REVIEW

pubs.acs.org/Biomac

Regioselective Esterification and Etherification of Cellulose: A Review

S. Carter Fox, Bin Li, Daiqiang Xu, and Kevin J. Edgar*
Macromolecules and Interfaces Institute, Virginia Tech, Blacksburg, Virginia 24061, United States

ABSTRACT: Deep understanding of the structure
property

relationships of polysaccharide derivatives depends on the
ability to control the position of the substituents around the
monosaccharide ring and along the chain. Equally important is
the ability to analyze position of substitution. Historically, both
synthetic control and analysis of regiochemistry have been very
dicult for cellulose derivatives, as for most other polysacchar-
ide derivatives. With the advent of cellulose solvents that are
suitable for chemical transformations, it has become possible to carry out cellulose derivatization under conditions suciently mild
to permit increasingly complete regiochemical control, particularly with regard to the position of the substituents around the
anhydroglucose ring. In addition, new techniques for forming cellulose and its derivatives from monomers, either by enzyme-
catalyzed processes or chemical polymerization, permit us to address new frontiers in regiochemical control. We review these
exciting developments in regiocontrolled synthesis of cellulose derivatives and their implications for in-depth structure
property
studies.

1. INTRODUCTION evidence of the monosaccharide content of commercial cellulose

Polysaccharides are among the most abundant natural poly-
mers on earth, possess remarkable structural diversity, and per-
form an incredible variety of biological functions. Our
understanding of this functional and structural diversity is still
growing rapidly. Cellulose is one of the simplest polysaccharides,
being a homopolymer (f4--D-Glcp-1f) of a single mono-
saccharide, with no branching or substituents in nature (Figure 1).
Cellulose is often cited (without supporting evidence) as the most
abundant polymer on earth; certainly as a major constituent of all
plant matter and of many other organisms (e.g., bacteria,1
tunicates2), it is vastly abundant. Because of this abundance, its
relatively low cost, and the fact that its properties and processa-
bility can be dramatically modied through substitution reactions
of its hydroxyl groups, cellulose is easily the most commercially
signicant polysaccharide, with billions of kilograms of its deriva-
tives sold each year for a wide range of applications.3
To develop new applications or to better predict the perfor-
mance of cellulose derivatives in current applications,4 it is critical
to understand structure property relationships in detail. This can
be dicult. The most important cellulose derivatives from an
applications perspective are esters5 and ethers.6 The simplest
cellulose ethers and esters contain only one substituent type;
cellulose acetate (CA) and methylcellulose (MC) are important
examples. For cellulose derivatives with one substituent type like
CA and MC, there are eight possible monosaccharides present in
the polymer. In the rather common case in which two substituent
types are present, such as cellulose acetate propionate (CAP) or
cellulose acetate butyrate (CAB), there are 27 possible mono-
saccharides (see examples of MC and CAP, Table 1). Standard
commercial methods for preparation of these cellulose deriva-
tives begin as heterogeneous reactions, involving in the case of
esters a subsequent back-hydrolysis reaction.7 There is good
ethers like methylcellulose and ethylcellulose because the sub-
stituents are stable under acid hydrolysis conditions. Therefore, it
has been possible to hydrolyze these cellulose ethers to mono-
saccharides, reduce the monosaccharides to alditols, and analyze
the alditol mixture by chromatography versus authentic standards.8
The analysis of monosaccharide content of cellulose esters is far
more dicult because esters are not stable under the conditions
needed to hydrolyze the polysaccharide to monosaccharides.
Reports of reductive cleavage processes for the conversion of
cellulose esters into monosaccharides without loss of the ester
groups were intriguing but have not proven to be useful in
application.9 In the simplest cases, such as cellulose acetate, it is
possible to quantify the bulk monosaccharide content by NMR
spectroscopy.10,11 These studies have indicated that commercial
cellulose acetate is indeed rather randomly substituted, as was
predicted. It is clear that control and analysis of regiochemistry of
substitution, even in such common and relatively simple cellulose
derivatives, is complex and challenging indeed.
Issues of monosaccharide sequence control in polysaccharide
synthesis are even more dicult. Standard methods of poly-
saccharide derivative synthesis, that is, by modifying a natural
polysaccharide, typically by reaction with electrophiles, oer no
possible expectation of monosaccharide sequence control. We
have to talk about expectations because most often we really do
not know the sequence of synthetic polysaccharide derivatives. In
the case of cellulose ethers, we can compare the individual
substituted anhydroglucose unit (AGU) quantities, determined
as alditols as described above, with those expected by modeling of
Received: February 24, 2011
Revised: April 11, 2011
Published: April 27, 2011

r 2011 American Chemical Society 1956 dx.doi.org/10.1021/bm200260d | Biomacromolecules 2011, 12, 19561972
Biomacromolecules REVIEW

Figure 1. Anhydroglucose unit (AHG) and numbering.

