C=O H2N, ~ H;'r=f_~N - r ~

I + ""C-C6Hs.HCl H 0 '/:::( .... , A

CH2C1 HN~ D 2. H C6HS N C6HS

un S6L H

V6i phan irng nay eo th~ nhan diroc cac thiazol khac nhau. Tuy nhien phirong phap nay thirong khong duoc ling dung rong rai M t6ng hop vong thiazol, VI cung v6i phan Ung nay con dien ra nhieu chieu hucng phu khac, va do do, rlit kho tach san pham tinh khier.

- Trong mot vai tnrong hop d~ t6ng hop cac oxazol va thiazol cling c6 the sit dung phan ang ngirng tu cua cac imino ete voi hop chat e-aminocacbonyl :

79

CH)" ¥O ~

r + H2N -C- NH2 CH2C1

I) H20 s6i 2) NaOH

CH3)-N

(C'>-- (70-75%)

S NH2

Co che cua qua trinh nay duqc gioi thieu duOi day. No dua tren co so tach ra duqc cac hop cha't trung gian :

- Cac hop chat a-aminocacbonyl hay cac dan xuat cua no voi nhom cacbonyl "An" co the phan img voi natri isoxianat hay ankylisothioxianat de tao ra cac dAn xu~t 2-mecaptoimidazol r6i sau do nhorn mecapto bi loai di de dang bOi tac dung cua chat oxi hoa:

1) HNO), 40-50oC

2) NaOH

(87,5%)

- Rieng d6i v6i yang imidazol cling con mot s6 phuong phap khac dugc gioi thieu dum day: + Tuong tac cua 1.2-dicacbonyl voi andehit va amoniac (hay amin)

H-C=O I H-C=O

H \

+ H-C=O

[)

N

I

H

+ 3 H20

Glioxal

Phan Ung nay mang ten Debu, Neu b6 xung fomandehit van hen hop phan Ung thl hieu sua't irnidazol tang len nhieu,

+ Phan irng cua n-oxixeton v6i fomandehit a nhiet d() 1 SO-IS()OC trong thai gian 2-4 gio.

so

R-C=O I R'-C=O

/OH R-C-NHCHO I

R'-C-OH

I

H

R-yH-NHCHO H2N -CHO R'-C=O

H

I

R-C-NHCHO I

R'-C-OH

"NHCHO

R-C-NHCHO II R'-C-NHCHO

RXN

-HCOOH r ~

--R' N/

I

H

Phan irng nay thirong cho mt)t hrong nho san pham phu lit oxazol chua hai nh6m the' lJ vi tri 4 va S. Nhung neu khong thuc hien nghiem ng~t dieu kien phan irng (du 16n fomamit, nhiet dl? 0

180-2OD°C) thl qua trinh tao thanh oxazol co th~ tro thanh chu yeu. Song neu dun sOi 3-6 gio oxazol nay v6i fomamit thl cu6i cung cilng nhan duqc imidazol vOi. hieu suat tho! dang:

R)-N R,.----zN)

,

H

+ S,! urong tac ella diamin v6i aneol, andehit hay axit eaeboxylie no trong su co m~t ella xiic tac Pt/ Al20J CJ nhiet d¢ eao (4000C) cling tao ra vong imidazol :

Cl

N R

I

H

- Ngoai cac phuong phap tren cac dan xu~t ella oxazol eon eo the nhan d1.lQ'e trong 51/ tU'C1I1g tac cira mot vai amit voi cac n-halogen xeton:

R-C=O I R'-CHX

HCONH2 [R-C = 0 ]_{

R,-bH-O-CH = NHz x

R-C- N

II II

R'-C rH

'0 ........... + HX

R-C=O

I

R'-CH-OH

Phan irng nay co th~ dien ra CJ nhiet dl? teen l000C, khOng c&n dung mOi va thirong b6 xung Cac03 vao hOn hop phan Ung lam ch~t 1!1Y HQ giiai ph6ng ra.

2.3. Tong hqp benzimidazol va benzoxazol

- Phuong phap t6ng hop benzimidazol dugc irng dung rong rai nhA't la s,! nrong lac clla o-phenylendiamin voi cac andehit hay axit cacboxylic. Thi du :

81

6-HHCCDV

@XNH2 + RCOOH P.P.A. CCl
..........._
NH2 N R
I
H
@XNH, [0] CCl
+ R-CHO (Schftng han)
NH:z N R
I
H - Benzoxazol dtrqc t6ng hop nrong tu khi di tit o-arninophenol:

r"YNH2

~ + R-CHO

OH

-

f"'yN=CH-R ~OH

[OJ

~l

~o R

-

2.4. T6ng hqp cac trlazol

2.4 .1. T ling hap 1 ,2,3 -triazol

- 1 ,2,3-triazol nhan diroc kha de dang bang sir ox i hoa ozazon bbi axit axetic va kali bicromat:

HC = N-NHC~5 K2Cr207 HC-N=NC6Hs FeCl3

Hi: = N - NHC6HS CH3COOH J- N = NC6HS HClloang

HC=CH

I \

~ N-Q,Hs

.... N ......

