Regiocontrol in Cellulose Chemistry - American Chemical Society

Chapter 2

Regiocontrol in Cellulose Chemistry: Principles and Examples of Etherification and Esterification

Downloaded by PURDUE UNIVERSITY on March 18, 2013 | http://pubs.acs.org Publication Date: April 17, 1998 | doi: 10.1021/bk-1998-0688.ch002

D. O. Klemm Institute of Organic and Macromolecular Chemistry, Friedrich Schiller University, D-07743 Jena, Germany

Regiocontrol means site-selective reactions of cellulose and related polysaccharides that form functionalization patterns essential for new properties. Experimental results are presented in synthesis, analysis, and subsequent reactions of silylethers, cellulose p -toluenesulfonates, and deoxy-thiosulfates (Bunte salts). Regiocon trol succeeds by selective loosening supramolecular structures, as well as by selective protection, activation, and migration of functional groups.

The topics of this paper relate to the essential interaction of cellulose functionalization with organic synthesis and structure analysis, as well as with product properties and applications. After some remarks on principles of regioselectivity in cellulose modification, the selective synthesis and subsequent reactions of cellulose ethers, the functionalization via ester intermediates of controlled stability and reactivity, and examples of structure properties relation ships will be described. General Principles of Regioselective Cellulose Chemistry Up to now there have been known four principal synthesis pathways to obtain functionalized celluloses (Figure 1): The first is the well-known polymeranalogous reaction of cellulose after isolation from plants or bacteria culture media. The second is the biosynthesis of functionalized celluloses using, for example, the copolymerization of β-D-glucose with N-acetylglucoseamine by Acetobacter xylinum (/). The third way is enzymatic in vitro synthesis starting, for example, from 6-0-methyl-B-cellobiosyl fluoride and purified cellulases in a stereo- and regioselective polymerization (2). The fourth is the chemical synthesis starting from glucose. Results from last year demonstrated the first chemosyntheses of functionalized celluloses by ring-opening polymerization of 3,6-di-O-benzyl-a-D-

©1998 American Chemical Society In Cellulose Derivatives; Heinze, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.

19

20

3

OH


Cellulose

Polymeranalogous reactions

Biosynthesis

Chemosynthesis F. N A K A T S U B O

S. TOKURA M. TAKAI

T.

Acetobacter xylinum R

2

-

Ph C©BF © 3

0 - .

NHCOCH3

Functionalized OH

NISHIMURA

4

celluloses

R - OH, R \ R

2

Ο HO HO

BnO ^ O B n .0

.OH + OH

OH

HO HO

Cellulase

R

1

-

OCH

3

OH Enzymatic synthesis Glucose derivatives

Glucose derivatives

S .KOBAYASHI

,R

1

HO HO

OH Cellobiose

\

0

derivatives

Figure 1. Principal synthesis pathways to obtain functionalized celluloses.

In Cellulose Derivatives; Heinze, T., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1998.


