Chiral Organofunctional Polysiloxanes: Synthesis, Properties, and

22 Chiral Organofunctional Polysiloxanes: Synthesis, Properties, and Applications

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on April 4, 2016 | http://pubs.acs.org Publication Date: June 10, 1980 | doi: 10.1021/bk-1980-0121.ch022

ERNST BAYER and HARTMUT FRANK Institute for Organic Chemistry, University of Tubingen Auf der Morgenstelle 18, D-74 Tübingen, Fed. Rep. Germany

The binding sites of most enzymes and receptors are highly stereoselective in recognition and reaction with optical isomers (1,2), which applies to natural substrates and synthetic drugs as well. The principle of enantiomer selectivity of enzymes and binding sites in general exists by virtue of the difference of free enthalpy in the interaction of two optical antipodes with the active site of an enzyme. As a consequence the active site by itself must be chiral because only formation of a diasteromeric association complex between substrate and active site can result in such an enthalpy difference. The building blocks of enzymes and receptors, the L-amino acid residues, therefore ultimately represent the basis of nature's enantiomer selectivity. The goal of the current investigation was to achieve further insight into the nature of these interactions and to understand the stereoselectivity of biological systems, partially a result of orientation factors. It has been observed for a number of enzymes that the environment of the active site is relatively 0-8412-0540-X/80/47-121-341$05.00/0 © 1980 American Chemical Society Carraher and Tsuda; Modification of Polymers ACS Symposium Series; American Chemical Society: Washington, DC, 1980.


342

MODIFICATION OF POLYMERS

n o n - p o l a r . T h i s has t h e e f f e c t t h a t any n o n - d i r e c t i o n a l i n t e r a c t i o n s of the enantiomeric substrate with a c h i r a l p o l a r m o i e t i e s a r e e x c l u d e d and a d e f i n i t e r e l a t i v e o r i e n t a t i o n o f r e c e p t o r and s u b s t r a t e r e s u l t s i n r e s p e c t t o t h e i r a s s y m e t r i c c e n t e r s . We a t t e m p t e d t o i m part to s y n t h e t i c polymers such e n a n t i o - s e l e c t i v i t y , w h i c h s h o u l d be p a r t i c u l a r i l y i n t e r e s t i n g f o r t h e d e v e l o p m e n t o f s t e r e o s e l e c t i v e c a t a l y s t s . As t h e polymeric b a s i s f o r s u c h a s y s t e m we c h o s e t h e p o l y s i l o x a n e s due t o t h e i r u n u s u a l l y weak i n t r a m o l e c u l a r f o r c e s . I n a d d i t i o n the s y n t h e s i s of a p p r o p r i a t e l y f u n c t i o n a l i z e d monomers i s r e l a t i v e l y u n c o m p l i c a t e d a n d t h e p r o p o r t i o n s o f p o l a r c h i r a l b i n d i n g s i t e s and a p o l a r environm e n t c a n f r e e l y be c h o s e n by e q u i l i b r a t i o n o f t h e p r o p e r amounts o f t h e c o r r e s p o n d i n g homopolysiloxanes. T h i s i n t u r n d e t e r m i n e s the r e l a t i v e d i s t a n c e between the i n c i v i d u a l c h i r a l groups. P o l y s i l o x a n e s a r e known t o be c h e m i c a l l y and t h e r m a l l y s t a b l e . Due t o t h i s f e a t u r e t h e y c a n be u s e d a s s t a t i o n a r y l i q u i d s i n g a s c h r o m a t o g r a p h y (3,£,_5) . The same i s t r u e f o r t h e c h i r a l p o l y s i l o x a n e s d e s c r i b e d h e r e . T h e i r use as s t a t i o n a r y p h a s e s i n gas c h r o m a t o graphy allows the c a l c u l a t i o n of the d i f f e r e n c e s i n e n t h a l p y and e n t r o p y f o r t h e f o r m a t i o n o f t h e d i a s t e r e o m e r i c a s s o c i a t i o n complexes between c h i r a l r e c e p t o r a n d two e n a n t i o m e r s f r o m r e l a t i v e r e t e n t i o n t i m e o v e r a w i d e t e m p e r a t u r e r a n g e . O n l y t h e m i n u t e amounts o f the p o l y s i l o x a n e s r e q u i r e d f o r c o a t i n g of a g l a s c a p i l l a r y are necessary f o r such determinations. From t h e s e numbers f u r t h e r c o n c l u s i o n s a r e drawn on t h e s t e r e o c h e m i c a l and e n v i r o n m e n t a l p r o p e r t i e s r e q u i r e d f o r d e s i g n i n g systems of h i g h e n a n t i o - s e l e c t i v i t y i n condensed l i q u i d systems. The n o v e l c l a s s o f p o l y m e r i c o r g a n o s i l i c o n e s o f f e r some new a s p e c t s t o p h a s e s e l e c t i v i t y i n g a s l i q u i d chromatography. Conventional s i l i c o n e s used f o r t h i s p u r p o s e are homopolymers o f the p o l y d i m e t h y l s i l o xane t y p e o r c o p o l m y e r s f r o m d i m e t h y l s i l o x a n e and simpl e o r g a n o f u n c t i o n a l s i l o x a n e s u n i t s , e.g. cyanoalkylmethylsiloxane u n i t s . E n a n t i o s e l e c t i v e s i l i c o n e s c a n be p r e p a r e d by f i r s t s y n t h e s i z i n g a p p r o p r i a t e l y f u n c t i o n a l i z e d p o l y s i l o x a n e s , to which a p o l a r c h i r a l moiety c a n be bound c o v a l e n t l y . C h i r a l g r o u p s o f h i g h s e l e c t i v i t y f o r a m i n o a c i d s a n d many o t h e r c h i r a l c o m p o u n d s a r e a m i n o a c i d d e r i v a t i v e s t h e m s e l v e s (§_,J) · Therefore c o u p l i n g o f an amino a c i d r e s i d u e t o a p o l y s i l o x a n e with o r g a n o f u n c t i o n a l carboxyl groups provides an adeq u a t e way o f s y n t h e s i z i n g e n a n t i o - s e l e c t i v e s i l i c o n e s . An i m p o r t a n t p a r a m e t e r f o r a c h i e v i n g o p t i m u m p r o p e r t i e s of the s i l i c o n e s i s the proper adjustment of the r a t i o

