Talanta 225 (2021) 121987

Contents lists available at ScienceDirect

Talanta

journal homepage: www.elsevier.com/locate/talanta

Review

Preparation and applications o cellulose-unctionalized chiral stationary

phases: A review
Xiaoping Wang a, 1, Hui Li b, 1, Kaijun Quan b, Liang Zhao b, Hongdeng Qiu b, c, *, Zuguang Li a, **
a
College o Chemical Engineering, Zhejiang University o Technology, Hangzhou, 310014, China
b
CAS Key Laboratory o Chemistry o Northwestern Plant Resources and Key Laboratory or Natural Medicine o Gansu Province, Lanzhou Institute o Chemical Physics,
Chinese Academy o Sciences, Lanzhou, 730000, China
c
College o Chemistry, Zhengzhou University, Zhengzhou, 450001, China

A R T I C L E I N F O A B S T R A C T

Keywords: Separation and identication o chiral enantiomers play an increasingly important role in many elds like
Cellulose derivatives pharmaceutical production, preparation o chemical intermediates and biochemistry. Although there are mul-
Chiral separation tiple methods or obtaining a single enantiomer, chiral chromatographic separation is still considered to be one
Stationary phase
o the most ecient methods. Among the numerous chiral separation materials, cellulose and its derivatives,
Chromatographic packing
with strong chiral recognition ability, large loading capacity and easy to unctionalization, have been presented
excellent enantioseparation perormance, which reveals their great prospect in chiral separation. In this review,
the types o cellulose derivatives, preparation o cellulose-unctionalized chiral stationary phases and their
application in chiral chromatographic separation in recent years were systematically summarized, and we hope
to provide a useul reerence or researchers working in chiral separation and inspire new discoveries in the eld
o cellulose-unctionalized chiral separation materials.

1. Introduction include chiral source synthesis, asymmetric catalysis and racemate

Nowadays, enantiomeric separation is widely required in many
research and industrial areas. Enantiomers are a pair o not superim-
posable mirror images stereoisomers that have the same physical and
chemical properties in the non-chiral environment but have signicant
dierences in the chiral environment [1]. The pharmacological activity,
metabolism and toxicity o chiral racemic drugs show great and even
opposite activities [2]. For example, R-thalidomide has sedative and
hypnotic eects, which could reduce the adverse reactions during
pregnancy while S-thalidomide had teratogenic eects [3]. Another
example, S-ketoproen has analgesic and anti-infammatory eects in
R/S-ketoproen [4]. S-furbiproen has a good therapeutic eect on
rheumatoid arthritis and osteoarthritis, while R-furbiproen has a
curative eect on Alzheimer’s disease [5]. Thereore, it is o great sig-
nicance to obtain a single enantiomer through separation or purica-
tion to conduct drug quality control, dosage analysis and drug saety
evaluation at the enantiomer level.
The main approaches to obtaining a single enantiomer usually
separation, etc. However, asymmetric synthesis was limited by the long
development cycle, high cost and complex induction actors [6]. Enan-
tioseparation is an important way to obtain a single enantiomer due to
which can simultaneously obtain two optical isomers with high ee
values, simple operation and high eciency [7]. Enzymatic and crys-
tallization chiral separation, although they have the advantages o
simple technology, low cost and mild conditions, they are limited by
complicated operation, time-conusing, low sensitivity, single enzyme
species, and so on [8]. Chromatography is still playing an increasingly
important role in the separation o racemic compounds in recent years,
because o its high sensitivity, strong reproducibility, high-speed and
wide application [9,10]. So ar, HPLC is considered to be the most
commonly used chromatographic method or separating optical active
compounds among various chromatographic like gas chromatography
(GC), high-perormance liquid chromatography (HPLC), capillary elec-
trochromatography (CEC), thin-layer chromatography (TLC), and su-
percritical fuid chromatography (SFC), etc. [11,12]. HPLC methods
have simple sample preparation, good selectivity, high sensitivity or

* Corresponding author. College o Chemistry, Zhengzhou University, Zhengzhou, 450001, China.