21

glucose- 1,2,4-orthopivalate (3), and by stepwise reaction of selectively protected allylethers of β-D-glucose (4). In the case of polymeranalogous functionalization of cellulose, the chemical reaction proceeds in a statistic or regioselective way. The term "regioselectivity'' means an exclusively or significantly preferential reaction at one or two of the three sites 2,3, and 6 of the anhydroglucose unit (AGU) as well as along the polymer chains. Typically simple examples are selectively C-6 or C-2,3 modified celluloses (A) and copolymers with block-like structures (B) as shown schema tically in Figure 2. The symbols used ( · , * ) denote different types of functional groups. The energy profile of a typical regioselective reaction demonstrates that steric hindrance (by bulky groups), entropie acceleration (caused, for example, by H O — H bonds), or electronic promotion (e.g., electronically withdrawn substituents) are essential to differentiate among the free enthalpies of activation as well as of rate constants and concentrations of the isomeric products formed. From the point of view of such differences, the varying reactivity of the O H groups in the A G U of cellulose - primary 6-OH, more acidic 2-OH - may be used for selective functionalization of cellulose. Moreover, a selective loosening of the supramolecular structure may be of importance in regiocontrol. In regard to the question: 'Why regiocontrol in cellulose chemistry?" three important fields should be pointed out: - Basic investigations, e.g., on structure and interaction in solution, as well as on formation of well-defined supramolecular structures using cellulose derivatives with known patterns of functionalization; - Design of advanced materials and nanoscale architectures in interdisciplinary research at the interface of organic and macromolecular chemistry. Potential fields of application are liquid crystalline polymers, selective membranes, multilayered assemblies, sensor matrices, recognition devices, and bioactive materials; - Better knowledge of reactions, mechanisms, and product structures and properties of present as well as of new commercial types of cellulosics of industrial largescale processes. Further knowledge of the control of processing and end-use properties by the pattern of functionalization. For example, regioselectively modified celluloses are of importance in investi gations into solution properties as well as into enzymatic degradation of cellulose derivatives. This work deals with fringed micelles at different aggregation stages in solution as demonstrated by Burchard (5), with the characterization of the reaction behaviour of cellulases using 6-0- and 2,3-di-O-methyl celluloses (6), and with the investigation of HO-—H bond systems and gelation of cellulose derivatives (7, 8) as published by Kondo. Our investigations on regiocontrol in polysaccharide chemistry have been based up to now on cellulose and starch including β-cyclodextrine as a model compound. Regioselectivity in the A G U and along the polymer chains may be low, high, or 100 % and may lead to copolymers (degree of substitution, DS, < 1) or homopolymers (DS = 1) by reaction at one preferred site of the A G U . Regiocontrol of the primary and of subsequent reactions succeeds by the reagent (e.g., steric 4



22

Figure 2. Examples of regioselectively functionalized celluloses.



23 hindrance) and by substituent effects (protection, activation, migration) and by the supramolecular structure in the reaction media (stepwise loosening of HO—H bonds, phase separation during reaction, structure in solution). Preferentially used cellulose types are cellulose powder obtained by acid hydrolysis and mechanical disintegration (degree of polymerization, DP, 150-300), spruce sulfite dissolving pulp, pine sulfate dissolving pulp (DP 600-900), scoured and bleached cotton linters (DP 800-2000), and cellulose prepared by Acetobacter xylinum (DP 1000-2000). Important synthesis routes to obtain regioselectively functionalized celluloses have been developed: Firstly, the complete functionalization of cellulose followed by a site selective reaction of the introduced groups and by the elimination of the primary groups. Secondly, the regioselective partial functionalization of cellulose and subsequent reactions of the free or functionalized OH groups followed by the elimination of the primary groups. Typical results of these investigations are summarized in Klemm et al. (Ρ). Silylcelluloses (soluble in organic solvents, DS 0.4-3.0, deblocking by HC1/H 0 resp. fluoride ions), tritylethers (soluble, detritylation by HC1), and cellulose p-toluenesulfonates (DS up to 2.3, soluble in organic solvents, reactive in nucleophilic substitutions), have been developed as suitable cellulose intermediates for regioselective functionalization. 2

Regioselective Synthesis and Subsequent Reactions of Cellulose Ethers The silylation of cellulosic O H groups leads to a preferred 6-0- or 2,6-di-Ofunctionalization. These silylether intermediates open up a wide field of subse quent reactions. The chemical modification of starch is included in the investiga tions. The trimethylsilylation (R = Me, cf. Figure 3) of cellulose dissolved in N methylpyrrolidone (NMP)/LiCl leads to DS values up to 3.0. At DS values of about 1.0, 60 % of the silylether groups are located at C-6. In a cellulose suspension in N-methylpyrrolidone/NH at -33 to -15 °C, the trimethylsilylcellulose dissolves at DS 1.3 after a heterogeneous reaction, and the silylation takes place up to DS values of 3.0. At DS values of about 1.0, 80 % of the silylether groups are located at C-6. In the case of thexyldimethylsilylation (R = CMe CHMe = Thx), this higher 6O-regioselectivity leads to a very high selectivity at the primary O H groups and to the formation of pure 6-O-thexyldimethylsilyl cellulose (10-12). This thexyldi methylsilylation in N M P / N H stops at the DS of 1.0. No further silylation takes place, even with additional amounts of chlorosilane, either at higher temperatures or after isolation and dissolution of the polymer in pyridine. We assume a low accessibility of the O H groups at positions 2 and 3 after swelling and decrystallization with ammonia, in contrast to OH groups in the cellulose dissolved in N M P / L i C l or Ν,Ν-dimethylacetamide (DMA)/LiCl (75). The low selectivity in case of dissolved cellulose is suitable to prepare 2,6-diO-thexyldimethylsilyl cellulose even with the bulky reagent thexyldimethylchlorosilane. As summarized in Figure 3, starting from primary 6-O-protected celluloses we 3