- 1,2,3-triazol cling dtroc t6ng hop bing phan ling cua azit v6i cac dAn xuat cua axetilen, Th1 du:

- Dan xuat elJa 1,2,3-triazol diroc tao ra d. trong si! nrong tac cua phenylazit voi benzyl nitrin:

2.4.2. T dng hop 1 ,2 ,4-triazol.

- PhU'011g phap dan gian t6ng hop I ,2,4-triazolla ngung tu diaxylhidrazin voi amoniae hay amin:

HN-NH

I I

R'10 COR

N-N

R JL J_ R (Hi~u sua't eao)

. N

I

R'

82

- M<)t phuong phap khac t6ng hop 1.2.4-triazolla d6ng vong hoa dAn xUal axyl cua semicacbazit, thiosemicacbazit hay aminoguanidin trong mOi truong kiern hay axit:

R'

I RCONHN -CNHz II

S

[(~ 1

R-S:-NH -H 0

I <, NR' ____1__,.

~~~SH

Rl\~H N N-R'

Y

S

o day clio nho dng d6i vei 1,2,4-triazol hay dAn xua't 1,2,4-triazol chUa 2 nh6m th~ nhu nhau d vi tri 3 va 5 luOn t6n tai d hai dang tautome: Dang 1- H (I) va dang 4- H (II).

N--CH

II II

HC <, /N N

I

CH3

(I)

(R)HN-CH I: @ II He'. N

~ .... /

NH(R)

VI vay cac ca'u true san phAm d cac phan ting tren tlnrc eha't la cua 1,2,4-triazol.

2.5. T6ng hnp 1,3,4·oxadiazol va 1,3,4·thiadiazol 2.5 .1. T dng h(lp 1,3 ,4 -oxadiazol

- Phuong phap t6ng hop 1,3,4-oxadiazol thuan tien nhat 18. dong vong hoa cac dAn xuat hidrazin voi Sl;J tach loai phan tit mroc, H2S, ... trong Sl;J co m~t tac nhan dehidrat hoa, Cling han: Ttrong tac cua hidrazin diaxyl hoa vm PO03 hay SOCl2 hoac H2SO4 khi dun nong manh dAn tm Sl;J tao thanh vong 1,3,4-oxadiazol.

RCONHNHCOR'

- Glio day xuat hien phuong phap t6ng hop m<)t giai doan cac 2.5-diankyl-l,3,4-oxadiazol (rat kho dat diroc) bAng sir dun nong axit eacboxylic va hidrazin clohidrat trong moi tnrong POClJ soi, r6i tiep thea ca't phan doan h6n hop:

N-N

. -iz i

R O?-R

Qua trinh cole di~n ra qua giai doan tao thanh clo anhidrit cua axit cacboxylic,r6i n6 axyl hoa hidrazin clohidrat d~n dAn xuat diaxylhidrazin. Sau do phan m.g tro lai nhu dugc mo ta d phuong phap tren.

83

2.5.2. T 6ng h{1P 1 .3 ,4 - thiadiazol

- Nhieu phuong pbap tOng hop I ,3,4-thi~ldiazol duoc biet d~u di tu ddt (lju 13. dfin xuf!t cua thiosern ieaebazit:

-_

Trong nhimg phan irng nay co the thay cloanhidrit bang H3P04, HCOOH, CSz, este o-fornic va nhieu tac nhan khac, Mac du dan xutft cua 1,3,4-thiadiazol dl19'C tim ra dau tien tt! narn 1882 bffi E.Fiseher, nhirng phan tir 1 ,3,4-thiadiazol kh6ng co nhom the mai den nam 1956 moi nhan dtroc,

2_6. Tong hop tetrazol

C6 nhieu phuong phap t6ng hop vong tetrazol.

- Ban than tetrazol duoc tao ra khi tl1<111g hie trong dung dicn nrou cua xianhidric v6i axit hidroazotic.

HCN + HN3 -

Mt)t 10i;l1 cac phirong phap dua tren SI! tU<1I1g tac ella cac dan xuat hidrazin voi mu6i diazoni. D6 lam thi du co the dan fa phan ling t6ng hop tetrawl-l,5-hai I;1n the: tit axetylhidrazin vai phenyldiazoni clorua:

- Mot trong nhUng phuong phap q uan trong nh fit cua sir t6ng hop cac tetrazol-1,5 -hai Ian the Iii phan ling cua xeton voi axit hidroazotie trong sir co mat ella axit v6 co (do Smith tim ra):

I

RCH2 II ~ -CH2R'

ItN~

Co eh€ phan trng Smith nay gAo lien v6i cac khai niem ve xuc tac axit:

.:t. HN3

- R-c= N-R' - ( H+)

84

III ~ TiNH CHAT

3 .. 1. Tinh ch!\t cua 1,2. va 1,3-azoJ

3 1.1 Phdn Irng the' electrophin (Sc)

"' V~ kha nang phan (rug voi cac tac nhan electrophin thi cac 1,2- va 1 ,3-azoltchiem vi tri trung ginn giua cac di vong thorn 5 canh 1 di 16 va piridin. Dieu nay duqc quyet dinh tnroc het boi tac dung h{\t electron ella di t6 trong vong, va boi mot dieu rang, nhieu phan irng the electrophin dien fa trong m6i tnrong axit manh, rna nhu vf!.y vong azol bi proton hoa va khi d6 cation azol, ta't nhien, be!' virng hem doi v6i sir tan c6ng ella cac rae nhan eleetrophin cting mang dien tfch duong. Chi\ng han: halogen hoa cac azol do Yang mat axit rnanh nen xay ra de dang hon nhieu so v6i phan U'ng nitro hoa hay sunfonic hoa,

o

S N

HCHO/HO

(57%)

Tren co sa cac du kien thuc nghicm e6 th~ xep kha nang phan ung d6i voi cac tac nhan electrophin trong day I ,2-azol theo thu tl,l" giam d,ln nhu sau:

