Cellulose derivatives with a low degree of substitution

The invention is directed to the formation of cellulose derivatives using homogenous phase reaction conditions. Cellulose is dissolved using DMAc/LiCl and a reagent system is added to promote the acylation of an appropriate acid anhydride or free carboxylic acid. One reagent system includes N,N-dicyclohexylcarbodiimide (DCC) and 4-pyrrolidinopyridine (PP). Another reagent system includes p-toluene sulfonyl chloride (TsCl) and pyridine (Py).

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The invention is directed to cellulose derivatives that have a low degree 
of substitution and a uniform degree of modification along the polymer 
backbone. The invention is particularly directed to an acylation process 
for producing the cellulose derivatives. 
2. Description of the Prior Art 
The chemical modification of cellulose, with esterifying and etherifying 
agents, represents a widely practiced industrial technology worldwide. 
Both cellulose ethers and cellulose esters have reached significant 
commercial importance. All commercially available cellulose derivatives 
are made by heterogenous reaction. Malm et al., Ind. Eng. Chem., 43(3), 
688-91 (1951) discloses two phase reaction chemistry in which cellulose 
remains suspended in a solution of a reagent in water or a solvent. The 
cellulose reacts gradually in a stepwise fashion beginning with the 
amorphous regions and proceeding to the crystalline regions. Uryash et 
al., Thermochim. Acta, 93:409-412 (1985), reported that cellulosic 
materials made using the two-stage reaction chemistry have a "blocky" 
character where neighboring sections can be unsubstituted or have a high 
degree of substitution or modification, depending on the accessibility. 
The practice of heterogenous reaction chemistry in connection with 
cellulose esters has resulted in products with a high degree of 
substitution, usually above 2.4. This means that on average, 2.4 of the 
hydroxy groups per sugar molecule in the cellulose backbone are 
esterified. Highly esterified cellulose materials have good solubility, 
improved thermal properties, and improved processability. However, 
cellulose esters with a high degree of substitution have reduced 
biodegradability, decreased moisture uptake, and decreased interaction 
with polar substances. In addition, commercially available cellulose 
derivatives produced using the two-phase reaction chemistry are limited to 
ester derivatives with acyl substituents having less than four carbon 
atoms (C.sub.4). 
McCormick & Callais, Polymer, 28:2317-23 (1987) have proposed the acylation 
of cellulose in lithium chloride (LiCl)/N,N-dimethyl acetamide (DMAC) 
using acyl chlorides and acid anhydrides of small size (less than 
C.sub.3). While acyl chlorides are highly reactive, they are collectively 
insoluble in the LiCl/DMAc solvent system, except for acetyl chloride. 
Homogenous phase reaction conditions are lost in reactions with propionyl 
or higher acyl chlorides. 
Shimizu and Hayashi, Cellulose Chemistry and Technology 23, 667-670 (1989) 
reported cellulose esterification using p-toluenesulphonyl chloride 
(TsCl). Specifically, Shimizu et al. disclosed the production of 
tri-substituted cellulose esters from an acetylation reaction. 
SUMMARY OF THE INVENTION 
It is an object of this invention to provide cellulose derivatives that 
retain a large portion of the hydroxy (OH) functional groups in an 
unmodified stage. 
It is another object of this invention to provide a cellulose derivatives 
that are modified by relatively large substituents (C.sub.6-20 or larger). 
It is yet another object of this invention to provide a cellulose 
derivative with a uniform degree of substitution along the polymer 
backbone. 
According to the invention, cellulose derivatives are prepared using 
homogenous phase reactions wherein the cellulose is dissolved using 
DMAc/LiCl and a reagent system is added to promote the acylation of an 
appropriate acid anhydride or free carboxylic acid. One reagent system 
includes N,N-dicyclohexylcarbodiimide (DCC) and 4-pyrrolidinopyridine 
(PP). Another reagent system includes p-toluene sulfonyl chloride (TsCl) 
and pyridine (Py). The acylation product is recovered by precipitation 
from solvent, such as warm (60.degree. C.) 50% aqueous methanol. The 
DCC/PP reagent system has been found to be very useful for the 
esterification of alkanoic acids of shorter chain length (i.e., 
.ltoreq.six carbon atoms (C.sub.6)), and the TsCl/Py reagent system is 
efficient for the addition of acids having C.sub.12 to C.sub.20 alkyl 
chains. Stoichiometric control of the reagents allows for control of the 
degree of substition (DS). In addition, experiments demonstrate that the 
esterification is selective for the C.sub.2 and C.sub.6 positions. 