Carraher and Tsuda; Modification of Polymers ACS Symposium Series; American Chemical Society: Washington, DC, 1980.


22.

Chiral Organofunctional

BAYER AND FRANK

Polysiloxanes

343

o f c h i r a l p o l a r g r o u p s a n d s i l i c o n e monomer u n i t s . I f t h i s number i s t o o s m a l l , s e l e c t i v i t y r e m a i n s l o w , b u t i f i t i s h i g h e r t h a n 0.2 t h e p h y s i c o c h e m i c a l properties o f t h e s i l i c o n e become u n f a v o r a b l e . The e n a n t i o - s e l e c t i v i t i e s a r e l a r g e l y d e p e n d a n t upon t h e s t r u c t u r e o f t h e o p t i c a l l y a c t i v e moiety* H i g h e s t s e l e c t i v i t i e s f o r amino a c i d s a r e e x h i b i t e d by s i l i c o n e s w i t h amino a c i d amide g r o u p s . The c l a s s e s o f compounds f o r w h i c h h i g h s e l e c t i v i t i e s a r e o b s e r v e d a s w e l l a r e o(-hydroxy c a r b o x y l i c a c i d s , amino a l c o h o l s , a m i n e s a n d g l y c o l s (8^) . O t h e r p o l y s i l o x a n e s containing c h i r a l 1 - a r y l - 1 - a m i n o e t h a n e g r o u p s (9) e x h i b i t h i g h e n a n t i o s e l e c t i v i t i e s f o r c h i r a l amines and amino a l c o hols containing aromatic rings. F o r a number o f a d r e n e r g i c c o m p o u n d s a n i n t e r e s ting p a r a l l e l of e n a n t i o - s e l e c t i v i t y of these s i l i c o n e s and t h e r e l a t i v e a d r e n e r g i c a c t i v i t i e s o f two a n t i p o d e s h a s b e e n o b s e r v e d , s u g g e s t i n g some s i m i l a r i t y o f i n t e r a c t i o n o f t h e s e drugs w i t h t h e i r r e c e p t o r s i t e s and w i t h t h e c h i r a l groups o f t h e s t e r e o s e l e c i t i v e polysiloxanes. With f u r t h e r i n s i g h t i n t o the stereochemistry of t h e d i a s t e r e o m e r i c complexes on s y n t h e t i c polymers, g e n e r a l i z a t i o n s on t h e n a t u r e and s t r u c t u r e o f b i o l o g i c a l a c t i v e s i t e s c a n be drawn. Experimental