Pirazol > isothiazol > isoxazol

V~ mat dmh lurong trong day 1,2-azol thi sll t;fu cong cua cac tac nhan electrophin xAy ra lJ vi rn 4, boi VI tr~ng tha: chuyen tiep dAn tai slf the a vi tri nay nrong d6i virng ben hon ca. Thi du:

Phu hop voi co che tren day ngiroi ta thay mot su that rang 5-metylisoxazol diroc nitro hoa va sunfonic hoa de dang hem nhieu 3-mctylisoxazol, vi khi do c6 anh hireng ella hieu irng situ lien hop do nh6m rudy] 0 vi trf 5 gay ra (rna nh6m the metyl a vi tri 3 khong co) Jam 6n dinh trang thai chuyen tiep.

Trong rnrong hop cua cac phenylpirazol thl su the eJectrophin c6 the xay ra a vong pirazol hay yang benzcn tuy thuoc vao dq axit cua moi tnrong.

B'rs;Or~ Br2 nO~

N CH COOH N

Cl N~ 3 CI N~

, ,

H H

HN03• ~~ N02

H2S04 N

Cl N~

,

H

85

Ngoai ra cac 1,2-azol cling c6 tht tham gia mot each yeu at vao cac phan U'ng Friedel-Crafts, Winsmeier hay ghep dOi voi mu6i diazoni.

* D6i vm cac 1,3-azol c6 the sAp xtp kha nang phan Ung trong sl! the electrophin theo thu tl! giam dAn nhu sao:

Imidazol > thiazol > oxazol

Chilng han: Imidazol dl1c;tc halogen hoa ngay ca khi vAng m~t xuc taco Nhung brom hoa thiazol trong cac dieu kien thong thueng c6 kern theo 51! tao thanh san phAm polibrom hoa, COn oxazol n6i chung khong tham gia vao cac phan ling tht electrophin,

Brom hoa imidazol trong dung moi hiiu co (a dl\y chac chAn xAy ra tac dung cua ion brOm vOi phan tir imidazol trung tfnh) dAn Wi Sl! t<,1O tbanh 4(5)-brom imidazol, Ngiroc lai cac phan ling ghep dOi v6i mu6i diazoni va trao dOi doteri trong moi wang kiem lai diin tm sV' tao thanh cac dAn xuat the a vi trf 2:

Neu vi tri 4 cua vong imidazol chua nh6m the day electron thi sl,l' the se dien ra a vi tri 5; con neu d hai vi trf 4 va 5 dell d! bi chiem thi co ban tac nhan electrophin tAD. ceng vao vi tri 2:

cac thiazol N-ankyl hoa tham gia vao phan U'ng the electrophin vCri su tao thanh cac san pharo the a V! tri 5 chil khOng phai vi trf 4. Di6u nay dt«;1C giai thfch rAng:

Thirc ch~t ion thiazol t6n tai a dang (B), nghia la di~n tich duang duf/C dinh xu tren hru huynh chtr khong phai tren di t6 nito,

86

Tir d6 ta thay dng trang thai chuyen tiep dan 161 sir the' " vi trf 5 co loi hem. ve mat nang luong so voi th€ iJ vi trf 4.

C1-NH 1) C12, He]

S 2 2) NaOH

Cling nhu pirazol, cac imidazol, thiazol va oxazol co chua nh6m the' phenyl thl thtrong diroc nitro hoa a vong benzen. Ngoai ra cac 1,3*azol ding tham gia it k€t qua vao cac phan ling Winsmeier, Friedel-Crafts,

3.1.2. Phon trng the' nucleophin (SN) va the' 86(· (SR)

* Cac phan ttl trung tinh cua day 1,2*azol c6 mat d¢ electron cao nhAt b vi tri 4, VI v~y nguyen tu halogen lien ket v6i cacbon iJ vi tri nay cling to ra c6 kha nang kern nhAt trong cac phan ling the nucleophin hrong phan ttl (SN2). Tuy nhien, cac phan ling nay dien ra nhanh hem. a cac dan xuAt halogen nrong ling trong day benzen. Ngoai fa .kha nang phan ling con phu thuoc nhieu vao tinh di).c bier cua d] vong va van ban chAt nhorn the c6 si\n trong vong cling nhu van vi tri cua nh6m the. Thi du:

Trong hop chAt tren chi c6 nh6m clo 0 vi tri 5 duqc thay the. Chieu huang nhu v~y cua Sl! the nucleophin c6 the duoc giai thich rang dien tich am xuat hien trong trang thai chuyen tiep d~ dang diroc giai toa hOi anh huong cua nhom nitrin. Cling nrong tu nhu vay d6i vci cac thf du sau day:

87

Trong khi d6 hop chat nrong t\1 nhung nguyen tu do a vi trf 3 thi lai khong tham gia vao phan tIng nay vi khOng c6 anh hirong img hI> cua nhorn phenyldiazo a vi tri 4 .

.. Ngiroc lai voi cac 1,2-azol, cac dan xu~t halogen cua imidazol, thiazol va oxazol d~u khong tharn gia van s\1 th~ nucleophin. Nhimg n~u trong phan tiI cua cac 1,3-azol co chua nh6rn th€ hoat hoa manh va d~c biet vCri tnrong hqp 2-halogenthiazol c6 kha nang phan ling cao, thl d~u c6 tht tham gia vOi mec dt> dang ke van cac qua trinh th€ nucleophin cac halogen. Thi du:

()_C1 Q to C)_O