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION 
Low degree of substitution cellulose derivatives are prepared by reacting 
the cellulose in the homogenous phase with a suitable carboxylic acid or 
anhydride and a reagent system selected from the group consisting of 
DCC/PP or TsCl/Py. The homogenous phase reaction produces a cellulose 
polymer with a large number of unsubstituted hydroxy groups uniformly 
distributed along the backbone of the cellulose, thus allowing the 
material to retain many favorable cellulose gel characteristics including 
moisture uptake, biodegradability, and interaction with ionic species. The 
invention allows the incorporation of large substituents on a cellulose 
backbone. 
Recent developments in acylation chemistry involving small-molecule 
alcohols unrelated to cellulose have demonstrated the used of 
dicyclohexylcarbodiimide (DCC) as an esterification agent. DCC has been 
used as a condensation agent in the coupling of amines and carboxylic 
acides in peptied and protein chemistry. Scheme 1, presented in Hassner & 
Alexanian, Tetrahedron Letters, 4475 (1978), shows the use of DCC in 
condensation of carboxylic acids into anhydrides. 
##STR1## 
By recycling the spent half of the anhydride, its concentration in the 
medium is kept constant. 4-pyrrolidinopyridine (PP) converts the anhydride 
into a highly reactive species which reacts readily with an alcohol to 
yield an ester. The base is used only in catalytic amounts (e.g., 0.01 
eq/OH). 
One embodiment of this invention involves the addition of DCC to a 
cellulose solution together with an acid anhydride or free carboxylic acid 
that is to be esterified to the cellulose backbone. The cellulose solution 
can be made with any solvent system for cellulose which will maintain 
cellulose in the homogenous phase; however, best results have been 
obtained with a 10% or less solution in LiCl/DMAc. A 2% solution of 
cellulose in LiCl/DMAc can be prepared in accordance with McCormick and 
Dawsey, Macromolecules, 23:3606-10 (1990); however, this procedure can be 
advantageously be modified to avoid water during the initial step of 
cellulose activation by employing the solvent exchange of solid cellulose 
dried at 80.degree. C. for 18 hrs. with methanol and then with DMAc 
followed by dissolution in DMAc/LiCl. PP in catalytic quantities (e.g., 
less than 0.1 eq./eq. of OH and preferably 0.01 eq/eq OH) is added to the 
cellulose solution which includes the DCC and acid anhydride or carboxylic 
acid. This solution is stirred for 48 hours at room temperature under an 
inert atmosphere. The acylation product is recovered by precipitation from 
warm (e.g., 60.degree. C.) 50% aqueous methanol or other suitable reagent. 
The precipitate is then filtered under suction, washed with water and 
methanol, and then purified by soxhlet extraction with methanol for 24 hrs 
followed by diethyl ether for 24 hrs. The residue was dried under vacuum 
at 60.degree. C. for 24 hr and stored in a desiccator at room temperature. 
During the reaction, DCC is converted to N,N-dicyclohexyl urea (DCU). If 
the reaction mixture is precipitated into water, both DCC and DCU will 
precipitate along with the cellulose derivative. An excess acid derivative 
may also precipitate. After removing water, DCC and DCU can be recovered 
by washing with methanol. Residual acids can be separated from DCU/DCC by 
reprecipitation in water and washing the precipitate with dilute aqueous 
alkali. DCU is dried and dehydrated to DCC by heating with various 
dehydrating agents such as TsCl/pyridine, POCl.sub.3, PCl.sub.5, P.sub.2 
O.sub.5, etc. 