Methods

Synthesis of enantioselective polysiloxanes comp r i s e s t h r e e main s t e p s : (a) s y n t h e s i s o f a p p r o p r i a t e l y f u n c t i o n a l i z e d d i c h l o r o s i l a n e monomers, (b) p r e p a r a t i o n o f a f l u i d c o p o l y m e r w i t h a s p e c i f i e d number o f f u n c t i o n a l g r o u p s p e r w e i g h t u n i t a n d (c) c o v a l e n t attachment o f a s u i t a b l e c h i r a l enantio-selective moiety. The f u n c t i o n a l i z e d d i c h l o r o s i l a n e monomers a r e s y n t h e s i z e d g e n e r a l l y by r a d i c a l a d d i t i o n o f d i c h l o r o m e t h y l s i l a n e t o an u n s a t u r a t e d c a r b o x y l i c a c i d e s t e r or an u n s a t u r a t e d n i t r i l e . C a t a l y s t s used f o r t h i s purp o s e a r e p l a t i n u m / c h a r c o a l (JJ), , or organic peroxides (Y2), b u t f o r l a b o r a t o r y s y n t h e s e s hexachloroplatin i c a c i d (J_3,J_4) p r o v e d t o b e m o s t c o n v e n i e n t (scheme 1 a) . scheme

1 a:

CH SiHCl

2

+ CH =CCH COOR

CH SiHCl

2

H~PtCl + CH =CH-CH CSN — —

3

H PtCl 2

2

6

3

C H S i C l C H (CH )COOR

I

CH SiCl CH CH CH CN

II

3

2

2

3

fi

3

2

2

3

2

2

2

2


344

MODIFICATION

OF

POLYMERS

The compounds I and I I r e p r e s e n t i n t e r m e d i a t e s f o r t h e s y n t h e s i s o f e i t h e r c a r b o x y f u n c t i o n a l o r amino f u n c t i o n a l p o l y s i l o x a n e s . To t h i s e n d I o r I I i s e i t h e r s a p o n i f i e d w i t h sodium h y d r o x i d e and c o n c o m i t a n t l y p o l y c o n densated to a p o l y ( c a r b o x y l a l k y l methyl siloxane) (III) o r r e d u c e d t o an amino a l k y l m e t h y l d i a l k o x y s i l a n e w i t h s o d i u m b o r o h y d r i d e (Jl_5) . scheme

1 b:

H 0(Oif ) _ η CH SiCl CH CH(CH )COOR — > [CH Si0 ^ CH CH(CH )COOHJ n


3

2

2

3

3

2

2

2

3

Η 0(0H~) η CH SiCl CH CH CH CN — > [Œ Si0 ^ Œ CH CH COOH) 3

2

scheme

2

1

2

2

3

NaBH. 2

2

2

2

2

Illb

n

c:

CH SiCl CH CH CH CN 3

2

Ilia

r

2

2

2

(CH-ΛΟΗ)