+ ~
S \
H
02?:~ NH3 02Nr~ === 02NrN-H
CI N) - H2N ~) H2N N)
I
H H .. M<)t trong nhOng tinh chfit d~ bi¢t cua vong isoxazol, rna qua do c6 the phan biet n6 v6i cac azol khac, la tinh rat khOng Mn duOi tac dung cua cac tac nhan nucleophin. Mac du trong tat d. cac truong hop deu dy ra S\1 dUt vo lien kl!t 1-2 (O-N) nhung san pharo tao thanh cac dang khac nhau va cau tao cua cluing phu thuoc nhieu vao vi trf ciing nhu ban cha:t nh6m thl! trong vong,

Nl!u a vi trf 3 khong c6 nhom thl! thl dum anh hUOng cua tac nhan nucleophin dy ra SI,l tach proton a vi tri 3 kern theo S\1 rna vong va phan b6 lai mat dl} electron.

NH3

-

Neu 0 vi tri 3 c6 nh6rn tht thl s\1 rno vong isoxazol c6 th~ xiy ra thea cac chieu hu6ng khac nhau tuy thuoc vao ~c tinh cua cac nhom the, Thi du :

88

----+

o 1

OOC-CH2-C-CJ-Is -

"0

N-

Trong t.ft't ca cac thf du tren (trir tnrong hop cu6i cung cua 3-axetylisoxazol) giai doan dau tien cua sl! vCJ vong Hl SlJ tach proton i:J vj tri 5 cua vong isoxazol,

* Cac qua trinh th€ g6c trong day azol noi chung r.ft't It diroc nghien ciru, Nguoi ta biet rang brom hoa thiazol a 2500c - 4000C chu yeu dan tai SI! tao thanh 2-bromthiazol. Con su phan huy benzoyl peoxit trong sir co mat isoxazol 5e tao ra hon hop ella d. ba d6ng phan:

D6i vOi cac azol khac kMng co thi du nrong nr nao ve su tifn cong cua cac g6c dong li vao nguyen tir cacbon cua vong,

Trong qua trinh th€ g6c tlJ do b mach nhanh ankyl co tht dan ra thl du v~ 51! halogen hoa sau day:

~-&

o

3.1.3. Phdn ung kim IOfJi hOG a 1,2- va 1,3 -azol

CUng dtroc biet mot vai thi du ve sir kim loai hoa cac 1,2-azol. Phan ling nay voi mire d¢ chon 19c cao dien ra "V! trf 5. D6i voi cac 1 ,3-azol thl sl! kim loai hoa xay ra dac bier a vi trl 2.

89

o

S N

1) n-C4H9Li(I1-lF

2) (CH3)2N-CHO

n...

OHC/z...S ... N

(75%)

CHrfi--N (S~CH(OH)CH

(48%) 3

Cac imidazol va pirazol kh6ng e6 nh6m the a di t6 nita trong vong co the: philn irng voi die kim loai hoar dong nrong nr nhu pirol nrong img nhung khac a cho Iii chi tao thanh dAn xuat the tren nita. Vi vay irng dung cua phan ung nay bi han che' nhieu.

Nhu phan tren d1! n6i, cac isoxazol ra-I kern ben duOi tac dung cua eric tac nhan nucleophin, BOi the cho nen khi nrong tac voi thu6e thu Grignard hay trong cac dieu kien cua phan irng chuyen kim loai thi vong isoxazol bj pha yo. Cling VI v~y trong day azol cac phan Ung co dinh tnroc s\f thay tM halogen bang kim loai noi chung it diroc img dung van thirc te .

3.2. Tinh chat cua cac triazol

* Tir dil kien ve sir phan b6 mat d<t electron trong vong 1,2,3·triazol d1! cho thay ro tinh "tro' tren cac nguyen tir eaebon cua n6 d6i voi cac tac nhan eleetrophin va ve tfnh bazo yeu cua n6 (pKa::::: 1,17). Ket luan nay cling diroc khang dinh bOi cac ket qua thirc nghiem.

Ben canh tfnh bazo yeu, cac I ,2,3·triazol cling bieu hien tinh axit yeu,

Tuy nhien yang 1 ,2,3·triazol r~t ben vtrng. Nhieu dan xuat cua n6 c6 th~ duqc ellt i:J ap suat thuong va nhiet d9 cao rna khong bi phan huy, Khi dun n6ng toi 2500C thi l-benzoyl-a.f-diphenyl- 1,2,3·triazol dtroc chu yen thanh 2,4,5·tripheny I oxazol .

0o.,_

C6H5::n N -CO-C6HS [C6H5-C- N -;;::-C-C6Hsl C6H)r_N

5lf.__~~ ~ II J -- f \\

C6HS ® C6H5-C@ C6HS OAC6Hs

>;0 1 ,2,4·triazol la mot h9'P chft't c6 d<t thorn cao. Cac dil kien thuc nghiern chi ra ding 1 ,2,4·triazo! nrong d6i Ira voi rae dung cua tac nhan rnanh nhu lithinh6m hidrua, KMn04, peoxit, ... Cac phan ling the electrophin tren nguyen tit cacbon cua Yang 1,2,4·triazol dien ra nit kho, Cho den nay cac phan ling sunfonic hoa, Friedel-Crafts (ca alkyl hoa va axyl hoa) 1 ,2,4-triazol deu chua duoc biet; can nitro hoa 1 ,2,4-triazol chi xay ra khi c6 rn~t nh6rn the dAy electron trong vong, Thi du:

90

Nhung cac phan irng gin lien v61 sl! ta'n cOng electrophin tren d! t6 nita diroc nghien coo nhieu hem dang k~, thi du cac phan irng Nvankyl hoa, Nsaxyl hoa va xian hoa,

3.3. Tinh chat cua 1,3,4-oxadlazol va 1,3,4-thladiazol.