Figure 2. Preparation of 6-O-trityl cellulose.
Table 1. Cellulose Derivative Monomer Content: Examples
and regiospecic techniques developed for synthesis of cellulose
CA, CAPa
ethers and esters. It pays particular attention to developments
CA monomer symbols CAP monomer symbols since the excellent review by Klemm and coauthors in 1997.26
(Note also the informative mini-review by Heinze and coauthors
1 UN 1 UN 10 36A 19 6A3P
in 2006,27 which largely focused on their own work.) By denition,
2 2M 2 2A 11 23P 20 2A36P every cellulose derivative synthesis is regioselective to some extent,
3 3M 3 3A 12 26P 21 3A26P so we imposed an arbitrary limit of 90% selectivity for one
4 6M 4 6A 13 36P 22 6A23P regioisomer for inclusion in this review to keep the scope manage-
5 23M 5 2P 14 2A3P 23 36A2P able and the review useful. We include as well for their instructional
6 26M 6 3P 15 2A6P 24 26A3P value a few examples that do not meet this criterion. We have
7 36M 7 6P 16 3A6P 25 23A6P organized the review by the general types of methodology that
8 236M 8 23A 17 3A2P 26 236A have been used by investigators, and we include a nal perspective
9 26A 18 6A2P 27 236P that attempts to point out as yet unconquered frontiers.
a
Legend: M = Methyl, A = Acetate, P = Propionate, UN = unsubstituted.
For example, 2A6P means cellulose 2-acetate-6-propionate.
2. REACTION OF CELLULOSE WITH BULKY REAGENTS
The advent of cellulose solvents that are useful for derivatiza-
ideal distributions, like random or copolymeric sequences, and tion reactions, beginning with N,N-dimethylacetamide (DMAc)/
evaluate the extent to which the measured quantities match those LiCl in the 1980s,20,28,29 created the possibility of far more selective
expected from a particular model.12,13 However, detailed analysis of reactions of cellulose. Researchers have explored in detail the
monosaccharide sequence for high polysaccharide polymers is simply possibility of taking advantage of inherent reactivity dierences
not possible using currently available analytical methods. Only by between cellulose hydroxyls. Key reactivity dierences include
using synthetic techniques that involve the laborious building of the greater acidity of the 2-OH and the fact that the 6-OH is a
polysaccharide sequences, adding monosaccharides to a growing primary alcohol and thus signicantly less sterically hindered
chain one-by-one using glycosylation reactions, with the accompany- than the other hydroxyl groups. To date, researchers have
ing protection and deprotection steps, or by using isolated poly- focused most heavily on exploiting the higher reactivity of the
saccharide biosynthetic enzymes (in the cases where they will accept 6-OH; the following sections describe the results of their eorts.
monosaccharides appropriately modied to achieve the desired 2.1. Etherification. Etherification has proven to be a far more
substitution pattern, or where biosynthetic enzymes are available effective and general strategy for regioselective substitution than
that catalyze appending the desired substituents to the polysacchar- has esterification, due to the closer proximity of the bulky group
ide chain after it is synthesized14) can we hope to approach specic, to the carbon atom to be substituted in ethers. The following
biologically important, complex polysaccharide sequences such as sections describe the useful tritylation and silylation chemistries.
those that control the specic protein binding of the glycosamino- 2.1.1. Tritylation. The reaction of cellulose with triphenyl-
glycans heparin15,16 and chondroitin sulfate.17
19 chloromethane, hereafter referred to as trityl chloride, is one of
The advent of modern cellulose solvents20
22 that permit the oldest and most effective protecting group strategies for
synthesis of cellulose derivatives in solution23
25 has provided an synthesizing regioselectively modified cellulose derivatives. It has
opportunity for polysaccharide chemists to attempt regioselec- long been known that because of steric demands, trityl chloride
tive or even regiospecic syntheses of cellulose derivatives. (For reacts preferentially with the primary hydroxyl group at the O-6
the purpose of this review, we consider reactions to be regiose- position on the cellulose backbone rather than with either of the
lective if they provide >90% selectivity for one regioisomer and to secondary hydroxyl groups at the O-2/3 positions30
33 (Figure 2).
be regiospecic if they provide >99% selectivity.) Cellulose Furthermore, the trityl group can be quantitatively removed by
hydroxyls are much more reactive in solution because dissolution acid hydrolysis after derivatization of the secondary hydroxyl
breaks up the extensive cellulose H-bonding network, meaning groups with acid stable functionalities (alkyl ethers, for example)
that reactions can be carried out under milder conditions to regenerate the free hydroxyl group at C-6. This permits
(temperature, catalysts) that permit higher selectivity. Clever synthesis of a variety of different cellulose derivatives where
cellulose chemists have taken advantage of this fact and of the hydroxyl O-2/3 substituents differ from those at O-6.
developing techniques for synthesis of polysaccharides from Tritylation of cellulose with high levels of crystallinity, such as
monosaccharides to prepare regioselectively substituted cellu- cotton cellulose or most dissolving pulps, fails to produce a
lose derivatives and make the rst advances toward full struc- readily soluble material. Thus, to obtain a soluble product, the
ture
property understanding. This review covers regioselective cellulose must be activated to disrupt its crystallinity prior to
1957 dx.doi.org/10.1021/bm200260d |Biomacromolecules 2011, 12, 19561972
Biomacromolecules
tritylation. A historically common method to activate cellulose
for tritylation is the complete deacetylation of cellulose acetate in
aqueous ammonium hydroxide.31 Mercerized cellulose is also
sometimes used.34,35 With these methods, the activated cellulose
is then transferred to dry pyridine to form a slurry that becomes
homogeneous as the reaction progresses. More recently, how-
ever, the cellulose solvent DMAc/LiCl has been used as the
reaction medium because it is a less time- and labor-intensive
procedure.36,37 Tritylation has also been performed homoge-
neously on cellulose dissolved in the ionic liquids 1-butyl-3-
methylimidazolium chloride ([Bmim]Cl)38 and 1-allyl-3-methy-
limidazolium chloride ([Amim]Cl).39 The degree of substitution
(DS) of the trityl group can range from 0.93 to 1.07, depending
on the reaction temperature, duration, and the molar ratios of the
reactants. Approximately 90% of the substituents are found at the
O-6 position, whereas a small proportion of the secondary
hydroxyls at O-2 and O-3 is also tritylated.31,40
Heinze et al.41 and Gomez et al.42 reported that the use of
methoxy-substituted trityl chlorides signicantly increased the
rate of hydroxyl substitution on cellulose. A DS of 0.96 could be
achieved within 4 h at 70 C using p-monomethoxytriphenyl-
methyl chloride as the tritylation reagent, whereas use of the
unsubstituted trityl chloride required over 24 h to achieve the
same DS under similar reaction conditions. The O-6 selectivity of
the p-monomethoxytriphenylmethyl chloride was found to be
similar to that of the unsubstituted trityl chloride. The observed
rate acceleration was attributed to stabilization of the triaryl-
methyl cation reactive intermediate by the electron-donating
methoxy group. Additionally, acid-catalyzed removal of meth-
oxy-substituted trityl groups requires only 5.5 h, whereas
complete removal of unsubstituted trityl groups requires 100 h.
This is particularly benecial because exposure of the cellulose to
acid during detritylation can result in reduction of the molecular
weight of the polymer.31 In fact, Kern et al.34 reported that the
molecular weight of 2,3-di-O-methyl cellulose ethers synthesized
using microcrystalline cellulose as a starting material had not
signicantly decreased after acid hydrolysis of monomethoxy
trityl groups from O-6. Additionally, the organic solubility of
cellulose derivatized with alkoxy-substituted trityl groups can be
modied by increasing the alkoxy chain length.43
Tritylation chemistry has made possible many structure/
property relationship studies on cellulose derivatives substituted
at the O-2 and O-3 positions.44 Among the rst of these
compounds synthesized and characterized were 2,3-di-O-methyl-
and 2,3-di-O-ethyl-cellulose.40 Kern et al.34 studied the behavior
of 2,3-di-O-methyl-cellulose in aqueous solutions. They reported
that subtle variations in the DS and distribution of the methyl
substituents can have dramatic eects on the phase separation
behavior of the cellulose derivative. Highly methylated cellulose
samples (DSmeth > 2.0) with a signicant number of anhydroglucose
units (AGUs) containing three methyl substituents would phase
separate upon heating of the aqueous solution. This observation
lends support to the hypothesis that phase separation in methyl-
cellulose solutions is due to the aggregation of these trisubstituted
AGUs. However, phase separation from aqueous solution at
elevated temperatures was also observed in under-methylated
cellulose samples (DSmeth < 2.0) containing many monomethylated
AGUs but no trimethylated AGUs, suggesting that monomethy-
lated AGUs are also prone to aggregation. The phase separation
occurred at a higher temperature in the under-methylated
samples compared with the overmethylated samples. No phase
separation was observed in the pure 2,3-di-O-methyl-cellulose
1958
REVIEW
(DSmeth = 2.0) aqueous solutions, and it was concluded that
the dimethylated AGUs do not aggregate upon heating.
Petzold-Welke et al.45 found that the water solubility of cellulose
methylated at the O-2 and O-3 positions with DS 0.90 was
dependent on the frequency of occurrence of disubstituted
AGUs along the cellulose backbone. Samples containing more
disubstituted AGUs were water-soluble, whereas samples contain-
ing more monosubstituted AGUs tended to be water-insoluble.
Synthesis of 6-O-alkyl cellulose ethers using tritylation chem-
istry is somewhat more problematic than the synthesis of 2,3-di-
O-alkyl-celluloses. After the 6-O-trityl cellulose has been made,
appropriate protecting groups must be chosen for the O-2 and
O-3 positions. These protecting groups must be stable to acid
hydrolysis during the detritylation step, and then they must be
stable to alkaline conditions during the alkylation of O-6. Finally,
they must still be easily removed after the alkylation step.
Kondo46 provided a solution to this problem by choosing allyl
groups as the protecting group for O-2 and O-3. After detrityla-
tion, 2,3-O-allyl-cellulose was isomerized to 2,3-di-O-(1-propenyl)-
cellulose using potassium t-butoxide. Then, after alkylation at
O-6, the 1-propenyl groups were removed by acid hydrolysis. It
was reported that this method provided better results than
protecting O-2 and O-3 as benzyl ethers.
Inter- and intramolecular hydrogen bonding in regioselec-
tively methylated cellulose samples was studied by FTIR and
solid-state 13C NMR.47 The analyses indicated that intermole-
cular hydrogen bonding was largely absent in 6-O-methylcellu-
lose, although it was prominent in 2,3-di-O-methylcelluloses.
This suggests that a free primary hydroxyl group is necessary for
strong intermolecular hydrogen bonding in methylcelluloses.
These studies were extended in the investigations of hydrogen
bonding within blends of regioselectively methylated cellulose
with poly(ethylene oxide) or poly(vinyl alcohol)47,48 as well as
the analysis of hydrogen bonding in aqueous solutions of
regioselectively methylated cellulose.49 It was found that the
specic interactions of the methylcellulose with the synthetic
polymers are highly dependent on the sites of substitution on the
cellulose. The 6-O-methylcellulose had high solubility in a variety
of organic solvents because of the lack of hydrogen bonding
between cellulose chains, whereas 2,3-di-O-methylcellulose was
soluble only in polar aprotic solvents.
Regioselectively synthesized analogues of other important
commercial cellulose ethers have also been produced using
tritylation chemistry. Hydroxyethyl and hydroxypropyl deriva-
tives of trityl cellulose were heterogeneously synthesized in a
mixture of isopropanol and water.50 With the aid of ionic and
nonionic surfactants in the reaction mixture, a molar degree of
substitution of 2.0 was obtained for both the hydroxyethyl and
hydroxypropyl derivatives. NMR analysis of the products showed
that the ethylene oxide and propylene oxide reagents reacted
preferentially with the free secondary hydroxyl groups on the
cellulose backbone rather than with any free hydroxyl groups on
the hydroxyalkyl side chains. After detritylation, the 2,3-O-
hydroxylethyl- and 2,3-O-hydroxypropyl-cellulose were soluble
in water at a molar degree of substitution of only 0.3 and 0.8,
respectively. For comparison, conventionally synthesized hydro-
xypropyl cellulose derivatives require a molar degree of substitu-
tion of 4.0 for water solubility. Regioselectively substituted 2,3-O-
carboxymethylcellulose was synthesized41,51 by reacting trityl
cellulose with sodium monochloroacetate, followed by detrityla-
tion with hydrogen chloride in methanol. The highest carboxymethyl
DS obtained was 1.91. It was reported that a DS of at least 0.6 was
dx.doi.org/10.1021/bm200260d |Biomacromolecules 2011, 12, 19561972
Biomacromolecules
required for the polymer to be water-soluble, compared with DS
0.4 for conventionally synthesized carboxymethylcellulose. How-
ever, Liu et al.52 reported that using the same synthetic proce-
dures as the previous papers DS of only 0.3 was required for water
solubility.
Tritylation chemistry has also facilitated the study of structure