Another embodiment of the invention involves the use of a p-toluenesulfonyl 
chloride or "tosyl chloride"/pyridine (TsCl/Py) system to esterify the 
cellulose polymer. 
The procedure of Shimizu et al., Cellulose Chemistry and Technology 23, 
667-670 (1989) was tested, but failed to produce an acceptable cellulose 
derivative. Instead a dark colored reaction mixture was formed which 
failed to yield the desired precipitate upon addition of a non-solvent. 
The sequence of steps for acids having six or more carbon atoms per alkyl 
substituent thereby involves (a) suspending solvent exchanged cellulosed 
in dimethyl formamide (DMF) (pyridine if the carboxylic acid has fewer 
than 6 C-atoms); (b) adding TsCl to this suspension (2 moles TsCl per 
cellulose OH equivalent); (c) adding free carboxylic acid (1, 2, or 4 
moles per cellulose OH equivalent); (d) heating to 50.degree. C. or higher 
for 20 hrs. The product in Shimizu was described as having a yellow or 
orange color. In homogenous phase, discoloration was experienced, and this 
was always associated with molecular degradation. In this reaction, TsCl 
is (a) present together with cellulose and neither a strong base (if the 
derivatizing acid is large and DMF is used as the solvent) nor a 
carboxylic acid, which is added subsequently (i.e., later); (b) any HCl or 
TsOH formed during the reaction of TsCl with any co-reagent is unbuffered 
and therefore capable of reducing cellulose molecular weight; and (c) the 
molar ratio of TsCl to carboxylic acid may exceed 1.0. After the addition 
of free carboxylic acid, any TsCl present will form a mixed anhydride 
which reacts freely with the OH groups of cellulose (heterogenous 
conditions). Free acids as large as C-4 (butyric acid) were reacted using 
pyridine as solvent but, acyl substituents having six or more carbon atoms 
were reacted using DMF as solvent and without base to buffer the strong 
acids produced during the reaction. Evidence of degradation to the 
starting polymer was observed and, the order of addition of reagents were 
cellulose in DMF, tosyl chloride, and free acid. 
The failure to produce satisfactory cellulose ester products using the 
Shimizu process can be attributed to the following: 
1. Shimizu and Hayashi process treats cellulose with TsCl in the absence of 
a strong base (e.g., pyridine) in the case of large substituents (i.e., 
six or more carbon atoms in the alkyl substituent); 
2. Free carboxylic acid is added too late, after cellulose, TsCl, and DMF 
have been mixed (giving rise to color; and 
3. The molar ratio of TsCl to carboxylic acid may exceed 1.0. 
In the present invention, as discussed above, the cellulose is first 
dissolved into homogenous phase using a suitable reagent system such as 
LiCl/DMAc. Less than 10% LiCl/DMAc systems are prefered. Scheme 2 presents 
the reaction sequence for the second embodiment of the invention. 
##STR2## 
TsCl and the carboxylic acid to be esterified to the cellulose backbone 
are first reacted together in pyridine. The tosylated reaction product is 
then reacted with the hydroxy moieties of the cellulose to produce an 
esterified cellulose derivative. Preferably the reaction vessel is warmed 
to 50.degree. C. maintained at a warm temperature for 24 hrs throughout 
the reaction sequence. The reaction sequence shown in Scheme 2 has been 
found to prevent the major competing reactions of polymer degradation, 
chlorination or tosylation. The reactions are completed in 24 hrs without 
any molecular weight losses. 
The reaction process used in this invention has the cellulose dissolved in 
DMAc/LiCl (homogenous conditions) and mixed with pyridine (3 moles per 
equivalent TsCl, before free carboxylic acid is added. At this stage, no 
TsCl is present in the reaction mixture. Only after free acid is added to 
the cellulose solution is TsCl added in equimolar amounts based on free 
acid, or less. Thus, the molar ratio of TsCl to AcOH is always 1.0 or 
less. This mixture is then heated to 40.degree.-50.degree. C. for 24 
hours. The important difference here is that TsCl will not react with 
cellulose in the presence of, at minimum, equimolar carboxylic acid since 
the carboxyl groups consume TsCl for the formation of a mixed anhydride. 