* Corresponding author.
E-mail addresses: hdqiu@licp.cas.cn (H. Qiu), lzg@zjut.edu.cn (Z. Li).
1
These two authors contributed equally to this work.

https://doi.org/10.1016/j.talanta.2020.121987
Received 2 September 2020; Received in revised orm 28 November 2020; Accepted 5 December 2020
Available online 9 December 2020
0039-9140/© 2020 Elsevier B.V. All rights reserved.
X. Wang et al.
superior resolution perormance, in addition to HPLC can do simulta-
neous two enantiomers separation and qualitative and quantitative
determination at the same time as well [13,14].
Chiral stationary phases are the key or chiral separation. There are
many dierent reported chiral separation materials such as poly-
saccharides, crown ethers, cyclodextrins, chiral covalent organic
rameworks, chiral spiral polymers and chiral cages [15–17]. Among
these chiral selectors, cellulose and its derivatives are widely applied
because o their wide range o chiral recognition (including alcohols,
acids, amines and other chiral compounds), strong chiral recognition
ability and high capacity [18]. Cellulose tris(3,
5-dimethylphenylcarbamate) has been proved to be the most represen-
tative chiral separation material due to the best enantiomeric recogni-
tion perormance, which has become a research hotspot in this eld with
its high chiral recognition perormance [19,20].
In this review, it was ocused rst on the introduction o types or
cellulose derivatives including ully modied, selectively modied,
dialdehyde and nanocrystalline cellulose derivatives. And then, the
preparation methods o cellulose-based chiral stationary phases
including coating, bonding, organic-inorganic hybrid or core-shell
would be introduced. Finally, the application o cellulose-based chiral
separation materials in GC, HPLC, CEC, TLC and SFC were summarized.
2. Cellulose and derivatives
Cellulose is one o the most abundant natural polysaccharide poly-
mer. Its structural unit is β-D-glucopyranose and connected by β-1,4-
glycosidic bond to orm highly ordered linear organic compounds
(Fig. 1). Each structural unit consists o a highly active primary hydroxyl
group and two secondary hydroxyl groups separately distributed in -C6,
-C2 and -C3 [21]. The microcrystalline cellulose (MCC) was composed o
roughly spherical with an average diameter o about 340 μm, the
prominent Raman band located at 1095 cm1, and the value or the
Young’s modulus was estimated to be 25 ± 4 GPa [22]. The crystallinity
o the MCC was ound to be 60–70% rom the X-ray diraction patterns,
and the specic surace area about 1.3 m2/g [23]. In addition, XRD
pattern o MCC showed several typical cellulose crystalline peaks were
14.5◦ , 16.6◦ , 20.4◦ , 22.6◦ , and 34.4◦ [17].
Although natural cellulose can be used in chromatographic separa-
tion to some extent, its own chiral recognition ability was not enough to
be used as chiral separation material to eciently resolve chiral enan-
tiomers. Thereore, in order to improve the enantioselectivity and
chromatographic separation o chiral materials o cellulose derivatives,
it is necessary to explore the application o cellulose modication and its
derivatives [24], The derivatization reagents, derivatives and products
o cellulose were listed in Table 1.
2.1. Fully modied cellulose derivatives
Cellulose derivatives with three hydroxyl groups modied in cellu-
lose structural units were called ully modied cellulose derivatives.
Hagel and Hesse rst modied cellulose at positions o C2, C3 and C6 to
prepare cellulose triacetate derivatives and then coated them on silica
gel or chiral stationary phases, but its chiral selectivity was low [25].
Subsequently, Yamamoto et al. reported a series o chiral stationary
phases derived rom cellulose tribenzoate by changing the position or
number o substituents on the benzene ring, the relationship between
dierent substituent groups, substitution position or chiral environment
Fig. 1. Chemical structure o cellulose.
2
Talanta 225 (2021) 121987
and chiral separation perormance were explored by their team [26].
Compared with acetic acid-derived cellulose, introduction o benzene
ring can signicantly improve the chiral recognition ability o cellulose
so as to be widely used and commercialized. Okamoto et al. investigated
chiral separation perormance with a series o polysaccharide triphenyl
carbamate derivatives which indicated that the 3- and 4-positions o
benzene with electron-withdrawing or electron-donating groups both
can improve the chiral separation perormance, and disubstituted ben-
zene derivatization reagent is better than that monosubstituted benzene
