5 Selective Substitution of Sucrose Hydroxyl Groups via Chelates E

5 Selective Substitution of Sucrose Hydroxyl Groups via Chelates E. AVELA, S. ASPELUND, B. HOLMBOM, and B. MELANDER Academy of Finland, Pyorokiventie 10, 00830 Helsinki 83, Finland

Downloaded by MIT on October 28, 2013 | http://pubs.acs.org Publication Date: June 1, 1977 | doi: 10.1021/bk-1977-0041.ch005

H. JALONEN and C. PELTONEN Abo Academy, 20500 Turko 50, Finland A l l of the three primary and five secondary hydroxy l groups of sucrose usually react with the same reagents causing p a r t i a l derivatization and producing a mixture of degrees of substitution and isomer locations. Due to the multistages of reactions required, the protection of some hydroxyls followed by specific substitutions and reconversions not only causes low yields but usually produces insufficient s e l e c t i v i t y . We have found that, i f instead, a reaction site i n a polyol molecule i s converted to a chelate group, usually involving binding two of the hydroxyl groups into a f i v e - or sixmembered ring compound, a high y i e l d s e l ective reaction i s obtained (1-4). Such a reaction i s , e.g. the selective monoacetylation of methyl 4,6-benzylidene-a-D-glucopyranoside mercuric chelate with acet i c anhydride giving a 94 mole-% y i e l d of 2-O-acetyl ester, 2% of 3-O-acetyl and 4% of the di-O-acetyl ester (5) . S i m i l a r l y , the methylation of the cupric chelate of the same compound with methyl iodide gives solely monoethers or 19 mole-% of 2-O-methyl ether and 73% of 3-0-methyl ether (2). The preparations of the s e l ectively reacting chelates are seen i n Figure 1. The substitution reaction can be i l l u s t r a t e d by Figure 2. The reason why a bidentate ligand gives solely monosubstitution instead of a diderivative can be explained by blockage of the underivatized oxygen by salt formation as shown i n Figure 3. In the present study, selective substitution v i a chelates w i l l be applied to etherification and e s t e r i fication of sucrose. To be a homogenous substrate for a selective reaction, sucrose should give stoichiomet r i c a l l y definable chelates that are s u f f i c i e n t l y soluble i n a dry aprotic solvent, such as N,N-dimethyIformamide or dimethylsulphoxide. One might question whether the unchelated hydroxyl groups of sucrose also would be derivatized. 62 In Sucrochemistry; Hickson, J.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.

5.

Substitution of Hydroxyl Groups via Chelates

AVELA ET AL.

x:

ONa

i : 2:c 1:2:0

il 1:1:0


: 0:0.5

III

|o:0

J

ix>o i

v 2:2:1 0:0:l|

x:

"0 cr ^0 ^ 2:4:1 VI 2:4

x

vu 1:1:1

0

1:2:1

x: Figure 1. Preparation and interchangeabilité of mono- and disodium alcoholates 1:1:0 and 1:2:0 resp., and copper (II) derivatives 1:2:1, 2:2:1, 2:4:1,1:1:1, and 1:2:2 of a dihydroxyl compound. Compounds characterized by mole ratio of diol:NaH:CuCl in synthesis; notations of + and — charges omitted. g

di-derivotive

mono-derivative

Figure 2

In Sucrochemistry; Hickson, J.; ACS Symposium Series; American Chemical Society: Washington, DC, 1977.

63

SUCROCHEMISTRY

64

—X

-OCu -OR

—

X

-OH -OR

Figure 3


Experimental E t h e r i f i c a t i o n o f S u c r o s e C h e l a t e s by A l l y l H a l i d e s , and S o d i u m B r o m o a c e t a t e . A l l y l bromide or c h l o r i d e was a d d e d t o a d i m e t h y l s u l p h o x i d e (DMSO) s o l u t i o n of sucrose c h e l a t e i n the r a t i o s of sucrose: a l l y l h a l i d e 1 : 1 , 1 , 1 : 1 , 3 , 1:2,0 a n d 1:2,5 a n d k e p t a t 80°C f o r 16 t o 48 h . The a l l y l b r o m i d e r e a c t i o n s w e r e c a r r i e d o u t i n s c r e w c a p , s e a l e d t e s t t u b e s and most o f the a l l y l c h l o r i d e r e a c t i o n s i n a sealed a u t o c l a v e . D e c o m p o s i t i o n o f t h e s u c r o s e was p r e v e n t e d b y k e e p i n g the r a t i o of sucrose t o a l l y l h a l i d e equal or l e s s t h a n t h e r a t i o 1:2,5. The r e a c t i o n b e t w e e n s u c r o s e c h e l a t e s a n d s o d i u m b r o m o a c e t a t e was p e r f o r m e d i n t h e f o l l o w i n g r a t i o s ; s u c r o s e : b r o m o a c e t a t e , 1:2,6, 1:3,8, 1:5,2 a n d 1 : 7 , 0 , i n DMSO f o r 72 h a t 70°C.

E s t e r i f i c a t i o n o f S u c r o s e C h e l a t e s by A c i d Anhydrides and C h l o r i d e s . A c e t i c , c a p r y l i c , s t e a r i c , m a l e i c o r p h t h a l i c a c i d a n h y d r i d e s were added t o a N , N - d i m e t h y l f o r m a m i d e (DMF) s o l u t i o n o f a s u c r o s e c h e l a t e i n r a t i o s o f s u c r o s e : a n h y d r i d e 1:1,3 o r 1:3. The r e a c t i o n m i x t u r e was a l l o w e d t o s t a n d w i t h a c e t i c a n h y d r i d e f o r 15 h a t 22°C, w i t h c a p r y l i c a n d s t e a r i c a n h y d r i d e f o r 3 h a t 60°C, o r w i t h m a l e i c a n d p h t h a l i c a n h y d r i d e f o r 10 h a t 60°C. The i s o l a t i o n , e . g . o f m o n o s t e a r a t e s , was made b y e x t r a c t i o n w i t h 1 - b u t a n o l (6) a f t e r a d d i t i o n o f 1 0 % a q s o d i u m c h l o r i d e t o t h e DMF. E s t e r i f i c a t i o n s w i t h a c r y l o y l , c a p r o y l and l a u r o y l c h l o r i d e s was c a r r i e d o u t o v e r 3 h a t 60°C. The h y d r o l y s i s i s a v o i d e d when no m o r e t h a n 3 m o l e s o f a c i d c h l o r i d e i s used p e r mole o f s u c r o s e .