property relationships of regioselectively synthesized cel-
lulose esters. To synthesize these compounds, trityl cellulose
was esteried at the secondary hydroxyl groups by reaction with
an appropriate carboxylic acid anhydride. The trityl protecting
group was then removed by hydrogen bromide in a mixture of
acetic acid and chloroform, and the regenerated primary hydro-
xyl group was esteried with a dierent carboxylic acid anhydride
to produce the desired cellulose-2,3-O-A-6-O-B type triester. 1H
NMR shifts for cellulose esters were assigned using 6-O-acetyl-
2,3-di-O-propanoyl-cellulose and 6-O-propanoyl-2,3-di-O-acet-
yl-cellulose synthesized via trityl cellulose intermediates.53 Single
crystals of cellulose 2,3-di-O-acetyl-6-O-propionyl cellulose, 6-O-
acetyl-2,3-di-O-propionyl cellulose, 2,3-di-O-acetyl-6-O-butyryl
cellulose, and 6-O-acetyl-2,3-di-O-butyryl cellulose were pre-
pared from solutions in dibenzyl ether and n-tetradecane.54
The crystal structures of both 6-O-acetyl-2,3-di-O-propionyl-
cellulose55 and 6-O-propionyl-2,3-di-O-acetyl-cellulose56 were
determined by X-ray and electron diraction analyses, and the
samples were further examined by atomic force microscopy57
and DSC.58 Regioselectively acetylated trityl cellulose was also
used to investigate the solution behavior of cellulose esters in
polar solvents.59,60 It was observed that the position of the ester
substituents has a large inuence on the cellulose chain con-
formations and associations in solution. Kasuya et al.61 investi-
gated 6-O-acetyl-2,3-di-O-benzoyl-cellulose and 2,3-di-O-acetyl-
6-O-benzoyl-cellulose as stationary phases for chiral separations
and found that the location of the specic substituents signi-
cantly aected chiral discrimination.
Cellulose derivatives with unconventional side groups synthe-
sized via tritylation chemistry have been studied to determine
their physical properties for use in a few advanced applications.
Several papers have described investigations of the liquid crystal-
line properties of regioselectively substituted cellulose derivatives
in organic solutions. Harkness and Gray62,63 found that 6-O-
trityl-2,3-di-O-ethyl-cellulose, 6-O-trityl-2,3-di-O-benzyl-cellulose,
and 6-O-R-(l-naphthylmethyl)-2,3-di-O-pentyl-cellulose formed
chiral nematic phases in several dierent organic solvents and
that the optical properties could be controlled by varying the
structure and DS of the hydroxyl substituents. Cellulose deriva-
tives with carbanilate64,65 and poly(ethylene oxide) substituents66
synthesized from trityl cellulose have also been studied for
their chiroptical properties. 6-O- and 2,3-di-O-octadecyl-cellu-
lose were successfully synthesized, cast into Langmuir
Blodgett
lms, and then studied by atomic force microscopy and X-ray
diractometry.67 Cellulose modied with carbazole side groups
was investigated for potential use in organic light emitting diode
applications, and it was discovered that placement of the
carbazole groups at the C-2/3 positions versus the C-6 position
impacted electronic properties of the polymer.68 The thermal
properties of poly(ethylene glycol) grafted cellulose were studied
for their potential usefulness in phase change materials for energy
storage.35 Kondo et al.69 synthesized cellulose-2,3-O-dicinna-
mate, cellulose-6-O-monoacetate-2,3-O-dicinnamate, and cellu-
lose 2,3-O-diacetate-6-O-monocinnamate using trityl protected
cellulose, introducing the cinnamate group to impart photosen-
sitive and electroconductive properties to the polymer.
1959
REVIEW
2.1.2. Regioselective Silylation. Silylation with thexyldimethyl-
chlorosilane ((CH3)2CHC(CH3)2Si(CH3)2Cl; TDMS-Cl) has
proven to be another effective protecting group strategy for
regioselective synthesis of cellulose derivatives, and one that is in
some respects superior to tritylation because the specific sites
that are protected can be controlled by the dispersity of the
cellulose in the reaction mixture. In addition, the regioselectivity
of this reaction can be higher than that achieved by tritylation,
and it is a route not only to 6-O-protected derivatives but also to
2,6-O-diprotected derivatives. Under heterogeneous conditions
with swollen cellulose, TDMS-Cl has been shown to react
exclusively at the C-6 position forming TDMS ethers. Homo-
geneous solution reactions between cellulose and TDMS-Cl, on
the other hand, are known to protect both C-2 and C-6 hydroxyl
groups (Figure 3). The first reported thexyldimethylsilation of
cellulose was performed in dimethylformamide saturated with
ammonia at
15 C, resulting in 6-O-thexyldimethylsilylcellu-
lose with a DS of 0.99.70 The selectivity of the reaction for the C-6
hydroxyl group was shown by NMR analysis of the permethy-
lated samples. Subsequent heterogeneous reactions of cellulose
with TDMS-Cl were run at
25 C in ammonia-saturated
N-methylpyrrolidone but resulted in products with a lower
DS.71
73 Homogeneous thexyldimethylsilation reactions were
first run on cellulose dissolved in DMAc/LiCl with pyridine,
resulting in products with a DS as high as 1.90.72 The DS and
distribution of the TDMS ethers along the cellulose backbone for
products produced under both homogeneous and heteroge-
neous reactions were confirmed by HPLC analysis of samples
that were permethylated and then acid hydrolyzed. Imidazole
was subsequently found to be a more effective base than pyridine
for homogeneous derivatization of cellulose with TDMS-Cl,
allowing the synthesis of 2,6-di-O-thexyldimethylsilyl cellulose
with a DS of 2.0,74 with near-perfect 2,6-regiospecificity.
Silyl protecting groups can be completely removed by treat-
ment with tetrabutylammonium uoride, opening up a relatively
simple pathway to the synthesis of cellulose ethers substituted
exclusively at the C-3 position. Table 2 lists all 3-O-substituted
cellulose ethers whose syntheses have been reported in the
literature to date as well as their reported solubility in various
solvents. A series of 3-O-alkyl cellulose ethers (methyl, ethyl,
n-propyl, n-butyl, n-pentyl, isopentyl, dodecyl) has been synthe-
sized by treatment of 2,6-di-O-thexyldimethylsilyl cellulose with
the appropriate alkyl iodide or alkyl bromide in the presence of
strong base, followed by deprotection of the two and six hydroxyl
groups.74
78 One interesting nding within this series was that
3-O-ethyl and 3-O-n-propyl cellulose were both soluble in water,
though they would phase separate at temperatures above 58.5
and 15 C, respectively. All other 3-O-alkyl ethers were not
soluble in water. The hydrogen bonding structure in 3-O-methyl
cellulose was studied by Kondo et al.79 3-O-Allyl cellulose was
synthesized by the reaction of 2,6-di-O-thexyldimethylsilyl cellu-
lose with allyl chloride followed by desilylation.74 This reaction
was later used to produce 3-O-hydroxypropyl cellulose with a
molar substitution of 1.0 by hydroboration of the allyl double
bond using 9-borabicyclo[3.3.1]nonane and subsequent alkaline
oxidation with hydrogen peroxide.80 3-O-Hydroxyethyl cellulose
with a molar degree of substitution of 1.0 has also been
synthesized via 2,6-di-O-thexyldimethylsilyl cellulose.81 Both
3-O-hydroxyethyl cellulose and 3-O-hydroxypropyl cellulose
were found to be water-soluble. As a gateway to producing
cellulose regioselectively substituted with dendritic substituents,
3-O-propargyl cellulose was synthesized.82 The terminal triple
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Figure 3. Cellulose heterogeneous and homogeneous thexyldimethylsilation reaction products.