2

2

3



24

1

R - CH

H C-^

3I

2

2

R = CH , - ^ - N 0 , CH = C H - @ 3

2

3

R - CCI ,-@-N0 , (CH ) CH 3

2

2

14

3

Figure 3. Subsequent reactions of 6-0-silylated celluloses.



25 developed effective ways to obtain different types of 2,3-di-O-esters and -ethers by reactions of the free O H groups as well as of esters by reaction of the silylether group (14). As in the case of the cellulose products, the subsequent acylation of 6-0- and 2,6-di-O-thexyldimethylsilyl starch leads to the 2,3-di-O- resp. 3-0-starch esters. Whereas the alkylation of 2,6-di-0-silyl celluloses is a suitable way to prepare the 3-0-ethers, the related starch derivatives form the 2-0-ethers with migration of the silyl groups to position 3. The same results could be observed in the benzylation of β-cyclodextrine thexyldimethylsilylated resp. t-butyldimethylsilylated in positions 2 and 6. The formation of the 2-0-alkyl-3,6-di-0-silyl derivatives was mainly concluded from Ή N M R spectra by the typical high field shift of the proton at C-2 after alkylation (75). In cooperation with P. Mischnick (16), we investigated the silyl group migration in alkylation of oligo- and polysaccharides with oc-glycosidic linkages as a suitable synthesis way to obtain the corresponding 2-0-ethers. Figure 4 shows 2-0methylation of 2,6-di-O-thexyldimethylsilyl starch as a typical example. The cyclic intermediates possessing two trans-diequatorial O H groups are formed under the reaction conditions because of interaction with the neighboring Ια-oxygen. After desilylation of the 2-0-ethers, a subsequent acylation resp. alkylation proceeds to form regioselectively trifunctionalized starches (cf. Figure 12). A further and well-known 6-0-blocking group in cellulose chemistry represents the trityl group suitable for the preparation of many of 2,3-di-O-derivatives (7720). With the aim of a complete detritylation under mild conditions, we investigated the formation and properties of methoxy substituted tritylethers with this result: The higher the methoxy substitution, the higher is the rate of tritylation and detritylation (27, 22). With respect to product stability, the p-monomethoxytrityl group is very suitable for 6-0-protection, e.g., for synthesis of 2,3di-O-carboxymethyl cellulose, including a complete deprotection with ethanolic HC1 (23) as demonstrated in Figure 5. Functionalization via Ester Intermediates of Controlled Stability and Reactivity The introduction of the p-toluenesulfonyl (tosyl) group into different types of celluloses in the DP range of 150-2000 is a suitable way to prepare 6functionalized derivatives under "Umpolung" of the reactivity at position 6. Donor agents such as sodium thiosulfate lead to cellulose-deoxy-thiosulfates (Bunte salts) with high 6-regioselectivity (22). The cellulose p-toluenesulfonates were synthesized in an N,N-dimethylacetamide/LiCl solution of cellulose in the presence of triethylamine (TEA). In the DS range of about 1 - controlled by the mol equivalents of the reagent tosyl chloride 80 % of the sulfonate groups are located at position 6 (24, 25). The subsequent reaction (DS values of cellulose p-toluenesulfonates up to 2.3) with sodium thio sulfate in a mixture of dimethylsulfoxide and water resulted in nucleophilic substitution of the primary tosylate groups forming water-soluble polymers (Figure 6). This Bunte salt formation takes place in the same way after subsequent functio nalization of free O H groups in the cellulose p-toluenesulfonates.