T r a n s e s t e r i f i c a t i o n . S i x t o 30 m o l e s o f m e t h y l or e t h y l a c e t a t e , m e t h y l c a p r i n a t e , l a u r a t e , o l e a t e , stéarate o r m e t h a c r y l a t e was a d d e d t o a DMF solution o f one m o l e o f s u c r o s e c h e l a t e . The r e a c t i o n m i x t u r e s w e r e a l l o w e d t o s t a n d 3 h a t 100° o r 120°C a n d a n a l y z ed.


5.

AVELA ET AL.


65

Analytical Sucrose e t h e r s and e s t e r s were a n a l y z e d a s t r i m e t h y l s i l y l d e r i v a t i v e s p r e p a r e d b y a d d i n g t o 0,5 m l o f r e a c t i o n s o l u t i o n , 0,1 m l h e x a m e t h y l d i s i l a z a n e a n d 0,05 ml d i m e t h y l c h l o r o s i l a n e . The c a r b o x y m e t h y l e t h e r s were g a s - c h r o m a t o g r a p h i c a l l y s e p a r a t e d o n a 12 f t 3% OV-17 g l a s s c o l u m n a t f i r s t w i t h t h e t e m p e r a t u r e p r o grammed a t 180°-280°C, 4°/min, a n d t h e n i s o t h e r m a l l y . The a l l y l e t h e r s w e r e s e p a r a t e d o n a 28 m, 0,33 mm i d OV-17 g l a s s c a p i l l a r y c o l u m n i s o t h e r m a l l y a t 245°C. The a c e t a t e s w e r e g a s - c h r o m a t o g r a p h i c a l l y separated on a 12 f t 3% OV-17 g l a s s c o l u m n , w i t h t h e t e m p e r a t u r e p r o g r a m m e d a t 2 4 0 -260° C, l / m i n , o r a t 245°C i s o t h e r mally. The r e s p o n s e v a l u e s f o r t h e p a r t i a l l y a c e t y l a t e d s u c r o s e d e r i v a t i v e s were d e t e r m i n e d by i n t e r p o l a t i o n based on v a l u e s o f s u c r o s e and s u c r o s e o c t a a c e tate. T h e c a p r y l a t e s , stéarates, m a l e a t e s a n d p h t h a l a t e s w e r e s e p a r a t e d o n a 1 f t 1% OV-1 g l a s s c o l u m n t e m p e r a t u r e p r o g r a m m e d a t 150°-340°C, 10°/min. The a c r y l a t e s a n d l a u r a t e s w e r e s e p a r a t e d o n a 1 f t 1% S E 30 g l a s s c o l u m n w i t h t h e t e m p e r a t u r e p r o g r a m m e d a t 150°-330°C, 10°/min. The m e t h a c r y l a t e s were s e p a r a t e d on a 4 f t 3% OV-17, w i t h t h e t e m p e r a t u r e p r o g r a m m e d a t 180°-280°C, 4°/min. The d e g r e e o f s u b s t i t u t i o n o f t h e e t h e r s a n d e s t e r s was d e t e r m i n e d b y LKB g a s c h r o m a t o g r a p h - m a s s s p e c t r o m e t e r (GC-MS). The p r o g r e s s o f t h e e s t e r i f i c a t i o n r e a c t i o n s w a s f o l l o w e d b y t h i n l a y e r c h r o m a t o g r a p h y (TLC) i n a d d i t i o n to gas chromatography. Merck s i l i c a g e l p l a t e s were developed with a mixture o f toluene - e t h y l acetate 95 % e t h a n o l ( 2 : 1 : 1 v / v / v ) (1)• The s p o t s were v i s u a l i z e d by spraying t h ep l a t e s with a s o l u t i o n o f 1 g u r e a , i n 4,5 m l 8 0 % p h o s p h o r i c a c i d a n d 48 m l 1 - b u t a n o l , d y e d p l a t e s h e a t e d i n a n o v e n a t 110°C f o r 30 m i n , a n d analyzed with a V i t a t r o n densitometer.


6

ô

Results A l l o f t h e sucrose metal complexes i n v e s t i g a t e d gave c o l o r e d s o l u t i o n s e x c e p t mercury c h e l a t e s , w h i c h were c o l o r l e s s . Results o f thea l l y l a t i o n reactions a r e shown i n T a b l e s I a n d I I . T h e c h e l a t e r e a c t i o n s are s u p e r i o r i n s e l e c t i v i t y t o t h e c o r r e s p o n d i n g a l c o holate reactions. F o r i n s t a n c e , i nTable H t h e chel a t e 2 : 4 : 1 : 4 , 0 g a v e 6 9 % mono- a n d 2% d i e t h e r s w h i l e t h e a l c o h o l a t e g a v e 5 0 % mono- a n d 3 5 % d i e t h e r s . Furtherm o r e , t h e c h e l a t e 2:4:1 w a s m o r e r e a c t i v e t h a n t h e c h e l a t e 1:2:1 a n d t h e s e l e c t i v i t y d e c r e a s e d f o r t h e c h e l a t e s when t h e r a t i o , s u c r o s e : r e a g e n t w a s i n c r e a s e d .