Table 2. Solubility of 3-O-Substituted Cellulose Ethers with The 3-O-allyl cellulose was methylated at the two and six
Free 2- and 6-Hydroxyl Groupsa hydroxyl groups, and then the allyl group was removed by
reaction with palladium chloride. The resulting 2,6-di-O-methyl
3-O-substituentb soluble in ref
cellulose was insoluble in water and common organic solvents,
methyl insoluble in water and common organic solvents 74 contrasting with the isomeric 2,3-di-O-methyl cellulose prepared
ethyl water below 58.5 C, DMSO, DMAc, DMF 76 via tritylation that is soluble in water.34
n-propyl water below 15 C, DMF, DMSO 77 Silylation of cellulose with tert-butyldimethylchlorosilane has
n-butylc insoluble in water 75
also been studied with respect to its regioselectivity. However, it
has been shown to be somewhat less selective for the substitution
n-pentyl MeOH, EtOH, THF, DMSO, DMF, 78
of the 2- and 6-hydroxyl groups than TDMS-Cl, as some 3,6-di-O
NMP, DMAc
functionalized AGUs were also detected after derivatization.
isopentyl MeOH, EtOH, dioxane, 78 Additionally, at high reaction temperatures, some trifunctiona-
THF, DMSO, DMF, NMP, DMAc lized AGUs were formed.86
2.2. Esterification. For the preparation of regioselectively
allyl DMSO 74 substituted cellulose esters, the simplest route would of course be
hydroxyethyl water 81 direct solution esterification of cellulose. As befits the commer-
hydroxypropyl water, DMSO, DMAc, DMF 80 cial importance of cellulose esters, many methods have been
2-methoxyethyl water, DMSO, DMAc, NMP 76 developed that attempt to improve regioselectivity versus con-
propargyl DMSO 82 ventional heterogeneous esterification methods. The most im-
ethylene glycold insoluble in common organic solvents 83 portant approaches and their successes and limitations are
dodecyl THF 78
reported here.
a 2.2.1. Direct Reaction with Activated Acyl Moieties. Since the
DMSO = dimethyl sulfoxide; DMAc = N,N-dimethylacetamide;
DMF = N,N-dimethylformamide; NMP = N-methylpyrrolidone;
advent of cellulose solvents suited for chemical modification
THF = tetrahydrofuran; MeOH = methanol; EtOH = ethanol. b DS reactions of cellulose approximately 30 years ago, one of the first
1.0, except when otherwise noted. c DS = 0.8. d DS = 0.5. explorations of each solvent system has been its suitability and
selectivity for cellulose esterification reactions, especially for the
reaction of cellulose with activated acyl moieties (carboxylic acid
bond of the propargyl group could then undergo a copper- chlorides, acid anhydrides, and others) to make esters of cellulose
catalyzed Huisgen reaction (click chemistry) with azido-pro- with organic acids. These studies can be summarized by saying
pyl-polyamidoamine (PAMAM) dendrons to produce 3-O-(4- that they have for the most part either indicated modest posi-
methyl-1-N-propyl-PAMAM-[1,2,3-triazole]) cellulose (Figure 4). tional selectivity or have not addressed the issue of positional
Cellulose derivatives with ethylene glycol chains of varying selectivity at all. It is clear that reactions of cellulose in commonly
lengths selectively attached at the 3-hydroxyl group were synthe- used cellulose reaction solvents with the relatively nonbulky
sized with a DS of 0.5.83 These derivatives were of interest to acylating reagents that are of greatest interest (e.g., acid chlorides
Kadla84 for producing cellulosic materials with a honeycomb-like or anhydrides of acetic, propionic, butyric, and hexanoic acids)
structure. give mixtures of acylated cellulose regioisomers. The limitations
The rst synthesis of 2,6-di-O-methyl cellulose from natural of relying on the steric hindrance of the esterification reagents to
cellulose was achieved using 3-O-allyl cellulose as an intermediate.85 drive regioselectivity were explored in a recent paper from the
1960 dx.doi.org/10.1021/bm200260d |Biomacromolecules 2011, 12, 19561972
Biomacromolecules
Figure 4. Synthesis of dendritic cellulose derivatives from 3-O-propargyl cellulose.
authors laboratory.87 Direct esterification of cellulose with
several very sterically demanding acylating reagents was ex-
plored; pivaloyl chloride, adamantoyl chloride, and 2,4,6-tri-
methylbenzoyl chloride, employing all three important classes
of cellulose reaction solvents (DMAc/LiCl, DMSO/TBAF,
[Amim]Cl) at the lowest practical reaction temperatures. Con-
ditions for synthesis of cellulose monoesters were identified in
many cases, but product analysis indicated that whereas O-6
substitution was consistently preferred, no conditions could be
identified in which it was exclusive; O-2/3 substitution was
always observed at significant levels even below DS 1.0. It should
be noted that in 2009, Zhang and coworkers reported synthesis
of cellulose benzoate with unusually high O-6 regioselectivity.88
Microcrystalline cellulose (MCC) was treated with benzoyl
chloride in an ionic liquid ([Amim]Cl) at 80 C for 2 h without
any base or catalyst to give a product with DS ca. 1. The 13C
NMR spectrum was interpreted to indicate reaction exclusively
with the primary 6-OH group, within the 13C detection limits. It
is difficult to rationalize such high selectivity with the lower
selectivity results obtained in the same solvent using a bulkier,
substituted benzoyl chloride (mesitoyl) in the work cited above.87
We believe that regioselective substitution strategies that rely only
on acylation with bulky activated carboxylic acid derivatives are
unlikely to be successful for most common, practical ester types.
(Perhaps only a very large dendritic acyl moiety, for example, could
afford more or even complete O-6 selectivity.)
2.2.2. Cellulose Formates. Researchers have explored the
synthesis of easily hydrolyzed cellulose esters, ideally under mild
conditions that might permit regioselective substitution, to sup-
port a strategy of protection of one hydroxyl (typically O-6),
derivatization of the other hydroxyls (typically O-2 and O-3), and
selective removal of the labile ester group. Cellulose formate (CF)
has some attractive properties for this role. Reaction of cellulose
with formic acid to prepare CFs has been known for some
time.89,90 It has also been shown that the formate groups are quite
labile; for example, they are easily removed in boiling water. (A DS
2.4 CF was completely deformylated within 10 h in boiling water.)91
With regard to formylation regioselectivity, Fujimoto and coworkers
1961
REVIEW
reported that uncatalyzed formylation of regenerated cellulose
and H2SO4-catalyzed formylation of crystalline cellulose af-
forded CF of DS 2.91 They examined these products by 13C
NMR and concluded that the O-6 positions were fully substi-
tuted and that the formylation preference was O6 > O2 > O3.36
More recently, formylation under relatively mild conditions has
been investigated by Schnabelrauch and coworkers, for example,
by reaction with formic acid at room temperature with phos-
phoric acid catalysis.92 The authors were able to obtain low DS
CF products with DMSO solubility, for example, with DS 1.0
after 10 h; previous workers had found poor solubility for low DS
CF products. The authors report that the regioselectivity of this
reaction is O-6 > O-2/3, as determined by 13C NMR analysis of
the CS products; in a DS 0.6 sample, they interpreted the 13C
NMR spectrum to indicate nearly no O-2 substitution because of
the absence of an upfield C-1 resonance due to the neighboring
substituent. It must be noted that 13C NMR is one of the few
available tools for determining the position of substitution in
cellulose esters but cannot be regarded as either quantitative or
definitive because of potential signal overlap, limited sensitivity,
and nuclear Overhauser effects.93 In 1996, Liebert et al. reported
cellulose formate with DS 2.2 and complete substitution of the
primary OH groups using a convenient method consisting of the
acylation of cellulose with mixtures of formic acid and phos-
phorus oxychloride within 4 h at room temperature.94 Reaction
of this CF with NaOH powder in DMSO, then with chloroacetic
acid, afforded carboxymethyl cellulose (CMC) with an unusual
substitution pattern, with much higher O-6 substitution than is
attained by conventional carboxymethylation of cellulose. Work
by Philipp and coworkers, however, highlighted a limitation of
the formate group as a protecting group for cellulose regioselec-
tive substitution.95,96 Sulfonation of cellulose formate of DS 2.5,
followed by hydrolysis of the formate groups, affords cellulose
sulfates of considerably higher DS than that of the DS(OH) in
the starting ester. Clearly, deformylation is occurring; formate is
not a stable protecting group under sulfonation conditions.
2.2.3. Cellulose Trifluoroacetates. Cellulose trifluoroacetate
(CTFA) is an interesting intermediate for the synthesis of
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selectively substituted cellulose ether and ester derivatives, in
part because the lability of the trifluoroacetate groups toward
mild alkaline hydrolysis makes them potentially useful protecting
groups. The use of trifluoroacetate groups as protecting groups
became more promising upon reports of regioselectivity in the
trifluoroacetylation. Liebert and coworkers reported97 that so
long as moisture is excluded and the trifluoroacetic anhydride
(TFAA) content is kept below 50%, acylation of cellulose with a
mixture of trifluoroacetic acid/trifluoroacetic anhydride is suc-
cessful, affording CTFA with DS 1.5. They found that at DS 1.5
trifluoroacetate (the maximum achievable without cosolvents),
complete substitution at O-6 was observed, in addition to partial
substitution at the secondary hydroxyls. It must be noted that this
conclusion was partially the result of 13C NMR spectral analysis
of the product, which was not quantitative; the published
spectrum also contains a number of unassigned resonances.
The researchers also attempted to quantify position of substitu-
tion by chemical degradative means. Mild methylation of
the CTFA (DS 1.5) with methyl triflate in trimethylphosphate,
deacylation with base, hydrolysis to monosaccharides, and
analysis of the monosaccharides by HPLC gave indications of
O-6 and O-2 trifluoroacetylation selectivity.13,98,99 CTFA can be
prepared under quite mild conditions, suitable for maximum
regioselectivity, for example, by dissolving cellulose in trifluor-
oacetic acid, affording CTFA with DS 1.21 to 1.34 after 25
days.100
102 The degree of O-6 selectivity is not entirely clear,
and the hydrolytic instability of the CTFAs probably contributes
to the difficulty in this determination.97 Other workers used the
DS 1.5 CTFA as a protected intermediate for the regioselective
synthesis of cellulose-3-O-sulfate,103 by sulfonation with SO3/
DMF, followed by alkaline saponification of the trifluoroacetates.
No detailed evidence was presented to indicate the degree of
regioselectivity obtained. Liebert and coworkers used CTFA as a
reaction intermediate for CMC, using alkylation in DMSO by
similar methods to those described in the same paper for CF.94
As observed with CF, unconventional CMC substitution pat-
terns were also observed using CTFA as starting material.
2.2.4. Tosylation. The synthesis of sulfonic acid esters of
cellulose, such as methanesulfonate and benzenesulfonate deri-
vatives, has long been used in synthetic cellulose chemistry, but
the reaction with p-toluenesulfonyl (tosyl) chloride to form tosyl
esters of cellulose has been the most frequently studied of the
group. Recently, tosylation has been widely used to synthesize
new cellulose derivatives substituted at the C-6 position.104
106
The benefit to this approach is that in addition to acting as a
protecting group, the tosyl moiety is also a good leaving group,
enabling the synthesis of a variety of 6-deoxy-cellulose derivatives
via nucleophilic displacement reactions. There are reports of
cellulose tosylation going back several decades32 in the literature,
but use of the reaction in synthetic cellulose chemistry increased
substantially after it was effectively demonstrated with a homo-
geneous solution of cellulose in DMAc/LiCl.107 A subsequent
investigation found that using triethylamine as an organic base in
the reaction rather than pyridine resulted in a higher DS for the
tosyl group and helped avoid side reactions (Cl
displacement of
tosylate) that formed chlorodeoxycellulose.108 Recently, homo-
geneous tosylation of cellulose was also demonstrated in the
ionic liquid [Amim]Cl.109
Rahn et al.110 published an in depth study of the homogeneous
tosylation of cellulose in DMAc/LiCl investigating how to
control the total DS(tosyl), the solubilities of cellulose tosylates
of varying DS, and the selectivity of the reaction for O-6.
1962
REVIEW
Figure 5. Partial DS of cellulose tosylate groups at C-6 (square
symbols) and at C-2/C-3 (round symbols) versus total DS tosylate.