This mixed anhydride, in the presence of nucleophilic cellulose OH groups, 
will form the target ester product with TsOH being displaced as a leaving 
group. TsOH leaves from the mixed anhydride because it is the weaker 
nucleophile compared to the cellulose OH groups; it remains in solution 
and is buffered by the pyridine. The formation of the mixed anhydride 
occasions the formation of HCl which is also absorbed by pyridine. 
Pyridine must be present, otherwise, HCl and toluenesulphonic acid, TsOH, 
would cause cellulose depolymerization. Thus, a key feature of the present 
invention is that in the homogenous phase reaction conditions, TsCl does 
not react with cellulose in the presence of sufficient free carboxylic 
acid and pyridine. 
Several cellulose derivatives have been prepared using the DCC/PP and 
TsCl/Py reagent systems including propionates, buryrates, hexanoates, 
laurates, myristates, and stearates. It has been discovered that the 
DCC/PP reagent system is better for modification of the cellulose with 
smaller esters (.ltoreq.C.sub.6), while the TsCl/Py reagent system is 
better for modification of the cellulose with larger esters (e.g., 
C.sub.10-20). Excellent efficiency of the reactions is shown in Table 1 
which presents the results of a stoichiometric control study in the 
preparation of cellulose hexanoates with DCC/PP and the preparation of 
cellulose laurates with TsCl/Py. 
TABLE 1 
______________________________________ 
Cellulose Esterification 
Cellulose Anhydride Acid 
Derivative 
Reagents (eg/OH) (eg/OH) DS 
______________________________________ 
Hexanoate 
DCC/PP 0.125 -- 0.06 
0.25 -- 0.1 
0.5 -- 0.4 
0.5 -- 0.5 
1.0 -- 0.9 
-- 0.33 0.15 
-- 0.7 0.43 
-- 1.0 1.0 
-- 2.0 2.1 
-- 3.0 2.5 
Laurate TsCl/Py 0.75 -- 0.61 
1.0 -- 1.3 
1.3 -- 2.0 
1.5 -- 2.5 
2.0 -- 3.0 
______________________________________ 
Characterization studies, including proton nuclear magnetic resonance (NMR) 
and fourier transform infrared (FTIR) confirmed the uniform degree of 
substitution on the cellulose derivative. The monomeric repeat unit of 
cellulose, anhydroglucose, possesses three hydroxy groups that differ in 
reactivity in accordance with intra- and intermolecular interactions and 
their particular electronic environment. Using proton-NMR, it was 
determined for a cellulose hexanoate of DS 0.5, there is an equal 
reactivity of OH groups in positions C.sub.6 and C.sub.2, and that both of 
these are three times as reactive as the OH group in position C.sub.3. 
No significant degradation of cellulose molecular weights were detected 
using either reaction methods as evidenced by gel permeation 
chromatography. The molecular weights of several cellulose derivatives 
varied between a degree of polymerization (DP.sub.n) between 150 and 200 
regardless of the substituent type as shown in Table 2. 
TABLE 2 
______________________________________ 
Molecular weights of Selected Cellulose Derivatives 
Cellulose Derivative DS DP.sub.n 
______________________________________ 
Cellulose (Whatman CF-11) 
0 191 
Propionate 1.6 190 
Hexanoate 0.9 157 
2.1 206 
2.5 208 
Myristate 0.5 208 
Stearate 0.4 179 
______________________________________ 
The invention has particular application in making cellulose based 
materials used for chromatography, water purification and gas 
purification. In particular, the cellulose materials can have functional 
groups esterified to the cellulose backbone which will be useful for 
affinity separation and ion exchange purposes. 
Another application contemplated by this invention is the production of 
medical implants and drug delivery vehicles. In particular, by attaching 
antibodies, drugs, and other active compounds to the cellulose backbone 
through an ester linkage, the esterases present in the human or animal 
body will release the active substance from the cellulose through 
enzymatic action. 