66

SUCROCHEMISTRY

Table I . Composition o f t h e e t h e r i f i c a t i o n products o f sucrose c h e l a t e s and a l c o h o l a t e s w i t h a l l y l bromide i n DMSO, 80°C, 48 h , m o l e - % . Reactions performed i n screw cap sealed t e s t tubes. Mole

ratio

NaH:metal allyl

of

sucrose:

chloride:

metal

Sucrose Unreacted

bromide

2:4:1:2,6

Mono-O-

D i - O -

Hydrolysis

ethers

ethers

products

C o

75

25

"

:4,0

"

59

41

"

:6,0

"

2

"

89

11

"

74

26

1:2:1:1,3


Chelating

"

:2,0

1:2:0:1,3 "

:2,0

98

-

N a

64

29

7

"

42

43

15

Table I I . Composition o f t h ee t h e r i f i c a t i o n products o f sucrose c h e l a t e s and a l c o h o l a t e s w i t h a l l y l c h l o r i d e a n d a l l y l b r o m i d e i n DMSO, 80°C, 16 h , m o l e - % . Reactions performed i n a sealed autoclave. Mole

ratio

NaH:metal allyl

of

sucrose:

chloride:

Chelating metal

Sucrose Unreacted

reagent

Mono-O-

D i - O -

Hydrolysis

ethers

ethers

products

-

Allylchloride 2:4:1:2,2

C o

45

55

"

:4,0

"

29

69

"

:5,0

"

7

1:2:1:2,0

"

63

37

-

1:2:0:2,0

N a

15

50

35

C o

63

37

-

"

56

43

Allyl

93

bromide

2:4:1:2,2 "

2

:4,0

1


5.

AVELA ET AL.


67

The r e s u l t s o f t h e c a r b o x y m e t h y l a t i o n r e a c t i o n c a n be s e e n i n T a b l e I I I . H e r e a g a i n t h e c h e l a t e s w e r e m o r e s e l e c t i v e than t h e a l c o h o l a t e s , although the d i f f e r e n ces were n o t as s i g n i f i c a n t as i n t h e former examples. The c h e l a t e 2:4:1:7,6 g a v e 4 1 % mono- a n d 4% d i e t h e r s and t h e a l c o h o l a t e 2 2 % mono- a n d 6% d i e t h e r s . Again, t h e s e l e c t i v i t y o f t h e c h e l a t e r e a c t i o n d e c r e a s e d when g r e a t e r r a t i o s o f s u c r o s e : r e a g e n t were used. Table I I I . C o m p o s i t i o n o f t h e e t h e r i f i c a t i o n products o f s u c r o s e c h e l a t e s a n d a l c o h o l a t e s w i t h sodium bromo a c e t a t e i n DMSO, 70°C, 7 2 h , m o l e - % .


Mole

ratio

Nahhmetal sodium

of

sucrose:

chloride:

Chelating metal

Sucrose Unreacted

Mono-O-

Di-O-

_

Co

71

29

"

:7,6

H

55

41

4

"

:10,4

H

37

50

13

"

:14,0

H

24

55

21

_

2:4:1:5,2

H

67

33

"

:3,8

H

45

48

"

:5,2

H

23

51

1:4:2:3,8

H

50

44

1:2:0:2,6

1:2:1:2,6

Hydrolysis

eth

ethers

bromoacetate

7 26 6

_

Na

85

15

"

:3,8

H

72

22

6

"

:5,2

M

58

32

10

The a l l y l a t i o n a n d c a r b o x y m e t h y l a t i o n r e a c t i o n v e l o c i t i e s d i f f e r from each o t h e r . For a l l y l a t i o n , the c h e l a t e s r e a c t e d slower than t h e a l c o h o l a t e s ,b u t the carboxymethylation proceeded f a s t e r w i t h c h e l a t e s than w i t h a l c o h o l a t e s . However, t h e s e l e c t i v i t y o f the c h e l a t e s , i n t h i s case, i s s t i l l b e t t e r than the selectivity of the alcoholates. The c o m p o s i t i o n s o f t h e p r o d u c t m i x t u r e s f r o m t h e treatment of sucrose w i t h a c e t i c anhydride are given i n T a b l e s I V a n d V. I t i s s e e n t h a t , w i t h 1,3 m o l e s o f a c e t i c a n h y d r i d e , t h e c o b a l t c h e l a t e formed from s u c r o s e , sodium h y d r i d e and c o b a l t o u s c h l o r i d e , i n t h e m o l e r a t i o 2 : 4 : 1 , g i v e s 98 m o l e - % o f m o n o a c e t a t e s . E v e n t h e c o b a l t c h e l a t e 1:2:1 a n d c o p p e r c h e l a t e s 1:2:1 a n d 2:4:1 g a v e o v e r 90 m o l e - % o f m o n o a c e t a t e s . The c o r r e s p o n d i n g s u c r o s e a l c o h o l a t e , 1:2:0, g a v e no s e l e c t i v i t y a n d a t b e s t , 59 m o l e - % m o n o a c e t a t e s . Mass s p e c t r o m e t r y d i s c l o s e d t h a t t h e p e a k s 1-8 i n t h e g a s c h r o m a t o g r a m r e p r e s e n t a l l t h e p o s s i b l e s u c r o s e mono-


68

SUCROCHEMISTRY

T a b l e IV« Composition o f the acetylation products of sucrose c h e l a t e s and a l c o h o l a t e s w i t h a c e t i c anhydride i n DMF, 1 5 h , 22°C, m o l e - % . Mole

ratio

NaH:metal A c

2

sucrose:

chloride:

Chelating metal

Sucrose Unreacted

0

1:2:1

1,3

M

Co

H

1,3

H

3

H

1,3 ii

H

Fe II

H

1/3 3

1:4:2

1,3

(II)

Mono-O-

Di-

acetyl

ace

10

90

8

92

32

66

5

46

(II)

4

93

3

(II)

24

71

5

(II)

Na II

Co

(II)

10

89

52

48

12

59

29

71

_

34

65

II

3

H

1/3

Fe

(II)

28

72

M

H

Cu

(II)

4

89

H

H

Hg

(II)

43

55

"