(Reprinted with permission from ref 110. Copyright 1996 Wiley-VCH
Verlag GmbH & Co. KGaA.)
Cellulose tosylates with DS from 0.4 to 2.3 were synthesized
by increasing the equivalents of tosyl chloride added to the
reaction. Those with a DS of 0.9 or above were soluble in polar
aprotic solvents such as DMSO, DMAc, and DMF. Tosylates
with DS to 1.4 are also soluble in acetone, dioxane, and
tetrahydrofuran. Further increasing the DS(tosyl) above 1.8
expanded the solubility range to halogenated hydrocarbons like
chloroform and dichloromethane. Evaluation of the selectivity of
the tosylation reaction was performed by displacing the tosyl
groups at C-6 with iodide. The investigators calculated tosylation
at the secondary OH groups by assuming that the primary
tosylates were completely substituted by iodide and that no
secondary tosylates were displaced by iodide. They then sub-
tracted DS(I) in the products from DS(Ts) in the starting
cellulose tosylates and assumed that the dierence corresponded
to the DS of tosylates at O-2 and O-3. This analysis indicated that
tosylation occurred at C-6 almost exclusively on derivatives with
a low DS (0.46) but that increasing the DS resulted in substitu-
tion occurring also at the secondary hydroxyl groups of cellulose.
Tosylation of C-6 was nearly complete in derivatives with a DS of
1.4. The graph in Figure 5, from Rahn,110 shows the relation-
ship between the partial DS values (at O-6 and at O-2/3) and the
total DS. However, it must be noted that these investigators
found by 13C analysis of the iodotosylates that the displacement
of tosyl by iodide was not completely selective for C-6 either
because the product contained a small amount of iodide at C-2
and C-3 as well. Therefore, whereas substitution reactions of
tosyl cellulose occur primarily by an SN2 mechanism at C-6, they
can occur at C-2/3 under the right conditions; whether by SN2 or
SN1 mechanisms is unclear. Increased selectivity for tosylation at
O-6 was reported for reactions carried out in [Amim]Cl.109 The
regioselectivity analysis, performed by 13C NMR, indicated
that tosyl cellulose with DS up to 0.84 was substituted almost
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Figure 6. Synthesis of 6-aminocellulose via cellulose tosylate.
exclusively at O-6, although substitution at O-2 became evident
at higher DS. Therefore tosylation is not as selective for O-6 as
are the reactions with sterically demanding alkyl or silyl halides
that we have discussed, such as tritylation. Despite the lack of
complete regioselectivity of tosylation for O-6 in cellulose, its
frequent use in the synthesis of regioselectively derivatized
cellulose compounds over the past decade and a half warrants its
inclusion in this review.
The thermal stability of tosyl cellulose with DS from 0.4 to 2.3
was studied by Heinze et al.,111 and it was found that the
compounds began to degrade between 169 and 196 C. Tosyl
cellulose was also investigated by dielectric spectroscopy to
determine the inuence of DS on the polymer chain mobility.112
The free OH groups of tosyl celluloses were reacted with a variety
of aliphatic, aromatic, and unsaturated acid anhydrides as well as
with isocyanates to form new compounds with a wide range of
solubilities.113
The most widely studied applications for tosyl cellulose have
been in displacement reactions with nitrogen-containing nucleo-
philes. A series of publications have examined the displacement
of tosyl groups at the C-6 position of cellulose with aliphatic and
aromatic diamines for the purpose of creating lms capable of
enzyme immobilization for biosensor applications.114
119 Mais
et al.120 synthesized cellulose-graft-poly(N-acetylethylenimine)
from tosyl cellulose by reaction with 2-methyl-1,3-oxazoline.
Bieser et al. recently published121 a study on the ecacy of using
similar cellulose graft copolymers synthesized from tosyl cellu-
lose as antimicrobial coatings. Chirality has been introduced to
the C-6 position of cellulose by the substitution of tosyl groups
with single enantiomers of 1-phenylethylamine.122 Water-solu-
ble cationic cellulose derivatives were made by reacting tosyl
cellulose with dierent trialkylamines.123 A group in Aachen
developed an interesting synthetic approach to truly regiospeci-
cally substituted cellulose derivatives from tosyl cellulose
(Figure 6);124 they rst reacted cellulose that had been fully
tosylated at C-6 with sodium azide. The resulting azido group at
C-6 was then reduced with lithium aluminum hydride to a
primary amine, which in the process reductively removed any
tosyl esters at the C-2 and C-3 positions on cellulose to generate
free hydroxyl groups. The resulting 6-amino-6-deoxy-cellulose
was then used to make both 6-N-sulfonated and 6-N-carboxy-
methylated cellulose. These derivatives were tested for their
platelet adhesion properties for potential use as coatings for
1963
REVIEW
biomaterials.125 This methodology is useful for cases in which
the desired 6-substituents are stable to the conditions required to
reduce o the 2,3-tosylate groups and is a clever way to circumvent
the selectivity limitations of tosylation. Liebert et al.126 also
synthesized 6-azido-6-deoxy-cellulose from tosyl cellulose, but
instead of reducing it to an amine, the azido groups were used
as sites for Huisgen reactions. Using this chemistry, 1,4-disubsti-
tuted 1,2,3-triazoles can be used as linkers to the C-6 position for a
wide variety of functional groups. Other nitrogen nucleophiles that
have been reacted with tosyl cellulose include methylamine,127
butylamine,128 and pyridine.128 In 2008, the Heinze group reported
reaction of 6-O-tosyl cellulose with DS = 0.58 (and with high O-6
regioselectivity at that low DS(Ts)) with propargyl amine. This
aorded an alkyne precursor for click reactions that were employed
to create dendritic structures.129
2.2.5. Cellulose Esters via Silyl-Protected Cellulose. Silyl ethers
of cellulose have been exploited for the regioselective synthesis of
cellulose esters partially because of the ready organic solubility of
these silyl cellulose derivatives, sometimes even in nonpolar
organic solvents.130 Two strategies have been employed, both
starting with regioselectively silyl-protected cellulose ethers:
reaction of the free OH groups with an acylating reagent under
mild conditions in the presence of an organic base or re-
placement of the silyl groups with acyl groups by reaction with
acyl halides in the absence of base, often at higher temperatures
(Figure 7).
Most of the published work has involved trimethylsilyl cellulose,
even though trimethylsilyl chloride is not suciently sterically
demanding to give highly 6-OH-selective etherication.131,132
Therefore, the silylcellulose ester and cellulose ester products
synthesized from these trimethylsilylcellulose ethers are of only
modest regioselectivity. The DS of the cellulose esters obtained
was either roughly equal to the DS of the trimethylsilyl cellulose
starting materials, via direct replacement of the silyl groups, or
proportional to the DS of free OH groups of these trimethylsilyl
cellulose derivatives, by way of acylation of the remaining OH
groups; as detailed below, which pathway is taken can be
manipulated by choice of reaction conditions.106
Klemm et al.133 used trimethylsilyl cellulose containing several
levels of trimethylsilyl substitution (DS 1.99, 2.46, 2.62) to make
cellulose esters by direct displacement of the silyl groups using
acid chlorides (e.g., acetyl, propionyl, and stearoyl chlorides)
under acidic conditions. The advantage for such reactions is that
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Biomacromolecules
Figure 7. Acylation of cellulose silyl ethers.
no solvent or catalyst was used, which is potentially economical
and aords a rather pure product after a simple work up
procedure; more pertinent to this review is that acylation
occurred exclusively at the trimethylsilyl-substituted cellulose
hydroxyl groups, whereas the unsubstituted hydroxyl groups
surprisingly did not react under these reaction conditions. This
was true even in the presence of excess acid chloride. The result is
that the product cellulose ester substituents are in the same
positions as the trimethylsilyl groups of the starting material.
Similar substitution reactions were demonstrated with nitro- or
bromobenzoyl chlorides.96 Clearly, if one can place the trialk-
ylsilyl groups regioselectively, this could be an interesting route
to regioselectively substituted cellulose esters. Remarkably, to
our knowledge, no publications have appeared describing appli-
cation of these techniques to more regioselectively substituted
silyl ethers of cellulose, such as the 6-thexyldimethylsilyl and 2,6-
bis(thexyldimethylsilyl) ethers mentioned previously. No evi-
dence has been published to indicate whether the thexyldi-
methylsilyl group can be directly replaced by acyl groups under
acidic conditions, as can the trimethylsilyl group.
An interesting example of reaction of regioselectively pro-
tected silyl ethers of cellulose with acylating reagents was
published recently by Luning and Schultz.134 They described
reaction of 6-thexyldimethylsilylcellulose (and also 6-tritylcellulose)
with diphenylketene. Ketenes are highly reactive toward alcohols,
aording esters without the generation of low-molecular-weight
byproduct.25 These workers observed clean reaction with diphe-
nylketene to aord cellulose diphenylacetate esters of DS 1 and
also observed that this DS did not increase even if reaction time
was extended, or a larger excess of reagent was used. They
concluded that reaction was proceeding at either the 2- or 3-OH
group, with high regioselectivity. Unfortunately, they relied
heavily on IR spectroscopy to characterize the products, did
not report NMR analysis of the derivatives produced, and
therefore could draw no conclusions about the actual position
of substitution. Still, this is a promising general approach that
deserves more attention; the reactive ketenes may permit the use
of low reaction temperatures, enhancing regioselectivity.
2.2.6. Cellulose Sulfate. Cellulose sulfates (CS) have been
of increasing interest in recent years because of their utility as
1964
REVIEW
film-forming materials, viscosity regulators, anionic polyelectro-
lytes, and their biological activity.125,135
137 Particularly for
biological applications such as use in killing viruses138
140 or
preventing blood clotting,141,142 the ability to synthesize CS
regioselectively may be essential for optimum activity and for
regulatory approval. The regioselectivity of CS synthesis has
been reviewed several times26,125,135,143 in the past two decades.
A variety of reagents and solvent systems have been developed in
search of regioselective substitution; these are detailed in this
section. The Mischnick laboratory has been a leader in develop-
ing analytical techniques for determining the position of sub-
stitution of polysaccharide derivatives, especially polysaccharide
ethers.144 Mischnick and coworkers have developed a method for
determination of the CS substitution pattern.145,146 This method
is based on methylation of the CS (MeI, LiCH2SOCH3, DMSO,
tetramethylurea), replacement of sulfate groups by acetate
(Ac2O),147 replacement of acetate groups by deuteromethyl
ethers (NaOH/CD3I), and hydrolysis of the methylated CS to
monomers (TFA/H2O/N-methylmorpholine-borane complex).
Their results from cellulose sulfates synthesized in various ways
are listed in Table 3. The ability to analyze the position of
substitution of CS quantitatively, as with cellulose ethers, is
extremely useful, and it is surprising that it has not been
frequently employed to date by researchers in the CS field. Most
researchers report only 1H and 13C NMR spectra to support
assignments of position of substitution; these techniques are
limited in the precision and accuracy of their ability to quantify
position of substitution generally and especially so for cellulose
sulfates in which the substituent is not directly measured but only
inferred from the shifts in nearby carbon and proton resonances.148
CS can be synthesized by direct cellulose sulfation hetero-
geneously in pyridine or homogeneously in ionic liquids. In 2000,
Baumann et al. reported the synthesis of cellulose-2,6-sulfate
with complete regioselectivity (DSS = 2.0, Figure 8) by the
reaction of preswelled cellulose with a complex of pyridine and
chlorosulfonic acid (ClSO3H).103 Such high regioselectivity as a
result of direct reaction of cellulose with a sterically undemanding
reagent is surprising; the only analyses reported by the authors
that could help elucidate position of substitution were 1H and
13
C NMR spectra. In 2009, Wang et al. reported homogeneous
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Biomacromolecules REVIEW