Ο —Si-R

R R - Thx, Bu'

Ο —Si-R

R

ii

O —Si-R

Figure 4. Silyl group migration in alkylation of 2,6-di-O-thexyldimethylsilyl starch.


27

H CO Downloaded by PURDUE UNIVERSITY on March 18, 2013 | http://pubs.acs.org Publication Date: April 17, 1998 | doi: 10.1021/bk-1998-0688.ch002

3

H CO-H C ^ 3

4

e

C,H

CI-C-C H 6

°--«

S

5

70°C

CICH COONa/ NaOH (DMSO) 70°C, 29h 2

H,CO

OH HCI C H OH/H 0 5

CH COONa CH COONa 2

2

5

2

CH,COONa CHoCOONa

Figure 5. Methoxytrityl ethers as very suitable 6-O-protective group in cellulose chemistry.



OH

O-Tos

Figure 6. Synthesis of cellulose-deoxy-thiosulfates (Bunte salts) via cellulose p-toluensulfonates.


29 Typical examples are the formation of the corresponding esters, cellulose-0-(4chloro-phenylcarbamate)-deoxy-thiosulfate and cellulose acetate-deoxy-thiosulfate, soluble in organic solvents such as tetrahydrofurane and acetone (cf. R in Figure 8). Further synthesis pathways to obtain Bunte salts of cellulose and cellulose derivatives consist in the reaction of different types of chlorinated and unsaturated cellulose esters described in Camacho Gomez (22). Examples are substitution reactions of cellulose-0-(3-chloropropionate), cellulose-0-(4-chloromethylbenzoate), cellulose-0-(2-chloroethylcarbonate), and cellulose-0-(N-2chloroethylcarbamate) with sodium thiosulfate in a mixture of dimethylsulfoxide and water at 80 °C for 24 h (cf. R in Figure 8), as well as addition reactions of cellulose-O-monomaleate with this reagent. Three important types of subsequent reactions of low-molecular Bunte salts are known in relation to the conditions (26) as shown in Figure 7. For the polymeric and watersoluble cellulose-deoxy-thiosulfates, the introduced anionic S-S(0 )0-groups are useful as protected alkene and thiol functions, suitable for subsequent crosslinking reactions in solution, as well as in films, ultrathin layers, recognition matrices, and spherical supports. These investigations are part of our ongoing research on regioselective functionalized celluloses and starches, including the preparation of artifical supramolecular architectures (27). First results demonstrate effective crosslinking of Bunte salts of cellulose and cellulose derivatives in the presence of oxidizing reagents such as iodine or hydrogen peroxide (cf. Figure 8). As a result of the crosslinking, the polymers precipitated from solutions and layers formed from water or organic solvents were insoluble after the described treatment. 1


2

2

Analysis of the Molecular Structure An important part of an investigation on regiocontrol in polysaccharide chemistry is the analysis of the functionalization patterns prepared. As suitable methods we used C and Ή N M R spectroscopy of the polymers and HPLC after chain degradation. In the case of HPLC a complete methylation of the free O H groups takes place (methyl inflate, ditert. butyl pyridine, 4 h 60 °C, 16 h 25 °C) before acidic degradation (0.2 Ν trifluoroacetic acid in water) occurs. Typical examples are described in Erler et al. (28). A suitable way to take Ή Ή COSY spectra of high molecular cellulose and starch derivatives is based on the stepwise introduction of methyl and acetyl groups under complete functionalization of free OH groups. Starting from the regioselectively functionalized silylethers, the subsequent chemical modification leads, e.g., to 6-0-acetyl-2,3-di-0-methyl cellulose (Figure 9). The ' H N M R spectra of the prepared polymers show a high resolution. The very intensive signals of the original silyl groups are eliminated, the methylation causes a signal shift of the proton at the functionalized C atom to higher field, and the acetylation of the former silylated OH groups a signal shift to lower field. Typical examples are presented in Figure 10 as well as in (12, 13, 29). l 3



30

e

R-X-CH,-CH,-S-S-O Na® NaOH

H 0 2

2

Η , Ο , H®

R-X-CH = CH, + Na S 0 + H0 2

2

R-X-CH -CH -S 2

2

R X~"CH2 CHg S 3

+ 2NaHS0

2

4

R-X-CH -CH -SH 2

+ NaHS0

2

4

Figure 7. Subsequent reactions of Bunte salts.