Mn

H

1,3 3

1:6:3

1,3 II

H

II H

II

H

II

1:6:0 3

2

49

Hg

H

1:4:0

_

-

Cu Mn

1:2:0

(II)

It

3

M


of

1

(II)

N a

"

20

-

37

63 42

43

48

_

(II)

34

66

Fe

(II)

29

71

Cu

(II)

12

84

Hg

(II)

62

38

Mn

(II)

59

41

65

31

7 2

58

Co

Na

1

-

-

4

4

T a b l e V. Composition o f the a c e t y l a t i o n products o f s u c r o s e c h e l a t e s w i t h a c e t i c a n h y d r i d e i n DMF, 15 h , 22°C, m o l e - % . Chelate:

Chelating metal

AC2O

:2,6

Co

:6

II

:2,6

Fe

Sucrose Unreacted

2

(II)

(II)

:6

Mono-O-

Di-O-

acetyl

acetyl

98 28

-

72

21

76

3

4

55

41

= 1,3

Cu

(II)

5

92

3

:1,3

Hg

(II)

17

71

12

:1,3

Mn

26

71

3

(II)


5.

AVELA ET AL.

69


T a b l e V I . C o n t e n t o f t h e d i f f e r e n t s u c r o s e mono-O-acet a t e s i n a c e t y l a t i o n products o f sucrose c h e l a t e s and a l c o h o l a t e s , y i e l d o f r e a c t i o n mole-%. Mole

ratio

of

sucrose: N a H : metal


A c

2

Chelating

Total

Peak

metal

mono-O-

acetates

chloride:

acetate

0

2:4:1:2,6

1

number 2

in 3

of

different

gas 4

Co(ll)

54

66

-

58

-

76

4

27

11

8

66

5

15

8

18

92

1:2:1:3,0

M

90

1:4:2:1,3

"

71

1:6:3:1,3

H

2:4:1:2,6

Fe(ll) II

6

8

7

4

68

98

H

1:2:1:1,3

5 mole-%

yield

1:2:1:1,3

mono-O-

chromatograms

54 60

-

5 5 1 1

-

26

-

33 31 10 7

14

5

7

10

5

5

2:4:1:2,6

Cu(ll)

92

24

1

38

13

5

4

2

5

1:2:1:1,3

"

92

26

1

35

15

5

2

2

6

ii

39

16

1

38

14

7

2

3

8

ii

84

11

3

35

18

7

1

3

6

70

12

6

22

8

9

8

2

3

71

9

18

15

10

12

—

5

2

17

11

12

2

2

3

8

10

13

2

5

6

1:4:2:1,3 1:6:3:1,3 2:4:1:2,6

Hg(ll) II

1:2:1:1,3

2:4:1:2,6

Mn(ll) H

1:2:1:1,3

71

8

16

89

5

40

1:3:1:1,3

Fe(lll)

65

6

5

12

18

12

3

3

6

2:3:1:2,6

Cr(lll)

63

12

7

22

7

9

3

1

2

1:2:0:3,0

Na

5

11

11

6

2

4

4

17

22

2

1

13

14

1

-

-

57

14

1:4:0:3,0

H

48

5

1:6:0:3,0

H

31

2

-


-

1


70

SUCROCHEMISTRY

acetate isomers. The c o b a l t o u s c h e l a t e s gave o n l y three d i f f e r e n t monoacetate isomers, t h e f e r r o u s chel a t e s gave seven, w h i l e a l l t h e o t h e r c h e l a t e s s t u d i e d Cu ( I I ) , Hg ( I I ) , Mn ( I I ) , F e ( I I I ) a n d C r ( I I I ) , g a v e a l l eight isomers. With f a t t y a c i d anhydrides, Table V I I , t h e sucrose c h e l a t e s g a v e much h i g h e r y i e l d s , o f m o n o e s t e r s , t h a n w i t h t h e c o r r e s p o n d i n g f a t t y a c i d c h l o r i d e s , a s shown i n Table I X . The m o n o e s t e r y i e l d a l s o was h i g h e r when, i n s t e a d o f d i s o d i u m a l c o h o l a t e s , t h e c h e l a t e s were t r e a t e d w i t h a n h y d r i d e s . The c o b a l t c h e l a t e 2:4:1 g a v e 82 m o l e - % o f m o n o s t e a r a t e o r 8 9 % o f m o n o c a prylate. E v e n t h e s l o w e r r e a c t i n g c o p p e r 2:4:1 c h e l a t e gave a h i g h e r a n d more s e l e c t i v e y i e l d t h a n d i sodium s u c r a t e . The c o p p e r c h e l a t e 2:4:1 g a v e t h e same t h r e e monostearates b u ta higher y i e l d than the disodium sucrate. C o b a l t c h e l a t e 2:4:1 g a v e o n l y t w o m o n o s t e a r a t e s w h i c h b a s e d o n T L C a n d GC-MS a r e n o t t h e same o n e s w h i c h a r e formed from sodium s u c r a t e . The c o b a l t c h e l a t e 2:4:1 r e a c t e d w i t h m a l e i c o r p h t h a l i c a n h y d r i d e s e l e c t i v e l y g i v i n g r e s p . 72 a n d 85 mole % o f monoesters as seen i n Table V I I I . I n cont r a s t t h e d i s o d i u m a l c o h o l a t e g a v e u p t o 6 5 % o f monoesters. No s e l e c t i v i t y w a s o b t a i n e d w i t h s u c c i n i c anhydride. Reacting the f a t t y acid chlorides with chelates and a l c o h o l a t e s u s u a l l y gave p r i m a r i l y m o n o e s t e r s , b u t the y i e l d o b t a i n e d from r e a c t i n g c h e l a t e s w i t h anhyd r i d e s was l o w e r , a s s e e n i n T a b l e I X . Table VII » Composition o f e s t e r i f i c a t i o n products o f sucrose c h e l a t e s and a l c o h o l a t e s w i t h c a p r y l i c o r s t e a r i c a n h y d r i d e i n DMF, 3 h , 60°C, m o l e - % . Chelate:

Chelating

anhydride

metal

Co

Sucrose Unreacted

8

-

44

28

1:2:0:1

3

Na

H

22

Stearic

14

3

Co

"

1:2:1:1

3

Cu

2:4:1:2

6

1:2:0:1

3

(II)

esters

11

H

6

esters

89

M

1:2:1:1

Di-

73

3 6

Caprylic

Mono-

19

1:2:1:1 2:4:1:2

2:4:1:2

(II)

Anhydride

5

61

25

82

13

63

14

H

23

II

"

25

62

13

Na

H

33

40

27

(II)


Triesters

-

6

_

-

5.