Table 3. Cellulose Sulfate Monomer Composition versus Synthesis Method

weight % monomer by sulfate group position

entry starting material synth. conditions none 2 3 6 23 26 36 236 DS

1 cellulose N2O4/DMF/SO3 51.3 2.2 1.4 42.0 0.2 1.8 0.7 0.4 0.5
2 cellulose propanol/H2SO4a 27.9 2.3 1.0 61.7 0.1 5.1 1.6 0.4 0.8
3 cellulose DMF/Ac2O/ClSO3Hb 19.9 6.0 1.2 50.8 0.3 20.4 0.9 0.4 1.0
4 CA DS 1.5 DMF/NH2SO3H 28.9 13.5 6.9 6.1 25.5 5.0 1.9 12.1 1.3
5 CA DS 2.5 DMF/ClSO3H 69.1 5.3 4.4 17.3 0.4 1.9 1.4 0.3 0.4
6 CA DS 2.0 DMF/ClSO3H 42.0 7.4 6.1 29.5 0.5 7.6 6.2 0.8 0.7
a
Heterogeneous (all others homogeneous). b After solvolysis of acetyl groups.

Figure 8. Regioselective cellulose sulfonation.

sulfation of bagasse cellulose in the ionic liquid [Bmim]Cl at
30 C using ClSO3H/DMF complex as sulfating agent, with modest
regioselectivity as determined by 13C NMR (sulfate distribution
C-6 > C-2 > C-3).149
A widely investigated and direct pathway starting from cellu-
lose is acetosulfation, followed by deacetylation.150
152 In 1995,
Philipp et al. rst reported the synthesis of CS by the reaction of
cellulose in system of ClSO3H/Ac2O/DMF at 50 C for 3
24 h,
followed by deacetylation in NaOH solution.150 They report that
the regioselectivity of this reaction is C-6 > C-2 . C-3 (entry 3,
Table 3). Cellulose-6-sulfate with DS around 0.8 was reported.
In 2008, Hettrich et al. studied the eect of various solvents
and sulfating agents on this reaction and reported that at DS < 1,
C-6 substitution is favored within a range of solvents (DMF,
DMAc, NMP) and reagents (ClSO3H, H2SO4, SO2Cl2, SO3-
DMF), as measured by 13C NMR.153 All of these routes that
either begin with cellulose acetates or create cellulose acetates
in situ (acetosulfations) are awed in that they depend on the
regioselectivity of acid-catalyzed acetylation, which the best litera-
ture evidence indicates is rather random.10,11 Product distributions
are generally quantied by 13C NMR techniques whose aws we
have already mentioned. The modest selectivity shown by Mis-
chnick and coworkers146 (Table 3) for samples generated by
acetosulfation reactions is cautionary evidence that NMR methods
may lack accuracy for quantifying regioselectivity of CS samples.
CS synthesis via organo-soluble intermediates may enhance
regioselectivity by permitting milder reaction conditions. Using
bulky protecting groups to block selectively one or two hydroxyl
groups (usually C-6 or C-2/6) is an eective way to obtain CS
with high regioselectivity. For example, in 2000, Heinze et al.
employed 6-O-(4-methoxy-triphenylmethyl)cellulose to synthe-
size cellulose-2,3-sulfate by sulfation (SO3/pyridine), followed
by deprotection.154 As previously noted in this Review, tritylation
of cellulose is quite selective for O-6; however, the sensitivity of
trityl groups toward acid may complicate this approach. In 1995,
Klemm et al. reported synthesis of cellulose-3-sulfate (DS 0.98)
using cellulose 2,6-triuoroacetate (DS 1.5) by reaction with
SO3/pyridine/DMF at 15 C for 3 h.155 They reported high (but
1965
unquantied) regioselectivity and ascribed this to activation of
the O-3 position by the neighboring triuoroacetyl group.103
Cellulose formate and acetate also can be used as intermediates
to synthesize cellulose sulfate.95 Partially regioselective hydro-
lysis at O-2/3 positions of the commercial CTA DS 2.4 to 2.6 is
reported to aord a 6-O-acetate intermediate, which can be sulfated
using NH2SO3H, followed by deacetylation to form cellulose-
(2/3)-sulfate, where the regioselectivity is O-2 > O-3.150,156
Direct, acid-catalyzed replacement of silyl ether groups, ana-
logous to the direct replacement by acyl groups previously
described, can also lead to CS.150,157,158 The regioselectivity of
sulfation of trimethylsilylcellulose with SO3 or ClSO3H in DMF
is O-6 > O-2 > O-3.150,159 The literature examples so far involve
the use of trimethylsilylcellulose, which, as we have noted,
typically contains a mixture of regioisomerically substituted
AGUs. Sulfation of trimethylsilylcellulose (DS 1.55) with
ClSO3H in DMF, followed by treatment with NaOH/EtOH, is
reported to aord a nearly completely regioselectively substi-
tuted cellulose-6-O-sulfate (DS 0.95); only NMR results are
reported to indicate position of substitution. At higher DS values,
C-2 and to a lesser extent C-3 are also substituted. In 2003,
Richter and Klemm studied the regioselectivity of sulfation of
nearly fully substituted trimethylsilylcellulose (DS 2.9) using
dierent SO3-complexes.157 The complexing agent employed
inuences sulfation regioselectivity to a moderate extent. Using
SO3-DMF, CS with higher DS at O-6 could be obtained; when
using SO3-triethylamine, a slight preference for O-2 sulfation was
observed. Cellulose trinitrite prepared from cellulose in situ has
been carefully investigated as an intermediate for CS regioselec-
tive synthesis. Cellulose trinitrite formed in situ by treatment of
cellulose with N2O4/DMF is reacted with various sulfating
agents.150,158 Whereas product regioselectivity is generally quite
modest (by 13C NMR), it is an interesting example in that
position of substitution depends strongly on the sulfating reagent
used and on temperature. Regioselectivity was attributed to two
counteracting eects: the high spatial accessibility of the O-6
nitrite group and the high intrinsic reactivity of the O-2 nitrite
group.135 This synthetic route may therefore provide products
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Biomacromolecules REVIEW

with diering regioselectivity depending upon reaction condi-

tions. For example, with SO3 as sulfating agent, the regioselec-
tivity at room temperature (20 C) is O-6 > O-2, but it reverses at
low temperature (
20 C) to O-2 > O-6. Room-temperature
sulfation with SO2 or NOSO4H gave high O-6 regioselectivity at
low total DS (0.31
0.36), much more selective than with SO3
under similar conditions.150,158
In summary, a number of routes for partially regioselective
synthesis of cellulose sulfates have been reported, and clearly
such regioselectively substituted cellulose derivatives would be
useful for investigations of properties and applications, particu-
larly biological eects like blood clotting and antiviral properties.
Unfortunately, there are no reports as yet of entirely regioselec-
tive CS synthesis, backed up by quantitative analytical methods
such as degradation and monomer analysis. It will be important
in the future to bring together the most powerful synthetic and
analytical techniques to enable truly regioselective syntheses of
these important cellulose derivatives. Figure 9. Mechanism for regioselective cellulose bromination from
Furuhata et al.160