* Phd tii ngoai da chi ra du tao thorn cua Yang 1 ,3,4~oxadiazol tuong tl! nhu trong benzen, Nhirng cac phan trng th€ electrophin tnrc tiep tren nguyen tir cacbon cua Yang I ,3,4~oxadiazol da khong diroc biet do no bi proton hoa trong moi tnrong axit va bi rna yang tiep thea.

Tac dung cua cac tac nhan nucleophin v611,3,4~oxadiazol thuOng dan toi; hoac su vo yang hoan toan, hoac su yang hoa lai thanh mot dj Yang khac.

CUng dircc bi€t su chuyen vi cua 1 ,3,4~oxadiazol voi str thay the oxi trong vong hoac bang nita hoac bang cacbon. Co che cua hai qua trinh nay c6 th~ nhu sau:

- Truong hap thu nha!:

- Truong hqp thu hai:

N_~.....c6Hs

}(A

C6HS 0 C~s

NC-CH2COOEt, -H+ (~Hs)3N trong ancol

Nhi6u dan xuat cua 1,3,4~oxadiazol f:ft Mn virng d6i v(ri tac dung cua nhiet.

* D6i v6i yang 1,3,4~thiadiazol cho de'n nay Mu nhu chua diroc biet cac phan Ung th€ electrophin,

Nhung Yang I ,3,4~thiadiazol kha nhay cam v61 cac tac nhan nucleophin. Cac nuc1eophin rnanh co the gay fa SI! phan huy vong 1,3,4~thiadiazol, va doi khi, can kern thea su chuyen vi, Oling han, 2~amino~ va 2-metylamino~I,3,4~thiadiazol duoc chuyen vi khi tac dong cua rnetylarnin trong

rnetanol 0 1500C thanh d6ng phan triazolinthion:

N-NH

I(NAS

CH3

SI! chuyen v] nhu the, hien nhien, dien fa v6'i sl! mo yang va Yang hoa lai tiep thea.

-

91

3.4. TInh chat ella tetrazol

Tctrazol la axit yeu, co thti tao muoi voi cac kim loai kiem. Dong thai cal' tetrazol cling co tfnh bazo nen co kha liang tao rnu6i voi mot vai axit. SI.! nghien cuu cac muoi retrazoli dff dAn toi van de "gia thorn" nit thti vi. Ngiroi ta dff cho rang khi khir hoa cac rnuoi terrazoli voi 2 nhorn th&' a vi tri 2 va 3 bang natri sunfua hay hidrazin hidrat thl tao thanh fomazan - mot hop ch.ft't rna ban dill! nguoi ta cho rang chung a dang mach rna:

C6HS-tr- N =N --l~6H5 N-NH-C6Hs

Nhung khi nghien ciru dn than su chuyen hoa nay thi thay phirc tap hon nhieu. Tnroc h6t cac kho khan Ian da: gap phai khi xac dinh C!lU tao ella ban than mu6i tetrazoli. Tren co sa cac du kien

1 1 2

ella ph6 hong ngoai (sir eo mat tl1n s6 ella lien ket C=N va dao dqng hoa tri N -N ), cling nhu sir

phu thuoc ella sl.! phan huy dien hoa cac mu6i tetrazoii vao ban ch.ft'l nh6rn the trong vong, ngum ta di'i thira nhan mot each tin nrong rang cluing eo cau true vong (I):

N __ N/R' ¥ ! III' R-C~ 4 3 @

N=N'R" (I)

-

_®_/R' N=N

R-C/ I

~-N'R" (II)

Cac san pham khir hoa muoi tetrazoli - tue ia cac fomazan - cling co the diroc mo ta i:J dang hai Cal! true cong huang (III) va (IV):

R' N-NH'

R-Cq

'N-N

(III) 'R"

-

N=N/R' /

R-C ~-NH

'R"

(IV)

R'

J

N~N,

R-C' ."> 'H 'N:":":'N'

(V) R"

Nhung khac voi mu6i tetrazoii, a day khong nen eho su uu lien cua bat kl mot dang nao. Hem nira pM hong ngoai ella fomazan cling xac nhan 51! e6 mat cau hidro, rna dieu nay chi ra tnrc tiep kha nang t6n tai ca'u true (V).

Cau true (V) nrong irng d~e tfnh "gia thorn" cua fomazan va diroc xac nhan bOi su 1<;10 thanh phirc niken ella fomazan:

-

R' R"

, ,

N-N N-N

R C' -r :» '~N'/ --, '

- .... ' .. ~ .. },/ 1. -, ; .,' ",C·-R

N-N "N'':':'''N

R" R'/

92

Ngirci ia cting xac "inh l:lng trong triphenylfomazinthi g6c R nam trong cung mat phang cua vong, con cac g6c R', R" va cau hidro di ra khoi m~t phang cua vong (hinh vi! ben). Chinh d~e tnrng cua cac nh6m the R' Vi'l R" va dai hrong g6e khong dong ph~ng e6 the di'i xac dinh sac thai SI,!' nhuom rnau cua fomazan (cac fomazan "vang" va "do").

H

~

Phu hop vci de qllan di~m If thuyet hien dai d~e tfnh "gia thorn" cua hop chat pbai duoc bi~u hien 6 su eo mat nang hrong On dinh hoa va su dien ra da s6 cac phan Ung d~e tnrng cho hop eMt thorn thong thtrong. Nhirng cac dfr kien thirc nghiern cho tai nay d5 khong cho thfty cac dieu nay d6i voi fomazan.

Thirc tt' tat ca de phan irng cua tetrazol e6 th€ xep van ba nh6m: Cac phan irng cua nguyen tii cacbon va gAn lien voi nh6m chirc cua chung, cac phan irng cua nguyen ur nito, V:I de phan IIDg rna trong d6 loan phan tir tham gia.