A further application of the technology is to produce cellulose materials 
that have a lower melting point than the degradation temperature. By 
esterifying cellulose backbone, the melting point is lowered to produce a 
material with a plasticity that allows melt processing. Hence, the 
esterified cellulose could be used as a substitute for cotton and other 
materials.

EXAMPLE 1 
DCC (1 eq./acid anhydride or 1 eq./acid) is added to cellulose solution in 
DMAc/LiCl followed by the addition of an acid anhydride or a free 
carboxylic acid. Good results have been achieved with Whatmann CF-11 
cellulose having a degree of polymerization (DP) equal to 190, and using 
solutions of cellulose in 9% lithium chloride (LiCl)/N,N-dimethyl 
acetamide (DMAc) as described in McCormick and Dawsey, Macromolecules, 
23:3606-10 (1990) which is herein incorporated by reference). A catalytic 
amount of 4-pyrrolidinopyridine (PP) is added to the solution. For 
example, rather than using base catalyst in quantities equimolar to the 
anhydride, the PP can be used in amounts less than 0.1 eq/OH. Good results 
have been achieved with PP provided in amounts of 0.01 eq/OH. The solution 
is stirred for 48 hours at room temperature under an inert atmosphere. The 
acylation product is recovered by precipitation from warm (60.degree. C.) 
50% aqueous methanol. The precipitate is washed thoroughly with water and 
then with methanol, and then soxhlet extracted with methanol for 24 hrs. 
Further soxhlet extraction with diethyl ether for 24 hrs may also be 
employed. 
EXAMPLE 2 
A 6% solution of cellulose (242 g, 1.5 moles) in 9% LiCl/DMAc (8 L) was 
prepared in a stirred glass reactor. A DMAc (310 mL) solution of DCC (455 
g, 1.86 moles/Anhydoglucose (AHG) unit) and solid PP (69 g) was added to 
the stirred solution at room temperature. Hexanoic anhydride (520 mL, 2.2 
eq./AHG unit) was added slowly and the resulting clear solution was 
stirred an additional 48 hrs. The product was recovered by precipitation 
into 50% methanol/H.sub.2 O (15 L). The residue was purified as in Example 
1 to produce 249 g of material with a degree of substitution of 0.89. 
EXAMPLE 3 
50 ml of cellulose solution (4% in 9% LiCl/DMAc) is diluted with 50 mL dry 
DMAc under nitrogen atmosphere. Pyridine (6 eq./OH) was added and then a 
solution of the carboxylic acid (C.sub.10-20) in DMAc (30-160 mL depending 
on the solubility of the acid) is added slowly. The resulting solution is 
stirred for 15 min and then a DMAc (30-50 mL) solution of tosyl chloride 
(1 ea./acid) is added to solution. The reaction occurs by raising the 
temperature to 60.degree. C. and maintaining the temperature for 24 hr. 
The products are recovered by precipitation into 50% isopropanol/H.sub.2 
O. The precipitates are further purified by soxhlet extractions with 
methanol and/or hexane, and ditheyl ether. 
EXAMPLE 4 
Solvent exchanged cellulose (100 g) is dissolved in 9% LiCl/DMAc to make a 
1.5% solution. Pyridine (449 mL, 3 eq./OH) is added to the solution, 
followed by the addition of a DMAc (1000 mL) solution of lauric acid (1 
eq./OH, 370 g). The cellulose solution is kept agitated using a stirrer 
assembly in a 12 L glass reactor (available from ACE Glass) under a 
nitrogen atmospher. A solution of tosyl chloride (327 g) in DMAc (1000 mL) 
is added slowly and then the reaction mixture is warmed to 50.degree. C. 
and maintained at that temperature for 24 hrs. The reaction is stopped by 
pouring the solution into 20 L of 50% isopropanol/H.sub.2 O. The 
precipitate is purified as described above. The reaction has yielded 150 g 
of product with a degree of substitution of 1.3. 
While the invention has been described in terms of its preferred 
embodiments, those skilled in the art will recognize that the invention 
can be practiced with modification within the spirit and scope of the 
appended claims.