3. DIRECT REGIOSELECTIVE HALOGENATION

Table 4. Cellulose Derivatives Synthesized from 6-Deoxy-6-
In 1992, Furuhata et al.160 published a method for regioselec- bromocellulose
tive halogenation of cellulose at the C-6 position without going
through an isolated intermediate like tosyl cellulose. This reac- C-6 substituent DSa reference
tion required the dissolution of cellulose in DMAc/lithium
sulfur nucleophiles and derivatives
bromide, followed by the addition of the reagents triphenylpho-
methanethiol 0.55 163
sphine (Ph3P) and N-bromosuccinimide (NBS). The 6-deoxy-6-
benzenethiol 0.41 163
bromo-cellulose product is analogous to the 6-O-tosylate in that
it can act both as a protecting group under certain conditions and mercaptoacetic acid 0.10 163
as a good leaving group for substitution chemistry at the C-6 L-cysteine 0.56 164
position. The advantage versus tosylation is that the bromination 2-mercaptoethanol 0.71 164
is completely selective for C-6. That is, no measurable amount of 3-mercaptopropanoic acid 0.92 164
bromination takes place at the secondary hydroxyl groups on 2-mercaptobutanedioic acid 0.51 164
cellulose. In addition, a maximum bromide DS of 0.98 has been 4-aminobenzenethiol 0.84 164
reported using this procedure, indicating that virtually every 2-aminobenzenethiol 0.76 164
primary hydroxyl group on the cellulose backbone has been 2-mercaptobenzoic acid 0.64 164
replaced by a bromide.161 Chlorination of cellulose dissolved in thiocyanate 0.88 167
DMAc/LiCl using Ph3P and N-chlorosuccinimide has also been
2-aminoethanethiol 0.79 165
reported,162 although it was found that chlorination also takes
isothiourea 0.80 165
place at the secondary hydroxyl sites for a maximum DS of 1.86.
The remarkable selectivity of the C-6 bromination is believed to mercaptan 0.79 165
be due to a combination of factors: the steric bulk of the sodium sulfonate 0.75 168
triphenylphoshonium intermediate, which leads it to prefer nitrogen nucleophiles and derivatives
reaction with the less hindered primary OH and the SN2 2-cyanoethylamine 0.86 166
mechanism of the subsequent bromide displacement reaction azide 0.96 161
(Figure 9). In the event that oxophosphonium intermediates do primary amine 0.96 161
result from reaction of the secondary OH groups, their SN2 a
Highest DS for the derivative reported in the literature is the DS
displacement by bromide will be disfavored both by the need for recorded in this Table.
the nucleophile to approach from the interior of the glucopyr-
anose ring and by the inversion of conguration at the 2- or
3-carbon that would result, causing the entire cellulose chain to Reactions involving various thiols were shown to be eective in
move in space. All of these energetic costs work against bromina- regioselectively attaching dierent pendent functional groups,
tion at the 2- and 3-positions. such as carboxylic acids, dicarboxylic acids, and amines, to the
The main disadvantage to regioselective bromination com- cellulose backbone. These included reactions carried out both
pared with tosylation is that the 6-deoxy-6-bromo-cellulose is not heterogeneously in aqueous alkali163 and homogeneously in
soluble in typical aqueous or organic solvents, although it can be DMAc/LiBr.164 Several of these derivatives were tested for
redissolved in DMAc/LiBr. Nevertheless, several highly regiose- their metal ion sorption capacities.165 6-Deoxy-6-(2-cyanoethy-
lectively substituted cellulose derivatives with substituents at C-6 lamino)-cellulose and 6-deoxy-6-thiocyanato-6-cellulose were
have been synthesized via nucleophilic displacement with synthesized beginning with a heterogeneous suspension of
6-deoxy-6-bromo-cellulose starting under heterogeneous condi- 6-deoxy-6-bromo-cellulose in DMSO and DMF, respectively.
tions. Table 4 provides a list of all compounds synthesized The reactions became homogeneous as they progressed, and
from 6-deoxy-6-bromocellulose, as reported in the literature. the products were used to study -relaxations in cellulose by
1966 dx.doi.org/10.1021/bm200260d |Biomacromolecules 2011, 12, 19561972
Biomacromolecules
Figure 10. Cellulose by cellulase-catalyzed polymerization.
dielectric spectroscopy.166,167 Water-soluble sulfonate deriva-
tives were synthesized by reacting the brominated cellulose in
aqueous solutions of sodium sulte.168 A regioselectively sub-
stituted cationic cellulose derivative was produced by synthesiz-
ing 6-deoxy-6-azido cellulose from the brominated cellulose,
followed by reduction of the azido group to a primary amine of
DS 0.96.161
In summary, phosphine-catalyzed bromination at O-6 is a very
attractive method for the regioselective, nearly regiospecic
modication of cellulose, and we expect that its utility as a
gateway method to enable access to other interesting, functional
cellulose derivatives will be the subject of further innovation in
the coming years.
4. DE NOVO SYNTHESIS OF CELLULOSE DERIVATIVES
Whereas polymerization of monomers is the standard method
for preparation of synthetic polymers, all polysaccharides and
their derivatives that are used in commerce are derived from
natural polysaccharides, which are isolated and puried from
plant or animal sources.169 Therefore, it was a major break-
through in polysaccharide chemistry when Kobayashi and
coworkers170 synthesized cellulose from monomers for the rst
time, polymerizing cellobiosyl uoride using a cellulase enzyme
catalyst. Armed with this vision of what was possible, Nakatsubo
and coworkers 5 years later171 succeeded in the rst purely
chemical synthesis of cellulose by cationic polymerization of a
glucose orthopivalate ester, later extending this method to
include cellulose derivatives. These de novo synthesis methods
have expanded the palette of regioselective synthesis methodol-
ogy, broadening the variety of regioselectively substituted deri-
vatives that can be synthesized.172 We will illustrate that variety
and give several important examples while also pointing out some
apparent limitations to the current state of the art.
4.1. Enzyme-Catalyzed Polymerization. Kobayashis pio-
neering synthesis of cellulose from -D-cellobiosyl fluoride by
enzymatic polymerization employing a cellulase enzyme has led
to a considerable exploration of this general method for the
synthesis of natural and unnatural polysaccharides.173 Manipula-
tion of the monomer concentration and solvent system enabled
the Tokyo group to successfully employ cellulase enzymes
(whose natural function is to hydrolyze the intermonomer
anomeric linkages of cellulose as part of its biodegradation) to
form anomeric bonds in selective fashion in the reverse of the
natural process. The original synthesis (Figure 10) was carried
out in acetonitrile and pH 5 buffer (using a high percentage of
organic solvent minimizes hydrolysis of the product cellulose by
the cellulase, whereas the presence of some water affords adequate
enzyme activity) and gave a reasonable yield (up to 65%) of
cellulose. The authors confirmed structure unequivocally by
conversion to cellulose triacetate (CTA), whose NMR spectra
were identical to those of CTA from natural cellulose. The
product was also a substrate for natural cellulase enzymes, giving
the expected degradation products. The synthetic cellulose had
degree of polymerization (DP) > 22, as measured by SEC; it has
1967
REVIEW
been demonstrated that CTA oligomers have spectral properties
equivalent to the corresponding CTA high polymer and thermal
transitions (Tg, Tm) somewhat lower than those of the high
polymer at a DP between 7 and 9.174 Note that throughout this
article we define DP as the number of glucose (or substituted
glucose) units because glucose is the chemical repeat unit of
cellulose; cellobiose is the spatial repeat unit, but in this account
we are concerned primarily with cellulose substitution chemistry,
so the glucose repeat unit is the appropriate one. Readers of
the cellulose literature must be careful because both glucose
and cellobiose are used as repeat units when DP numbers are
presented in different articles.
The glycosylase-catalyzed synthesis of polysaccharides is a
promising and interesting development, which has been used for
the synthesis of a variety of natural (chitin,175 xylan,176 amylose,177
mixed-linkage -glucans178) polysaccharides. It has even been
used to make mixed linkage polysaccharides, such as a glucan
containing alternating -1f4 and -1f3 linkages.179 It has the
advantage of requiring only a relatively simple activation of the
anomeric position (conversion to glycosyl uoride) and not
requiring protection of the other hydroxyl groups. By proper
enzyme selection, the stereochemical and positional selectivities
are excellent, providing -1f4 linkages in the case of cellulase and
R-1f4 linkages in the case of amylase, for example.
The major limitation of enzyme-catalyzed polymerization for
synthesis of substituted cellulose derivatives is the ability of the
cellulase enzymes to accept substituted monomers. In the case of
cellulose, there are only two cases of which we are aware in which
unnatural substituents may be present; one is the synthesis180
of 1-deoxy-1-thio analogues of cellulose, which is not relevant to
our account, and the other is the synthesis of cellulose derivatives
containing methyl ethers, which is quite relevant. Kobayashi and
coworkers found181 that by working with selectively methylated
-cellobiosyl uoride, they could by cellulase catalysis synthesize
selectively methylated cellulose ethers. Using protective group
chemistry well-known to carbohydrate chemists, they were able
to synthesize 6-O-methyl--cellobiosyl uoride. Polymerization
of this disaccharide using cellulase in acetonitrile and pH 5.0
acetate buer aorded a cellulose derivative in which alternating
monomers were methylated at O-6 (Figure 11).
Note that by polymerizing a disaccharide substituted selec-
tively in only one of the two rings, the authors were able to obtain
a product containing not only regiospecic substitution but also
completely controlled monosaccharide sequence (a perfectly alternat-
ing AB copolymer). The product was a mixture of oligomers (DP
ca. 8
14), and conversion to the cellulose acetates allowed
conrmation by NMR that the linkages were uniformly -1f4.
In contrast, the closely related cellobiosyl uoride derivative
diering only in that the methyl group is on the 6-OH of the
other ring gave much more modest polymerization in the
presence of the cellulase, aording DP of 4 (although -1f4
selectivity was observed).
Unfortunately, these are the only examples of which we are
aware in which tolerance by the cellulase for ether or ester