* C H S i (OCH ) C H C H C H C H - N H 3

3

2

2

2

2

2

2

Completeness of the s a p o n i f i c a t i o n i s c o n t r o l l e d by I R - s p e c t r o s c o p y m o n i t o r i n g t h e d i s a p p e a r a n c e o f t h e e s t e r c a r b o n y l b a n d a t 1 740 cm"'' a n d t h e s i m u l t a n e o u s i n c r e a s e of e i t h e r the c a r b o x y l a t e a b s o r p t i o n at 1580 cm~1 o r t h e p r o t o n a t e d c a r b o x y 1 g r o u p a t 1700 cm"'' ( f i g u r e 1). Another c r i t e r i o n i s the disappearance of the e s t e r s i g n a l i n the p r o t o n - or 13c-NMR-spectra. The a n a l y t i c a l c o n t r o l o f t h i s s t e p i s o f s p e c i a l importance: the a l c a l i n e s a p o n i f i c a t i o n i s performed a t a r e l a t i v e l y l o w pH i n o r d e r t o p r e v e n t c l e a v a g e o f t h e s i l i c o n - c a r b o n b o n d . The c l o s e r t h e electron-with drawing c a r b o x y l group i s l o c a t e d to the S i - C - b o n d , the l a r g e r i s the danger of s c i s s i o n . T h e r e f o r e , f o r the β - s i l y l c a r b o x y l i c a c i d d e r i v a t i v e s t h e pH d u r i n g s a p o n i f i c a t i o n should not surpass 10.5; h o w e v e r , a t t h i s pH s a p o n i f i c a t i o n of the methyl e s t e r r e q u i r e s about 1 day, e v e n a t 6 0 ° C . F o r t h e J ' - s i l y l d e r i v a t i v e s , t h e pH o f t h e r e a c t i o n m i x t u r e i s n o t c r i t i c a l . We t h e r e f o r e now e x c l u s i v e l y u t i l i z e the latter. The h o m o p o l y m e r i c carboxyalkyl s i l i c o n e i s p r e c i p i t a t e d f r o m t h e s a p o n i f i c a t i o n m i x t u r e by a d j u s t m e n t o f t h e pH t o a b o u t 1 . A f t e r s t a n d i n g o v e r n i g h t a c l e a r , v i s c o u s s i l i c o n e i s d e p o s i t e d on the bottom o f t h e v e s s e l , The s i l i c o n e i s r i n s e d a c i d - f r e e , and h e a t e d t o 1 0 0 ° C i n v a c u o t o remove l a s t t r a c e s o f w a t e r and low m o l e c u l a r w e i g h t s u b s t a n c e s . Then the r e s i n o u s s i l i c o n e i s heated to 180°C under n i t r o g e n f o r a p p r o x i m a t e l y 1 h o u r i n o r d e r t o condense most o f the r e s i d u a l s i l a n o l g r o u p s . The p r e s e n c e o f f r e e s i l a n o l g r o u p s i n



22. B A Y E R A N D F R A N K

Polysiloxanes

345

the s i l i c o n e i s indicated by the presence of downfield s h i f t e d s a t e l l i t e s of the signals of the two s i l i c o n attached carbons i n the 3c-NMR-spectrum (figure 2). The removal of free s i l a n o l groups i s important for correct c a l c u l a t i o n of the r a t i o of the two monomers i n the subsequent c o e q u i l i b r a t i o n - s t e p . This step i s required i n order to generate a copolymer of approp r i a t e v i s c o s i t y and to separate the functional groups i n .the polysiloxane by a t l e a s t f i v e d i a l k y l s i l o x y u n i t s . The reason f o r t h i s necessity i s discussed below. Poly(carboxyalkyl methyl siloxane) and octamethyl c y c l o tetrasiloxane are mixed i n a monomer r a t i o of 1:6, hexamethyl disiloxane i s added to bring the polymerization degree of the ensuing s i l i c o n e to about 60, and 6 volume percent of concentrated s u l f u r i c acid are used as equilibration catalyst.


1

scheme 2 : a HOOC(CH ) 2

SiO^

n

(CH )Si0 3

2 / 2

+ b (CH ) 3

S i 0 2

2

/2

+

2 ( C H

3

)

> (CH ) Si-0-^(CH )Si(CH ) COOH-qJ — 3

3

3

2

n

a

The components are placed i n a round bottom f l a s k and shaken vigourosly u n i t l a homogeneous mixture i s obtained. As an increasing s i z e of the organo-residues of the s i l i c o n e reduces the rate of e q u i l i b r a t i o n considerably (Jj6,J_7) , two weeks are required for a batch of a few gramms depending on the e f f i c i e n c y of the mixing. A solvent at t h i s step i s omitted since t h i s may r e s u l t i n a misleading homogeneity at an early stage of equil i b r a t i o n . I f a s t a t i s t i c a l d i s t r i b u t i o n of the f u n c t i o nalized s i l o x y - u n i t s i s not achieved the properties of the r e s u l t i n g polysiloxane are unfavorable. After the reaction the mixture i s d i l u t e d with 20 volume percent of water and shaken f o r another hour. The two phases are separated by c e n t r i f u g a t i o n , the polysiloxane i s d i l u t e d with 1 volume of ether and extracted with water u n t i l the t e s t for s u l f a t e i s negative. The solvent i s removed i n vacuo. The f i n a l step i n t h i s sequence i s the coupling of a suitable c h i r a l group to the s i l i c o n e . In reaction scheme 3 the attachment of an amino acid amide residue i s given as an example. The carboxy functional copolymer i s dissolved i n dichlormethane/dimethylformamide and an amino aid -amide i s coupled with dicyclohexyl


346


WAVE NUMBER (cm" ) 1

4000 3000

2000


_l

3

L

1000

1500

5

6

I

7

I

900

800

700

L

8

9

10

11

12

13

U

WAVELEN6HT (microns)

Figure 1.