Cho den nay chi diroc biet mot twang hop the electrophin tren nguyen tir cacbon elm vong tetrazol, Do HI. khi brom hoa l-phenyltetrazol d1t nhan diroc kha d€ dang I-phenyl-5-bromtetrazol. Nlurng kni nitro hoa ding l-phenyltetrazol lai nhan dircc l-(p-nitrophenyl)-tetrazol. Clo noi chung khong phan irng voi l-phenyltetrazol,

Ngiroc lai, ngtroi ta lai bier kha nhieu de phan irng the nuc1eophin cac nh6rn chirc tren nguyen Ii'! eaebon cua tetrazol. Thi du : Cac nguyen ti'! halogen 6 vi tri 5 cua vong tetrazol co th~ dircc chuyen thanh nh6m hidroxi boi tac dung cua kiern. Va r6i ehinh nhorn hidroxi lai Juqc: thay the

thanh clo boi tac dung cua photpho oxiclorua (POCI3). 5-Amino-I-phenyltetrazol dufJi tac dung cua h6n hop axit nitro va clohidric dii eho 5-c1o-l-phenyltetrazol. Ngoai ra mot vai tfnh chat cua nhom the a vi tri 5 da clnrng minh cho tinh thorn cua vong tetrazol, chang han nhir diazo hoa nhorn amino voi sir tao thanh diazotetrazol hay tinh hoat dong cua nhorn metyl.

Thuoc ve phan irng tren nguyen ti'! nito cua vong tetrazoJ chu yeu la ankyl hoa va axyl hoa.

Ankyl hoa tetrazol dien ra tren nguyen tll nito a cac vi tri I va 2. Ban than tetrazol duoc ankyl hoa de dang boi diazometan. Trong phan ,Ung voi cac ankyl halogenua hay diankylsunfat thi cac mu6i tetrazoli tham gia t6t hon ca.

Thuoc ve loai phan irng thu ba cua tetrazol la mot vai phan irng chuyen vi va chuyen hoa nhiet, Thf du : 5-aminotetrazol co g6c phenyl 0 vi tri I khi dun n6ng dtroc d6ng phan hoa thanh 5 -pheny lam inotetrazol:

C6H5NHTNtJ N'WN

Ro rang qua trlnh chuyen vi mang dac tfnh can bang, han nita su chuyen dich can bang v~ phfa d6ng phan v6i nhom amino diroc thay the de dang xAy ra khi co mat nh6m the hiit electron. NguOi. ta gia thiet rang sir chuyen vi dugc thirc hien theo CO" che sau day:

GL e

C6H5-C- N -C6H5 NH2-C- N -C6H5 HN =C - NHC6H5 HN--C - NHC6H5

II \ __ I ,. --" I J II

N~N-:.N ~ N~N_;W ~ :N~N9N ~ N~N/N

93

Nhu vay, ban dllu xay ra SI! rna vong tetrazol v61 SI! tao thrum guanylazit hoat dong r6i sau d6 quay ngiroc lai theo true C-N. va cu6i cimg vong hoa lai thanh d6ng phan nrong img,

Chuyen vi diroc neu tren chi la tnrong hop rieng cua phan irng t6ng quat hon trong day d! vong vci ten goi Ill. chuyen vi Dimrot,

Trong sir nhiet phan (hay quang_ phan), 5-aryl-4-axyl tetrazol duqc chuyen vi thanh vong 1,3,4- oxadiazol, CC1 che' cira chuyen vi nay duoc xac nhan nho sii dung cac nguyen tii danh da:u (Nt va N4 trong 4-benzoyl-5-phenyltetrazol la 15N):

Ngoai ra vong tetrazol voi cac nhom the' khac nhau cting th~ hien tfnh leba ben vilng d6i vm tac dung cua axit, kiem, chat oxi hoa va tac nhan khir hoa, Dieu nay diroc clnmg minh qua thi d1,1 chuyen hoa xianphenyltetrazol du61 day:

N - N -C6HS KOH N - N -C6Hs HNO N - N ----/c5'- N02

\ )( I 3}( I~

- N - N -

NC WN HOOC N HOOC W

IHI

-

SnCI:z

N - N ----/c5'- NH2

II I\~

HOOC...-"...N'N

I

H

N-N h II

"N'N

I

H

IV - cAe Mu6I BAZO NITO B!e B6N eVA 1,2- V A 1,3-AZOL

Phan Ung cua cac tac nhan ankyl hoa vOl cac irnidazol va pirazol e6 chua nh6m thl b vi tri I dAn 161 su t .... o thanh cac mu6i bazo nita b~c b6n ciia cluing. Cau t .... o cua cac mu6i nay diroc bieu dien bang cong tmrc A va C. chii khong phai B va D.

(~-R' UN 0 II"'i UN-RO [~-R

) ('fJ.) r "N-R' (~T"N .: ~N-R r ) Q-R

N R"N'R N e R,N'R' S S 0 O .... ®

I ,I ® t;.

R R - ~

(A) (B) (C) (D) (E) (F)

94

Cac azol khac khi tuong tac vtSi tac nhan ankyl hoa ding tao thanh cac rnu6i bazo b~c b6n tucmg tu, Nhtrng voi thiazol va isothiazol thi cau tnic cua cluing b dang E, nghia la dien tich duong duqc dinh xU" tren hru huynh chu khong ph iii tren nita. Trong khi do voi oxazol va isoxazol lai co clfu tao binh thuong theo k.i~u F voi su dinh xu dien tfeh dirong tren nito.

Nguyen tit hidro 6 vi tri 2 trong cac rnu6i bazo bac b6n ella 1,3-azol ra.""t linh d~ng nen c6 the dtroc trao d6i doteri mot each nhanh chong qua cau tnic ilit di vong trung gian. Thi du:

v - GI(JI THI~U MOT so LO~I DAN XUAT eVA 1,2- vA 1,3-AZOL

5.1. Cac dAn xuat hidroxi

Cac dan xuat hidroxi cua I ,2-azol nam trong su can bang voi dang xeto nrong trng. Nhung tuy thuoc vao vi tri cua nhom hidroxi rna mot trang hai dang d6 chiem uu the.

)0. OH 0

N - ~-H

X AX,N

b day X = 0, Shay NH.

Dan xuat 4-hidraxi cua cac 1,2-azol it diroc nghien ciiu, nhirng dii bitt 4-hidraxipirazol narn trong trang thai can bang tautome cua no v6i dang xeto:

o

(;N

I

H

95

Cac dan xuat 2-hidroxi ella cac 1,3-azol ton tai ehu yeu a dang xeto, Tirong h! cac dan xuat 4- va 5-hidroxi ella 1,3-azol ciing nhu vay:

N H HOrN °tN

[N [ - /I

~ ~ 7 \ . 1 ~~ ~

X~OH X~O' X/ X/

£)~ J:)

HO X ° X

X=O,S,NH.

Khi khao sat tinh chat ella cac diin xuat hidroxi trong day azol can nhan manh rang t6e d~ si! chuyen hoa nrong h6 cua cac d6ng phan tautome thong thirong eao han nhieu t6e dl) phan ung cua chung. BOi the cho nen e6 the xay ra phan Ung voi ngay ca dong phan nam 6 dang n6ng di) nbO.

Thl du :

u-f.0 { Phan img b

A~/ N -CH dang xeto

C6H5 S 3 e6 n6ng di)

(89%) nho

} Phan irng iJ dang enol c6 n6ng d{) nho

5.2. Cac d<in xuat amino

Cac aminoazol tuy cling nam trong s!f chuyen hoa tautome hoa, nhung iJ mire dl) thap han nhieu so vai cac hidroxiazol. Thuong cluing khong t6n tai 6 dang imino, rna thirc te chi 6 dang amino. VI v~y rna nhieu aminoazol mang tinh chat nrong nr amin thom. Thi du: cluing e6 the diroc diazoni hoa dE eho cac mu6i diazoni ben vimg.

5.3. Cac axit eaeboxylic

Cac axit cacboxylic cua day awl dircc xem nhir cac axit cacboxylic thorn. Chung diroc decacboxyl hoa a to :?: 200°C, trong d6 nhorn cacboxyl nao cang gan di t6 thi cang d~ bi decacboxyl hoa, Thi du :

Hooe

"r»:

HOOe---ZS.-N

mesitilen

Dun s6i 2 gia

Decacboxyl hoa axil isaxazol-3-cacboxylic dien fa khong binh tlurong va kern thea su vo vong.

Thi du:

96

5.4. Cac dan xu~t ankyl cua azol

Nh6m ankyl va d~c biet nhom metyl a vi tri 2 cua vong thiazol hay vi tri 5 clla vong isothiazol tharn gia M dang vao phan img ngimg tu voi cac andehit.

Cac dan xullt metyl cua cac azol khac n€u ducc hoar hoa bOi. sl! chuyen thanh mu6i haw nita b~c bon hay boi SI! co m~t nhom nitro trong vong azol thl d~c bier dk dang tham gia van sl! ngung tu Claisen, Liic do vi tri nhom nitro hoat hoa c6 y nghia quyet dinh. Thi du:

} Ngung 1\1 dlI1;1C v&i andehit do cacbanion trung gian diroc 6n djnh bbi anh huang cua nh6m nitro.

5.5. Cac dan xuat axyl eua azol

Cac dan xuat N-axyl cua cac azol rAt d~ thuy phan ngay trong moi tnrong trung tfnh vei sl! tach loai nh6m axyl,

Di~u nay dulJC quyet dinh bOi. khuynh hirong thorn hoa vei mli'c d~ 100 lao cua cac M di vong nay, cung nhu boo tac dung hut electron cua nguyen tit nita trong vong. Khi d6, m~t d~ electron tren nguyen tu nita lien k€t v(ri nh6m axyl b] giam dang ke lam cho lien ket C-N trong nh6m N-CO-CH3 bj y€u di, Do vay, cac dan xuat N-axyl azol dll'qc img dung rt';tng rai trong cac t6ng hop

hiiu co khac nhau.

97

7-HHCCDV

VI ~ cAc HOP CHAT CHUA VONG AZOL TRONG THIEN NHfEN V A EUQC UNGD~NGTRONGTHVCTE

6.1. Cric hep chat chua vbng imidazol Y3 pirazol

* Cac hop chat chua vong imidazol co rflt nhieu trong the gioi dong vat, CU!1g nhu trong thann phan mot s6 ancaloit a thuc v~t. Quan trong nhat trong s6 ancaloit do la pilocarpin. No co uic dung kich thfch h¢ than kinh ngoai bien, tuyen mroc bot, tuyen m6 hoi, lam giam noi Ilhan ap v~_ lam thu nho con nguoi cua mat. VI vay pilocarpin diroc lam thu6c chua benh gkmcome (oenh thien dhu th6ng) va cac benh khac cua milt.

Pilocarpin

Histidin

Histidin 1a mot axit amin clnra vong irnidazol, N6 Iii m91 mat xich nci lien phflil ber.ca (globin va hemin) v6i cau tnic porphirin trong hemoglobin.

Diroi lac dung ciia cac vi khuan hay m9t vai loai men, histidin bi rkc:;cbc~yi hmi tl.anh histarnin.