AVELA ET AL.


71

Table V I I I . Composition o f e s t e r i f i c a t i o n products o f sucrose c h e l a t e s and a l c o h o l a t e s w i t h maleic and phthal i c a n h y d r i d e i n DMF, 3 h , 60°C, m o l e - % . Chelate:

Chelating

anhydride

metal


2:4:1:

4

Co

Anhydride

Sucrose Unreacted

(II)

Mono-

Di-half-

half-esters

esters

46

54

2:4:1:16

II

18

72

10

1:2:0:

2

Na

31

60

9

2:4:1:

4

Co

Maleic

(II)

90

10

2:4:1:16

II

15

85

1:2:0:

Na

34

65

8

Phthalic

T a b l e IX. Composition o f e s t e r i f i c a t i o n products o f sucrose c h e l a t e s and a l c o h o l a t e s w i t h a c r y l o y l , lauroyl a n d o l e o y l c h l o r i d e s i n DMF, 3 h , 60°C, m o l e - % . Chelate:

Chelating

Acid

acid

metal

chloride

chloride

1:2:1:1

5

1:2:0:1

5

1:2:1:2

(II)

Na

Unreacted

Mono-

D i -

ester

ester

49

51

42

58

"

44

55

Acryloyl

-

Lauroyl

46

49

5

II

H

26

59

15

5

Na

H

39

57

4

Co

Oleoyl

59

41

_

M

69

31

H

92

8

Co

2:4:1:4 1:2:0:1

Co H

2:4:1:3

Sucrose

1:2:1:1

5

2:4:1:2

6

1:2:0:1

5

Na

(II)

(II)

-



72

SUCROCHEMISTRY

I n c r e a s i n g t h e amounts o f a c y l c h l o r i d e r e l a t i v e t o s u c r o s e t o m o l a r r a t i o s o f o v e r 3:1 d i d n o t i m p r o v e the e s t e r y i e l d b u t r a t h e r i n i t i a t e d t h e h y d r o l y s i s o f sucrose. H y d r o l y s i s was n o t f o u n d t o o c c u r a t l o w e r levels of acyl chloride. A r a t i o o f sucrose t o a l k y l c h l o r i d e o f 1:1.5 was f o u n d t o b e p r e f e r a b l e . A simil a r r e a g e n t t h r e s h o l d a m o u n t was f o u n d i n t h e e t h e r i f i c a t i o n o f sucrose w i t h a l k y l h a l i d e s . The u s e o f 1.3 m o l e s o f e . g . m e t h y l i o d i d e p e r m o l e o f s u c r o s e c h e l a t e seemed p r e f e r a b l e . R a t i o s over 3 moles o f a l k y l h a l i d e c a u s e d s u c r o s e h y d r o l y s i s , a s was o b s e r v e d w i t h e a r l i e r attempts a t sucrose e s t e r i f i c a t i o n (_). The t r a n s e s t e r i f i c a t i o n o f s u c r o s e w i t h t h e r e a d i l y a v a i l a b l e , f a t t y a c i d methyl esters i n the presence o f a l k a l i n e c a t a l y s t s ( 6 , 9 ) i s a common m e t h o d o f p r e p a r i n g sucrose f a t t y a c i d e s t e r s w i t h a low degree o f substitution. When t h e r e a c t i o n was a p p l i e d t o s u crose c h e l a t e s , i t produced predominantly monoesters, with diesters. The c h e l a t e t r a n s e s t e r i f i c a t i o n t h u s i s more s e l e c t i v e and g i v e s h i g h e r y i e l d s t h a n t h e standard t r a n s e s t e r i f i c a t i o n . F o r example, t h e s u c r o s e c o b a l t c h e l a t e 2:4:1 w i t h e t h y l a c e t a t e y i e l d e d 92 m o l e - % o f e s t e r s w i t h t h e c o m p o s i t i o n o f 6 8 % o f m o n o a c e t a t e , 2 4 % o f d i a c e t a t e a n d 8% o f u n r e a c t e d s u crose. The c h e l a t e s r e g u l a r l y g a v e h i g h e r sucrose e s t e r y i e l d s (60-92%) t h a n t h e c o r r e s p o n d i n g disodium stéarates ( 3 2 - 6 3 % ) i n t h e t r a n s e s t e r i f i c a t i o n s s t u d i e d . I n c r e a s i n g t h e r e a c t i o n t e m p e r a t u r e f r o m 80°C t o 120°C, o r t h e amount o f m e t h y l e s t e r , i m p r o v e d t h e s u c r o s e ester yield. Reaction o f sucrose chelates w i t h a c i d anhydrides and c h l o r i d e s g i v e s s e l e c t i v e p r o d u c t i o n o f m o n o e s t e r s a n d o n l y some d i e s t e r s , i n c o n t r a s t t o t h e r e a c t i o n products of sucrose alcoholates with a c i d anhydrides, c h l o r i d e s a n d e s t e r s g i v i n g s u c r o s e mono- a s w e l l a s diesters. T h i s r e s u l t i s i n good a c c o r d a n c e w i t h o u r e a r l i e r observations of s e l e c t i v e s u b s t i t u t i o n of polyols v i achelates (1-5). I n t h i s case as w e l l , t h e r e a s o n why o n l y o n e o f t h e t w o o x y g e n a t o m s o f a c h e l a t e group i s d e r i v a t i z e d i s o b v i o u s l y t h a t f u r t h e r s u b s t i t u t i o n o f another oxygen i s b l o c k e d by s a l t formation. Adding water w i l l convert t h i s oxygen back t o a h y d r o x y l group, w h i l e t h e other oxygen i s d e r i v a t i z e d t o e s t e r , a s shown i n F i g u r e 4. In case o f t r a n s e s t e r i f i c a t i o n , the b l o c k i n g react i o n i s n o t e f f e c t i v e because a cobaltous d i a l c o h o l a t e , -O-Co-O-CH^is f o r m e d w h i c h r e a c t s f u r t h e r c a u s i n g p a r t i a l e s t e r i f i c a t i o n o f t h e o t h e r o x y g e n w h i c h was involved o r i g i n a l l y i n the chelate formation. The p r i n c i p a l mono- a n d p a r t i a l d i e s t e r f o r m a t i o n f r o m