substituents has been demonstrated, and of course the rather low
dx.doi.org/10.1021/bm200260d |Biomacromolecules 2011, 12, 19561972
Biomacromolecules
Figure 11. Cellulase-catalyzed synthesis of alternating glucose-6-O-methylglucose copolymer.
Figure 12. Monomethylcelluloses via orthopivalate polymerization.
DP attained is also a drawback. It is to be hoped that future
investigations will show the way to broader substrate tolerance
and higher DP products, permitting the use of the excellent
selectivity and eciency of cellulase-catalyzed polymerization as
a general method for synthesizing regioselectively substituted
cellulose derivatives.
4.2. Acid-Catalyzed Orthopivalate Polymerization. The
Nakatsubo group demonstrated the first chemical synthesis of
cellulose, attaining a DP of ca. 15, by polymerization of an
orthopivalate derivative. The Nakatsubo and Kamitakahara
groups have demonstrated the value of this general synthetic
approach for a considerable number of regioselectively substi-
tuted cellulose derivatives. The methodology has several distinct
and valuable features:
1 Under the right conditions of catalyst, temperature, solvent,
and substituent, the reaction is remarkably selective for
-anomeric stereochemistry.
2 Because the starting material is a monosaccharide, one can
take full advantage of the sophisticated chemistries available
for regioselective substitution of monosaccharides to eciently
synthesize monomers with desired (and dierentiated) sub-
stituents at O-3 and O-6. Along with the O-2 pivalate
substituent that arises from the polymerization reaction, this
1968
REVIEW
can give cellulose in which all three hydroxyls have substituents
that are dierentiated by reactivity.
3 Because the starting monomer is substituted, the polymeric
products are substituted. This prevents excessive hydrogen
bonding and the resulting crystallinity in the product,
greatly enhancing product solubility versus the cellulose
oligomers produced by cellulase-catalyzed polymerization
of -cellobiosyl uoride. As a result, product precipitation is
much less likely to severely limit attainable product molec-
ular weight.
These features of the Nakatsubo/Kamitakahara de novo
synthesis method have permitted the remarkable synthesis of
all six signicant possible homopolymers related to methylcellu-
lose. (Two of the eight related homopolymers are synthetically
trivial; the homopolymer of the unsubstituted AGU is just
cellulose, whereas the homopolymer of the trisubstituted AGU
is 2,4,6-trimethylcellulose, which does not require regioselective
synthesis.) For example, Figure 12 shows the synthetic metho-
dology used182 to prepare the key monomers for synthesis of the
monosubstituted homopolymers 2-methyl-, 3-methyl- and
6-methylcellulose.
Kamitakahara and coworkers were able either to methylate
the monomer regiospecically prior to polymerization (3M, 6M)
dx.doi.org/10.1021/bm200260d |Biomacromolecules 2011, 12, 19561972
Biomacromolecules
Table 5. Solubilities of 2,6-O-Methyl/ethylcelluloses190 a,b,c,d
solvent 2E6E 2E6M
H2O I I
MeOH PS I I
EtOH PS I I
acetone PS I I
CHCl3 S S
MeOH/CH2Cl2 (1/4, v/v) S S
a
Reprinted with permission from ref 190. Copyright 2009 Springer
ScienceBusiness Media B.V. b Solubility was evaluated at a concentra-
tion of 5 wt %. c S: soluble (clear solution); PS: partially soluble (cloudy
solution); I: insoluble. d 2E6E: 2,6-di-O-ethyl-cellulose; 2E6M: 2-O-
ethyl-6-O-methyl-cellulose; 6E2M: 6-O-ethyl-2-O-methyl-cellulose.
or append protective groups such that selective deprotection
and monomethylation of the product cellulose derivative was
straightforward (2M). This same group has also made the
regiospecically substituted dimethylcelluloses by analogous
routes: starting from 3-O-benzyl-6-O-pivaloylglucose-1,2,4-
orthopivalate, polymerization with BF3 3 Et2O, followed by depi-
valoylation (NaOMe/THF/MeOH) at O-2 and O-6, methyla-
tion (MeI/NaH/DMSO), and nally debenzylation at O-3 (H2/
Pd(OH)2) aorded 2,6-di-O-methylcellulose, isolated as the
3-acetate;85 starting from 3,6-di-O-methylglucose-1,2,4-orthopi-
valate, polymerization with BF3 3 Et2O, followed by depivaloyla-
tion (NaOMe/THF/MeOH) at O-2 aorded 36M, isolated as
its 2-O-acetate;183 and polymerization of 6-O-allyl-3-O-methyl-
glucose-1,2,4-orthopivalate, followed by depivaloylation at O-2
(NaOMe/THF/MeOH), methylation at O-2 (MeI/NaOH/
DMF), and deallylation at O-6 (PdCl2/MeOH/CHCl3) af-
forded 23M, isolated as its 6-O-acetate.183
These syntheses of the dierent methylcelluloses are elegant
and useful; they have already permitted NMR studies183 of the
individual regiospecically substituted homopolymers, charac-
terization of lm properties,184 and the utilization of these
homopolymers as blocks in subsequent syntheses of blocky
cellulose ether derivatives,185
188 just to name a few representa-
tive studies. Kamitakahara, Nakatsubo, and Rosenau have de-
monstrated that these methods are rather general for cellulose
ethers;189 indeed, their only drawbacks for the synthesis of
regiospecically substituted cellulose ethers appear to be their
multistep nature and the fact that the attainable DP of the
products is limited (depending at least in part on the types of
3,6-substituents on the glucose-1,2,4-orthopivalate monomer;
3,6-di-O-benzyl monomer gives DP approaching 20,190 mixed
3,6-O-(pivalate ester/benzyl ether) derivatives give DPs in the
5
10 range,191 and some simple 3,6-dialkyl ether monomers
have aorded alkylcelluloses of DP 20
70192). An example of
the interesting structure
property studies enabled by these
synthetic methods is the synthesis of regiospecically substituted
cellulose ethers containing methyl and ethyl substituents; the
impact of regiochemistry on solubility is highlighted in Table 5,
adapted from the Kamitakahara article.190
The nature of these substituents is restricted by the require-
ment that the monomer be reactive toward cationic polymeriza-
tion. Electron-withdrawing substituents at O-3 and O-6 of the
orthopivalate reduce the stability of the intermediate carboca-
tion, dramatically reducing reactivity. From a practical point of
view, at least one ether substituent is essential for polymerization
success, and two are preferred.191 One implication is that the
REVIEW
attractive possibility of attaching dierent ester substituents to
O-3 and O-6 in the monomer stage and then polymerizing to
6E2M
aord a regiospecically substituted cellulose ester is not a
I practical approach. Because Nakatsubo and Kamitakahara have
already demonstrated the synthesis of cellulose ethers with fully
dierentiated substitution at the three hydroxyls (for example,
3-O-allyl-6-O-benzylcellulose-2-O-pivalate193), there is reason to
believe that this chemistry could be adapted to the regioselective
PS
synthesis of cellulose esters. The two drawbacks will be the need
PS
to carry out highly selective deprotection and esterication
reactions on the polymer, which will be less conducive to
reactivity and selectivity than the orthopivalate monomer and
the relatively restricted attainable DP. To date, the aforemen-
tioned mixed cellulose ether esters (like the 3,6-di-O-benzyl-2-
pivalate) have been the only reported syntheses of regioselec-
tively substituted cellulose esters by the orthopivalate method,
but we can anticipate such studies in the future.
5. CONCLUSIONS AND FUTURE PROSPECTS
Cellulose researchers now have available to them some
remarkable synthetic tools that did not exist 20 years ago.
The protecting group chemistry embodied in the thexyldimethyl-
silyl and trityl groups has made possible the synthesis of all
possible methylcellulose homopolymers and some novel cellu-
lose ester homopolymers. Protecting group chemistry has in-
herent drawbacks such as extra synthetic steps, lost yield at each
step, the potential for molecular weight degradation, and the
possibility that the reactivity of some protected derivatives may
not be as desired. Nonetheless, we can expect protecting group
chemistry to play an important role and to be further improved
methodologically, as researchers attempt to synthesize more
cellulose ester derivatives and derivatives containing two or more
substituent types.
The ability to synthesize cellulose derivatives substituted with
halogens regiospecically at C-6 is a very important advance,
bringing to bear not only greater steric accessibility at C-6 but
also the selectivity advantages of an SN2 substitution reaction, as
previously mentioned. This family of reactions aords even more
perfect regioselectivity than do the best ether protecting group
reactions and has already served as a gateway reaction to regios-
pecically substituted cellulose derivatives such as azides, den-
drites, and suldes. We can expect further exploitation of this sort
of chemistry as well to include other types of derivatives and other
chemistries, taking advantage of its very high regioselectivity.
De novo syntheses are also notable for their near-perfect
regioselectivity. There is no question that researchers will further
exploit the potential of this chemistry, making new cellulose
ether structures, combining de novo synthesis with chemical
synthesis of specic oligosaccharides to make blocky structures,
and in ways not yet imaginable. So far, these chemistries (and
biochemistries) have not proven generally valuable for the
synthesis of regiospecically substituted cellulose esters; break-
throughs will be needed to open up this important additional
dimension.
The work cited in this Review has helped the eld of cellulose
derivative research move into a new era, in which we will begin to
attain a much more complete understanding of structure
prop-
erty relationships, and can begin to modify commercial synthetic
processes to take advantage of the most desirable structures and
properties. We still have only the most modest tools to explore the
dimension of monosaccharide sequence of cellulose derivatives. We
1969 dx.doi.org/10.1021/bm200260d |Biomacromolecules 2011, 12, 19561972
Biomacromolecules
can look to the great advances in the biochemistry of other important
polysaccharides, most notably in alginate biosynthesis194
196
and in vitro synthesis of highly controlled monosaccharide
sequences197
199 to see the next potential dimension of
cellulose derivative regioselective synthesis. There is little
doubt that interdisciplinary advances combining chemistry
and biochemistry200 will be required to enable important progress
toward this next dimension of regiochemical control.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kjedgar@vt.edu.
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