IR spectrum of incompletely saponified methylsiloxane

poly-2-methoxycarbonylpropyl-

Ç1 CH-CH, H

I I Figure 2. C-13 NMR spectrum of poly-2-carboxypropylmethylsiloxane. Free silanol groups give rise to a downfield satellite of the signals of the two siliconattached carbons.


22.


BAYER AND FRANK

Polysiloxanes

347

carbodiimide i n the usual manner (J_8) with N-methyl morpholine as base.

scheme 3 : Downloaded by UNIV OF CALIFORNIA SAN DIEGO on April 4, 2016 | http://pubs.acs.org Publication Date: June 10, 1980 | doi: 10.1021/bk-1980-0121.ch022

CH..

CHI

DCCI -Si-0

1

m H N-CH-C0NHR I o

I

I

2

(CH ) I ζ η

3

-Si-O(CH >

9

9

I

COOH

2

n

CO m 1

NH-CH-CONHR I

R

m

After one hour the organic s o l u t i o n i s extracted with 0.5 Ν hydrochloric acid, then with water and f i l t e r e d . The solvent i s evaporated, the residue redissolved i n hexane and the solution i s s t i r r e d for one hour with 10% a c e t i c acid i n water. The s o l u t i o n i s f i l t e r e d again, the aqueous layer i s discarded and the organic layer i s washed three times with 5% sodium bicarbonate solution. F i n a l l y the solvent i s evaporated, the residue redissolved i n butanol and applied to a column of LH-20 i n the same solvent. The f i r s t t h i r d of the f r a c t i o n s between dead volume and t o t a l bed volume i s pooled, the solvent i s evaporated, and the s i l i c o n e i s heated to 180°C for one hour i n vacuo. A clear s i l i c o n e of a v i s c o s i t y of about 50 000 centi-stokes at room temperature i s obtained. Results and Discussion In scheme 4 the general formula of the s i l i c o n e s described here i s shown:

American Chemical Society Library 1155

16th St. N. W.

Washington, D. C. 20036 Carraher and Tsuda; Modification of Polymers ACS Symposium Series; American Chemical Society: Washington, DC, 1980.

348


scheme 4 : CH (CH )3S1-O3

CH 3

3

-Si-OCH 3

-Si(CH )

-Si-O-

3

3

-•η CO


NH

R

R

m The r a t i o of η to m i s between 6 and 7 i f the c h i r a l group i s an amino a c i d , but roughly 4 i f the c h i r a l moiety i s an amine. In f i g u r e 3 the IR-spectrum f o r such a polysiloxane carrying a valine-t-butylamide re sidue i s shown. Of p a r t i c u l a r diagnostic value i s the shape of the absorption band between 9 and 10 μ, a su perposition of two bands. A polysiloxane of normal f l u i d i t y shows both bands i n a roughly equal i n t e n s i t y . The band at 9.8 μ obviously r e f l e c t s the f l e x i b i l i t y of a s i l i c o n e chain over a longer segment, as i t i s absent i n highly crosslinked polysiloxanes or i n l i n e a r shortchain s i l i c o n e s . As indicated above coupling of c h i r a l groups to a carboxyfunctional homopolymer does not lead to a s u i t a b l e s i l i c o n e . In such a case a material of high r i g i d i t y and s e m i - c r i s t a l l i n e consistence i s ob tained. I t does not e x h i b i t any e n a n t i o - s e l e c t i v i t y and i s thermally unstable. I n t e r e s t i n g l y the IR-spectrum of such a material, as shown i n f i g u r e 4, reveals a very weak absorption at 9.8 μ, another proof f o r the low f l e x i b i l i t y of the polysiloxane backbone due to formation of a large number of i n t r a - and i n t e r - c h a i n hydrogenbonds. We have synthesized several s t r u c t u r a l analogs of these s i l i c o n e s and examined t h e i r e n a n t i o - s e l e c t i v i t y by gas chromatography. The structure of the connecting group i s of l i t t l e influence on phase s e l e c t i v i t y (table 1), but much more important i s the structure of the o p t i c a l l y active group i t s e l f .


Chiral

BAYER A N D FRANK

Organofunctional

349

Polysiloxanes

WAVENUMBER (cm-1)


4000 3000

,

2000

1500

1000

900

800

I., , . I l• .. I I I 1 1 I

"Τ

3

700 1

1

1

1

—ι

1

1

.

1

1

1

1

r-

Chiral Organofunctional Polysiloxanes: Synthesis, Properties, and

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