5.


AVELA ET AL.

73


Table X. C o m p o s i t i o n o f t r a n s e s t e r i f i c a t i o n p r o d u c t s of sucrose c h e l a t e s and a l c o h o l a t e s w i t h e t h y l a c e t a t e , m e t h y l c a p r i n a t e , l a u r a t e , stéarate, o l e a t e , a n d e t h y l m e t h a c r y l a t e i n DMF, 3 h , 80°-120°C, m o l e - % . Chelate:

Chelating

ester

metal

2:4:1:20

Co

1:2:0:20

Na

2:4:1:20

Co

1:2:0:10

Na

2:4:1:20

Co

1:2:0:15

Na

2:4:1:20

Co

1:2:0:10

Na

2:4:1:20

Co

1:2:0:10

Na

2:4:1:12

Co

1:2:0:

Na

6

>

R-C

—o

-Of

Unreacted

(II)

Acetate

(II)

(II)

(II)

(II)

D i -

ester

ester

29

45

68

24

8

Caprinate

30

58

12

H

61

34

5

H

(II)

Mono-

26

35

56

9

55

38

7

Stéarate

34

55

11

H

37

50

13

Oleate

40

52

8

H

58

32

10

Methacrylate

45

45

10

H

38

37

25

Laurate

—o-c

.Co

Co

Ester

+

"CI

^O ^

—O-Co-CI

-

R

- O - C o - O - C f

— OH

^

^

R

- O H

Figure 4


74

SUCROCHEMISTRY

sucrose v i a t r a n s e s t e r i f i c a t i o n , shown i n F i g u r e 5.

°\

X

OCH

Co

v

X

R

c a n be w r i t t e n a s

OCH

-R

3

S

•

+

—O

—0-Co-OCH

— 0-Co-OCH

3

R y

— °

3

_

C

\

O R

-o-c*°


—OH

Figure 5

Summary S u c r o s e c h e l a t e s i n DMSO r e a c t s e l e c t i v e l y w i t h a l l y l h a l i d e a n d s o d i u m b r o m o a c e t a t e t o p r o d u c e monoethers i n high yields. S u c r o s e c h e l a t e s i n DMF s o l u t i o n react s e l e c t i v e l y with a c i d c h l o r i d e s , anhydrides a n d e s t e r s t o p r o d u c e s u c r o s e m o n o e s t e r s o r , i n some cases, d i e s t e r s as w e l l . The y i e l d s a n d s e l e c t i v i t i e s of the p a r t i a l e s t e r i f i c a t i o n o f sucrose v i a chelates i s h i g h e r t h a n w i t h o t h e r methods. The y i e l d r a n g e o f t h e a c i d d e r i v a t i v e s s t u d i e d a r e shown i n T a b l e X I . Table X I . Composition o f E s t e r i f i c a t i o n Products sucrose cheTates w i t h a c i d d e r i v a t i v e s , mole-%. Acid

derivative

reacting sucrose

Acid

Yield

with chelate

chlorides

Acetic Higher

acid

anhydride

fatty

acid

anhydrides

Dicarboxylic

acid

anhydrides

Acetic

esters

acid

Methacrylic Higher

fatty

acid acid

ester esters

of sucrose

ester,

mole-':

Total

Mono-

Di-

esters

esters

esters

41-74

41-59

90-98

90-98

95-100

82-89

82-85

72-85

0-10

71-80

43-50

26-30

55 60-70

0-15 0 11-13

45

10

52-58

8-12


of

5.

AVELA ET AL.


75

Acknowledgements The f i n a n c i a l a i d f r o m T h e I n t e r n a t i o n a l S u g a r R e s e a r c h F o u n d a t i o n , I n c . , B e t h e s d a , M a r y l a n d , U.S.A. a n d f r o m The N a t i o n a l R e s e a r c h C o u n c i l o f T e c h n i c a l S c i e n c e s o f The Academy o f F i n l a n d i s g r a t e f u l l y a c k n o w l e d g ed.


Abstract The partial derivatization of sucrose hydroxyls generally gives isomer mixtures with various degrees of substitution. We have reported earlier a method to selectively monoetherify or monoesterify polyols and glucosides via metal chelates instead of using multistage organic protection and reconversion reactions. Sucrose chelates also give directly a selective and, to a certain DS level, limited reaction. The chelates are prepared in anhydrous DMF or DMSO by ionization of the desired number of hydroxyl groups of the sucrose molecule with stoichiometric amounts of sodium hydride to form alcoholates which, with metal salts, give the chelates. The etherification of sucrose with alkyl halides or esterification with organic acids causes hydrolysis. The hydrolysis or diether formation is avoided if sucrose chelate is etherified at moderate temperatures and with only a small excess of a l l y l halide or sodium bromoacetate, giving 55-69% mono- and 0-2% diallyl ethers respectively, 41-48% mono- and 4-7% dicarboxymethyl ethers of sucrose. The partial esterification of sucrose with organic acid chlorides, anhydrides or esters gives mixtures of esters and a low yield. Acid chlorides with chelates in anh. DMF give monoester 41-59 mole-%, diester 0-15% and no higher esters. Acid anhydrides give mainly monoesters, low molecular weight anhydrides 80-98%,and higher fatty acid anhydrides 82-89%.Transesterification of chelates with acetic acid ethyl ester gives monoesters 45% and diesters 26%, and higher molecular fatty acid esters give monoester 52-58% and diester 8-12%. Literature Cited 1. Avela, E . , Finn. Appl. 2578/1971, Brit. Pat. 1 410 033/1975, Austrian 321319/1975, Can. 981663/1976, U.S. 3,972,868/1976. 2. Avela, E . , and Holmbom, B . , Acta Acad. Aboensis, (1971), 31, 14, 1. 3. Avela, E . , Melander, B . , and Holmbom, B . , Ibid