derivatization reagent. Among them, cellulose tris (3,5-dimethylphenyl
carbamate) has remarkable chiral recognition ability, which can solve
more than 80% o the separation o chiral enantiomers [27–29].
2.2. Partially selective modied cellulose derivatives
Cellulose structural units contain a relatively active primary hy-
droxyl and two secondary hydroxyl groups, the reactivity o dierent
hydroxyl groups is dierent to some extent. Thereore, dierent deriv-
atization reagents in structure or unction can be used to construct
regioselective cellulose derivatives with adjustable substitution posi-
tion, substitution design and controllable quantity [30,31] (Fig. 2).
Okamoto et al. prepared regioselective cellulose carbamate derivatives
at positionsC 2, C3 and C6 by selective protection position C6 o cellu-
lose, and later ound that dierent phenyl carbamates introduced into
glucose units have better chiral recognition ability than one phenyl
carbamate or one cyclohexyl carbamate [32]. Zhang’s group took
advantage o the high regioselective benzoylation o cellulose with
1-allyl-3-methylimidazolium chloride prepared regioselective
substituted cellulose mixed esters without protecting and deprotecting
process [33]. Yin et al. prepared 18 kinds o cellulose phenyl carbamate
derivatives with dierent groups by homogeneous reaction in 1-allyl-3--
methylimidazolium chloride. They ound that partially substituted cel-
lulose phenyl carbamate exhibited a comparatively decreased chiral
separation ability maybe due to non-specic adsorption eect caused by
excess hydroxyl groups, while ully modied cellulose phenyl carbamate
showed the preerable perormance [10] (see Fig. 3).
2.3. Dialdehyde cellulose derivatives
Dialdehyde cellulose (DAC) is a kind o cellulose oxidation product,
which can be partially oxidized by hydroxyl groups o cellulose on C2
and C3 into aldehyde groups and the corresponding carbon-carbon bond
o pyranose glucose ring to obtain 2, 3-dialdehyde cellulose in aqueous
solution [34]. The aldehyde groups o DAC have high reactivity and easy
to undergo nucleophilic addition reaction with various unctional
groups such as amine, hydrazine and amide to prepare DAC derivatives
[35,36]. Compared with cellulose, it has been widely used in many elds
or good solubility, strong selectivity and biodegradability [37]. Dang
et al. obtained DAC through ultrasonic pretreatment o MCC and
oxidation o sodium periodate, which was green, ecient and sustain-
able [38]. Hua et al. prepared DAC by selective oxidation o sodium
periodate to construct DAC crosslinked chitosan dense lm, which
improved the acid resistance and tensile elongation [39]. Jiang et al.
prepared high-strength DAC/GEL hydrogels with low swelling rate and
high mechanical strength with oxidized DAC by Schi base reaction
[40]. Zhang et al. prepared cellulose-based Schi base by condensation
o DAC and lysine, and obtained a new material with high antibacterial
activity, non-toxic and good biocompatibility [41]. Gao et al. prepared a
series o DAC chiral stationary phases by bonding and derivatizing DAC
with amine modied silica gel, obtained satisactory separation peror-
mance, which indicated that the application o dialdehyde cellulose
derivatives in chiral separation has a good research prospect [17,42].
2.4. Nanocrystalline cellulose derivatives
Nanocrystalline cellulose (NCC) is the product o cellulose
X. Wang et al. Talanta 225 (2021) 121987

Table 1
Synthesis methods o cellulose derivatives.
No. Reagents Cellulose derivatives Advantages Reerences

1 3-methyl-4-chlorophenyl isocyanate short reaction time, ionic liquid as solvent, low toxicity, high yield [10]

2 glacial acetic acid simple preparation and strong chiral recognition ability [25]

3 benzoyl chloride strong solvent tolerance, enhanced chiral recognition ability [26]

4 3,5-dimethylphenyl isocyanate wide resolution range, resolution o more than 80% enantiomers, good [29]
stability, simple preparation method

5 3,5-dimethylphenyl isocyanate, 3,5-dichlor- selective protection o the 6-position hydroxyl group in the orm o [32]
ophenyl isocyanate trimethyl ether

6 benzoyl chloride, 3,5-dimethylphenyl mild reaction conditions, high yield, ew by-products, strong selectivity [33]
isocyanate

7 acryloyl chloride, 3,5-dimethylphenyl strong solvent tolerance and high selectivity [66]
isocyanate

8 allyl isocyanate, 3,5-dichlorophenyl mild reaction conditions, high yield o directional synthesis, ew side [68]
isocyanate reactions

9 3, 5-dinitrobenzoyl chloride high yield, up to 98.4% [90]