Trong the gioi dong vat, histamin co h1Q'11g nho Irong phoi, gan va mang nhaycua da day. No Co tac dung him giarn huyet ap, kfch thtch heat d¢ng va su tiet dich cua da day. Nhung s\! du histamin trong co the Iii. cue ki nguy hiem VI no dan den su pha huy nghiem trong qu{i trinh trao d6i char,

Ngoai ra nhieu dAn xuat cua vong imidazol con Cl1tje su dung lam tll'_)::;,~ chua benh nhir: dibazol, priscol va nirvanol (diphenin):

~lcH2c6H5

,

H

Dibazol

Nirvanol (dipncnin)

Dibazol la chat thu6c lam giam huyet ap.

Priseol ia chat heat d~ng lam gian mach L1<lU va c6 the dl1tje str dung lam thuoc chua mot s6 benh duong ruot.

Nirvanol la chat chong co giat e6 hieu qua.

* V ong pirazol tuy khong (:6 nhieu trong cac hop ch:!t thien nhien, nhung dan xuat cua lIO duoc tmg dung thirc re, dac biet trong cac Iinh vue y, duoc, ph 11m nhuom, chat phat xa va huynh quang, ...

Trang s6 cac chat thu6c thl dan xuat cua antipirin (nrc la I-phenyl-2,3-dimctyl-5-pirazalon) c6 gia tri d~c biet,

Rio than antipirin cting 1a mot chat thu6c giarn s6t manh. Trong thuc tc no diroc dieu che bang tac dung cua cac tac nhan metyl hoa voi l-phenyl-Lmctyl-Svpirazolon.

98

0::

O~N- .

C6HS antipirin

-

Pirarnidon va analgin - cac thu6e giam s6t - cling Ia cac dAn xufit cua antipirin,

Piramidon

Analgin

Danh sach cac eha't thu6e rna trong thanh phan phan til c6 vong pirazol dii khong ngirng tang len, Da e6 nhimg thong bao v~ tac dung seda (an th~) cua rn¢t vai dAn xuAt ankyl va aryl cua pirazol hay chat sunfamit "Orisul" e6 tac dung eh6ng vi trung lau dai:

"Orisul"

Ngoai ra, nhieu dAn xu fit cua pirazol con dltqC dung lam chat di~t con trimg (isolan, pirolan, pirazoxon) hay Hun phdm nhuom hoac dung trong phim anh,

isolan

pirolan

pirazoxon

6.2. Cac hop chAt chua yang thlazol va isothiazol

* Thiazol va cac dAn xuat cua n6 thuoc vao loai cac hqp ehfft di yang e6 vai tro ra't dang ke trong nhieu qua trinh hoat d¢ng s6ng, chu ye'u trong the' gi6i dQng v~t.

99

Thiamin (lUC la vitamin B1) la hop chat c6 chua hai di Yang: pirimidin va thiazol. Thiamin can thiet phai c6 du trong thanh phan thirc an cua con ngiroi, n€u thieu vitamin Bl nguoi ta se b] benh tt phu (benh beri-beri). Vitamin Bl thuong co nhieu trong mot s610~i men, trong cam, tnmg va trong nhieu loai thirc vat khac.

:>"" CH1-... @ Cl0 {R = H: Thiamin (nrc vitamin BI)

l~ ~ ~CH3 . HCl ?H 9H

CH3 N NH2 l_S CH2CH20R R=-P-O-P-OH:Cocaeboxylaza

II II

o 0

Trong co th~ dong vat, thiamin thtrong t6n tai iJ dang thiamin pirophotphat (can goi la cocacboxylaza). N6 la nh6rn hoat dong co ban cua men cacboxylaza va c6 tac dung xuc tac cho nhieu phan irng sinh hoa ding nhu qua trinh trao dbi chat trong co th~ dong v~t.

Cac chat khang sinh ho penixilin cling la nhirng hop chat chua yang thiazol trong phan tir.

CH3 S

~C/ ilNHCOR CH3 I

HOOC-CH-N '<:::0

Cac penixilin 11111 dAu tien dl1q'c tach ra tir mot s6 loai nam chua penixilin, r6i sau do duoc nghien CUu va phat tri~n manh tir h6i chien tranh the gioi th(r hai. Ngay nay ca 6 dang penixilin d1i duoc biet chi khac nhau hOi. nh6m R. T6ng hop toan phan pen ix ilin duoc thirc h ien vao narn 1957.

Phan dO<_l11 Yang thiazol iJ dang P-(thiazolyl-2)-p-aJanin tham gia vao thanh phan cua chllt khang sinh bottromixin, rna chat nay d1i duqc tach ra tir thuc v~t streptomyces bottropensis.

rr--N

'S J-yH -CH2-COOH NH2

Nhieu dAn xuat cua thiazol con diroc dung lam thu6c, d*c biet trong ho sunfamit, nhu sunfathiazol chang han:

rr--N 'SJ-NHS02-@-NH2

Ngoai ra nhieu dAn xuat cua yang benzothiazol con diroc dung d~ san xuat phAm nhuorn va cac chat nhay sang.

*' D6i v6i Yang isothiazol thi it tim thay trong cac hop chat thien nhien va su irng dung cluing trong thuc te cling han che hem. Tuy nhien, cling diroc biet mot chat ho sunfamit c6 tac dung ch6ng vi trung lau dai, do la 5-p-aminobenzensunfamido)-3-metylisothiazol (I) va cha:t 5-(aminoaxetamido)-3-metylisothiazol (II) thuoc ho analgin,

, r:---;r-CH3

fhN -@-S02NH-ZSJr (I)

NR'R" 'I II CH3

R"'-CHCONH-ZS/N

(II)

100