76

SUCROCHEMISTRY

(1971), 31, 15, 1. 4. Avela, E., La Sucrerie Belge, (1973), 92, 337. 5. Avela, E., and Melander, B., Paper presented at VI Int. Symp. on Carbohydr. Chem., 1972, Madison, Wise, U.S.A. 6. Hickson, J.L., Sucrose Ester Surfactants, Int. Sugar Res. Found., Inc., New York 1960, pp. 1-10. 7. Weiss, T. J., Brown, M., Zeringue, Jr., H.J., and Feuge, R.O., J. Am. Oil Chem. Soc. (1971), 48,145. 8. Black, W.A.P., Dewar, E.T., Paterson, J.C., and Rutherford, D., J. Appl. Chem. (1959), 9, 256. 9. Osipow,L., Snell, F.D., York, W.C., and Finchler,A., Ind. Eng. Chem. (1956), 48, 1459. 10. Avela, E., Abstracts of papers, 138th ACS Nat. Meeting, New York, (1960), 18D, No. 51.

Biographic Notes Professor Eero Avela, Ph.D., Prof, of Chem. Educated at Helsinki Univ., Oxford Univ., State Univ. of New York, and Hamburg Univ. Director of Research at Oy Kaukas Ab (Finland), Norland Papier GmbH & Co. (West Germany), Dir. of Res., Academy of Finland, Prof, of Technical Polymers and Plastics Chemistry, Abo Academy, Finland. Some 86 papers and 4 patents on cellulose, polymers and carbohydrates. Academy of Finland, Pyorokiventie 10, 00830 Helsinki, 83 Finland.



Discussion

Question; Has t h e r e b e e n a n y s t u d y o f t o x i c i t y of o r LD50 w o r k d o n e w i t h , t h e t e t r a c h l o r o " g a l a c t o " sucrose d e r i v a t i v e ? f

P r o f e s s o r Hough: S t u d i e s h a v e been i n i t i a t e d by T a t e and L y l e b u t , as f a r as I know, t h e r e s u l t s a r e not yet a v a i l a b l e . One m u s t n o t e , o f c o u r s e , t h a t we came a c r o s s t h e sweetness a c c i d e n t a l l y . I t obviously i s a hazardous p r o c e s s t o t a s t e compounds h a p h a z a r d l y . Yet, because o f t h i s a c c i d e n t a l d i s c o v e r y , w h a t we h a v e t o do now i n o u r p r o g r a m o f w o r k , w h i c h we h a v e n o t d o n e p r e v i o u s l y b e c a u s e we n e v e r s u s p e c t e d t h a t t h e s e c o m p o u n d s w o u l d be s w e e t e r t h a n s u c r o s e , i s t o s u b m i t a l l o f o u r c o m p o u n d s t o t o x i c i t y s c r e e n i n g b e f o r e we t a s t e t h e m . O t h e r w i s e , I m i g h t l o s e many r e s e a r c h s t u d e n t s i n t h e p r o c e s s , and t h e y a r e t o o v a l u a b l e t o l o s e I I m i g h t j u s t comment on how u n p r e d i c t a b l e t h e s w e e t n e s s was, b e c a u s e i t has b e e n b e l i e v e d t h a t a l l the monoacetates are l e s s sweet than s u c r o s e . Suc r o s e o c t a a c e t a t e , as I m e n t i o n e d , i s v e r y , v e r y b i t ter. The g e n e r a l p r e d i c t i o n , t h e r e f o r e , was t h a t y o u c a n n o t make s u c r o s e s w e e t e r t h a n i t i s . Question: A l t h o u g h one may n o t f i n d t o x i c i t y i n s u c h a t e s t , i t m i g h t be t h a t t h e c o m p o u n d may be a c o m p e t i t i v e i n h i b i t o r , which c o u l d r e s u l t , f o r example, i n hypoglycemic a c t i v i t y . There i s a f u r t h e r c o m p l i c a t i o n ; i t c o u l d be h y d r o l i z e d , a n d p r o b a b l y w o u l d be h y d r o l i z e d t o c h l o r o g a l a c t o s e and c h l o r o f r u c t o s e . I f s o , someone h a s t o s t u d y a g r e a t d e a l o f t h e b i o c h e m i s t r y o f c h l o r o g l u c o s e and c h l o r o f r u c t o s e . As f a r a s I k n o w , no s t u d i e s h a v e b e e n c a r r i e d o u t i n t h i s r e g a r d .

77


78

SUCROCHEMISTRY

P r o f e s s o r Hough; Dr. Norman T a y l o r , o f c o u r s e , i s quite correct. As a n e x p e r t on f l u o r o c a r b o h y d r a t e s , he i s w e l l aware o f the p r o b l e m s i n t h i s f i e l d . He has made i t a l i f e t i m e s t u d y . I s h a l l h o p e t h a t he w i l l t a k e up c h l o r o c a r b o h y d r a t e s now, and a s s i s t u s i n o u r work i n e x p l o i t i n g t h e c h l o r o d e r i v a t i v e s o f s u c r o s e by studying t h e i r biochemistry. Professor Taylor: May I a d d i n h i b i t o r of glucose transport.

that

saccharin

is

an


Question: Are the dianhydrosucrose d e r i v a t i v e s appreciably soluble i n organic solvents? P r o f e s s o r Hough: Y e s , t h e y a r e . They a r e more s o l u b l e than sucrose i t s e l f , which, f o r example, i s d i f f i c u l t to dissolve i n pyridine. The d i a n h y d r o s u c r o s e d i s s o l v e s v e r y much m o r e r e a d i l y . Question: atization?