31

— C - 0 - C H

R

3

=

Η or

2

C H

2

—

,

— C-NH-CH CH 2

2

— ,

R S 0 Na 2

2

3

Figure 8. Crosslinking of Bunte salts of cellulose in the presence of oxidizing reagents.



32

\

Si / I Ο

\

V

/I

Si

NaH, CH I 3

Ο. HO

OH

(THF) H,CO 25°C, 24h + 50°C, 48h

OCH, Bu N® F© (THF) 4

Y ο

5 0 ° C . 24h OH

ο

H CO a

(CH CO) 0, pyridine 3

Ν OCH,

Ο-.

2

25°C, 24h + 100°C, 4h

H C0 3

OCH,

Figure 9. Synthesis of acetyl-methyl celluloses for Ή Ή COSY NMR spectros copy.



Figure 10. Ή Η COSY NMR spectrum of 6-O-acety 1-2,3-di-O-methylcellulose preparedfrom6-O-thexyldimethylsilyl cellulose (DS = 0.78).



34 Conclusion The silylation of cellulose and starch with the bulky thexyldimethylchlorsilane represents an important example of a regioselective polysaccharide functionalization. This etherification is controlled by a partial (6-O-silylation) or complete (2,3-di-O selectivity) loosening of the supramolecular structure caused by decrystallization and solvation of the polymers. In the case of cellulose these silylethers are suitable intermediates to prepare 2,3di-O and 3-0 ethers and esters (protection group technique) as well as to synthesize 6-0 and 2,6-di-O esters (activation by silylation of the O H groups) as summarized in Figure 11. The corresponding starch functionalization additionally leads to 2-0 ethers as a result of migration of the 2-0-silyl groups to position 3 (Figure 12). In all cases the subsequent reactions may be used to prepare different types of completely functionalized polymers suitable for *H N M R analysis and investigation into structure properties relationships. As an important example of ester intermediates in regioselective cellulose functionalization, water-soluble and film-forming Bunte salts (deoxy-thiosulfates) represent crosslinkable polymers with a wide range of additional functional groups. Prepared from cellulose p-toluenesulfonates, Bunte salts react like anionic protected alkene and thiol groups suitable for controlled polymer modification. Acknowledgements The author is indebted to Dr. Th. Heinze, Dr. Katrin Petzold, Dr. Armin Stein, Dipl.-Chem. Andreas Koschella, Dipl.-Chem. Juan Chamacho Gomez, and Dipl.Chem. Kerstin Rahn for their creative work in the field of the described ethers and esters of cellulose and starch. The financial support of the work on regioselective functionalization by the Deutsche Forschungsgemeinschaft, by the Bundesministerium fur Ernàhrung, Landwirtschaft und Forsten, as well as by the Fonds der Chemischen Industrie of the FRG, is gratefully acknowledged. Literature Cited (1) Shirai, Α.; Takahashi, M.; Kaneko, H.; Nishimura, S.; Ogawa, M.; Nishi, N.; Tokura, S. Int. J. Biol.Macromol.1994, 16, 297. (2) Kobayashi, S.; Kashiwa, K.; Kawasaki, T.; Shoda, S. J. Am. Chem. Soc. 1991, 113, 3079. (3) Nakatsubo, F.; Kamitakahara, H.; Hori, M. J. Am. Chem. Soc.1996, 118, 1677. (4) Nishimura, T.; Takano, T.; Nakatsubo, F.; Murakami, K. Mokuzai Gakkaishi 1993, 39, 40. (5) Burchard, W. Adv. In Colloid and Interface Sci. 1996, 64, 45. (6) Nojiri, M.; Kondo, T. Macromolecules 1996, 29, 2392. (7) Kondo, T. J. Polym. Sci., Polym. Phys. 1994, B32, 1229. (8) Hagaki, H.; Takahashi, I.; Natsume, M.; Kondo, T. Polymer Bull. 1994, 32, 77.



35

ÔSiMe R

R'-Hal NaH

2

2

R0 N® B u F ® 4

OR

2

2

R - Me

.OH ACTIVATION

MeO

OMe

2,3-di-O1

SO, I R - CH,

ÔS0 HO

e 3

.OAc

Ν a® e

OH(OS0 Na®) 3

MeO

OMe

6-0-, 2,6-di-O1

R - Me, Thx, Bu' R = Me, Bn, Ac 2

Figure 11. Regiocontrol by selective protection and activation.


1

36


MIGRATION 0-SiMe R

1

2

ΗΟ^Τ-ή 1

R Me,S

1

OSiMe,R N a H

R'Me Si0' 2

OR

2

,° Ο N® B u F © 4

2,6-di-O-

ÔSiMe R

HO

OSiMe,R

3-0Thx,

2

- Bn

(i) Bu'

R = Me, Bn

OBn

2-0-

1

AcO

R

1

2

Me,

N

(")

1

R Me SiCI 2

A

c

. AcO

2 °

ÔSiMe R

1

2

AcO

or M e l

OBn (Me) AcO

ÔAc(Me) OBn

Figure 12. Regie-control by selective protection and silyl group migration.



37

(9) Klemm, D.; Stein, Α.; Heinze, Th.; Philipp, Β.; Wagenknecht, W. In Polymeric Materials Encyclopedia; Salamone, J.C., Ed.; CRC Press, Inc.: Boca Raton, FL, USA, 1996, Vol. 2c; pp 1032-1054. (10) Stein, A . PhD Thesis; University of Jena, Germany, 1991. (11) Henze-Wetkamp, H.; Zugenmaier, P.; Stein, Α.; Klemm, D.Macromol.Symp. 1995, 99, 245. (12) Klemm, D.; Stein, A. J. Macromol. Sci., Pure Appl. Chem. 1995, A32, 899. (13) Klemm, D.; Heinze, Th.; Stein, Α.; Liebert, T. Macromol. Symp. 1995, 99, 129. (14) Stein, Α.; Klemm, D. Macromol. Chem., Rapid Commun. 1988, 9, 569. (15) Petzold, Κ. PhD Thesis; University of Jena, Germany, 1996. (16) Mischnick, P.; Lange, M.; Gohdes, M . ; Stein, Α.; Petzold, Κ. Carbohydr. Res. 1995, 277, 179. (17) Harkness, B.R.; Gray, D.G. Macromolecules 1990, 23, 1452. (18) Harkness, B.R.; Gray, D.G. Macromolecules 1991, 24, 1800. (19) Kondo, T.; Gray, D.G. Carbohydr. Res. 1991, 220, 173. (20) Kondo, T. Carbohydr. Res. 1993, 238, 231. (21) Camacho, Gómez, J.A.; Erler, U.W.; Klemm, D. Macromol. Chem. Phys. 1996, 197, 953. (22) Camacho Gómez, J. PhD Thesis; University of Jena, Germany, 1997 (23) Heinze, Th.; Röttig, Κ.; Nehls, I. Macromol. Rapid Commun. 1994, 15, 311. (24) Rahn, K.; Diamantoglou, M.; Klemm, D.; Berghmans, H.; Heinze, Th. Angew. Makromol. Chem 1996, 238, 143. (25) Heinze, Th.; Rahn, K.; Jaspers, M.; Berghmans, H. J. Appl. Polym. Sci. 1996, 60, 1891. (26) Milligan, B.; Swan, J.M. Rev. pure appl. Chem. 1962, 12, 72. (27) Schaub, M.; Wenz, G.; Wegner, G.; Stein, Α.; Klemm, D. Adv. Mater. 1993, 5, 919. (28) Erler, U . ; Mischnick, P.; Stein, Α.; Klemm, D. Polymer Bulletin 1992, 29, 349. (29) Stein, Α.; Klemm, D. Das Papier 1995, 49, 732.


Regiocontrol in Cellulose Chemistry - American Chemical Society

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