W o u l d t h i s be

a route

to further deriv-

P r o f e s s o r Hough: C e r t a i n l y , yes. I t i s a very i m p o r t a n t r o u t e t o f u r t h e r d e r i v a t i z a t i o n i n my v i e w b e c a u s e o n l y f o u r h y d r o x y l s a r e now e x p o s e d , w h i c h i s s o m e t h i n g t h a t we c a n e x p l o i t , a n d t h e d i a n h y d r i d e i s readily available. Question: Is i t possible to prepare galacto-sucrose?

1 4

C-labelled-

P r o f e s s o r Hough: D r . R i a z K h a n c o u l d make e x p e r t comments s i n c e he h a s d e s c r i b e d a g o o d s y n t h e s i s o f galacto-sucrose i n Carbohydrate Research. Taking randomly--L4c l a b e l l e d s u c r o s e , p r e s u m a b l y p r e p a r e d p h o t o s y n t h e t i c a l l y , i t c o u l d be c o n v e r t e d r e a d i l y i n t o galacto-sucrose. The i m p o r t a n t o b j e c t i v e i s a g o o d radiochemical y i e l d . Dr. Khan: The s y n t h e s i s o f g a l a c t o - s u c r o s e s u c r o s e p r o c e e d s i n q u i t e a good y i e l d .

from

Question: Why a r e t h e b u l k y s u l p h o n y l c h l o r i d e s more s e l e c t i v e f o r t h e C - l - p o s i t i o n ? 1

P r o f e s s o r H o u g h : We w o u l d h a v e p r e d i c t e d t h a t r e a c t i o n would occur p r e f e r e n t i a l l y at the 6 , o p p o s i tions. T h i s , i n f a c t , does happen i f you reduce the q u a n t i t y of the reagents. The n e x t r e a c t i v e p o s i t i o n c e r t a i n l y i s the I m p o s i t i o n i n s u l p h o n y l a t i o n . This


79


DISCUSSION

r e a c t i o n does depend, I b e l i e v e , upon the r e l a t i v e acc e s s a b i l i t y and a c i d i t y o f t h e h y d r o x y l g r o u p s , i n c o n trast to nucleophilic substitution reactions. When you i n t r o d u c e a f o u r t h s u l p h o n a t e s u b s t i t u e n t , i t goes t o t h e C-2 g r o u p i n g o f s u c r o s e , s i m i l a r t o e t h e r i f i c a tion. I t h i n k t h i s accounts f o r the r e a c t i v i t y of the 1^-position. I f you l o o k c l o s e l y a t the mechanism o f the r e a c t i o n , i t depends l a r g e l y upon the s t e r e o c h e m i s t r y , which i s a l l r i g h t at the primary p o s i t i o n s . In a d d i t i o n , t h e h y d r o x y l g r o u p must r e a c t w i t h b a s e and t h e s u l p h o n y l h a l i d e w i t h the removal of hydrogen, or a proton, from t h a t primary p o s i t i o n . T h i s i s more f a v o r able at the 1 ^ - p o s i t i o n than i t i s , f o r example, at the 4-position. T h i s i s how I w o u l d e x p l a i n t h e r e a c t ivity. Question: In bimolecular n u c l e o p h i l i c s u b s t i t u t i o n r e a c t i o n s , the 1 ^ - p o s i t i o n i s very hindered. W o u l d y o u comment? P r o f e s s o r Hough: N u c l e o p h i l i c s u b s t i t u t i o n i s q u i t e d i f f e r e n t i n mechanism from a s e l e c t i v e a c y l a t i o n r e a c t i o n because, i n the l a t t e r , o n l y the hydrogen of a h y d r o x y g r o u p i s b e i n g r e p l a c e d by a b u l k y g r o u p . No a t t e m p t i s b e i n g made t o r e p l a c e o x y g e n p l u s t h e b u l k y group by a r e a r w a r d a t t a c k . Therefore, e s t e r i f i c a t i o n a t t h e l - p o s i t i o n w i l l p r o c e e d as a t a n o r m a l primary hydroxyl. 1

Question: Dr. Khan, would you r e p e a t the c o n d i t i o n s you used f o r your h y p o o x i d a t i o n s ? You had h i g h y i e l d s , a n d y o u do n o t l o s e a n y o f t h e a c e t a t e g r o u p s . Dr. Khan: A c t u a l l y , t h e p r o d u c t i s c o m p l e t e l y d e e s t e r i f i e d b u t , i n o r d e r t o i s o l a t e i t , we r e e s t e r i f y i t , a n d t h e n we g e t t h e a c e t y l d e r i v a t i v e s . Question: P r o f e s s o r H a l l , have you e s t a b l i s h e d which protons i n the f r u c t o s e r e s i d u e are r e s p o n s i b l e f o r t h e r e l a x a t i o n o f ^H? Professor Hall: I am a f r a i d n o t . To do t h i s , we n e e d e i t h e r a 1,000 m e g a c y c l e n.m.r. m a c h i n e , w h i c h i s n o t a v a i l a b l e , o r t o make t h e c o r r e s p o n d i n g d e u t e r a t e d derivatives. We w o u l d be v e r y i n t e r e s t e d t o know i f a n y b o d y h a s a n y g o o d i d e a s o n how t o g e t t h e c a r b o x y l i c a c i d s , b e c a u s e t h e n we c o u l d g e t t h e d e u t e r i u m i n . T h a t i s t h e r e a s o n why we w o u l d l i k e t o g e t d e u t e r a t e d sucrose d e r i v a t i v e s .


5 Selective Substitution of Sucrose Hydroxyl Groups via Chelates E

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