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Applications of nanomaterials

in enantioseparation and relatedtechniquesCuilan Chang, Xin Wang, Yu Bai, Huwei Liu

Chirality is an important, universal phenomenon in nature. For the in-depth study of pharmacology and biology, efficient

enantioselective technologies are indispensable. Nanomaterials with large surface-to-volume ratio and specific physical and

chemical properties have demonstrated great potential in chiral discrimination. Many publications show that utilization of

nanomaterials could improve the selectivity, the stability and the efficiency of enantioseparation.

This review summarizes the applications of various enantioselective nanomaterials, including mesoporous silica, organicpolymers, metal-organic frameworks, metal nanomaterials, magnetic nanomaterials, carbon nanotubes and well-oriented chiral

nanolayers. After proper preparation and modification, these functionalized nanomaterials are effective for chiral separation

through their specific enantioselective adsorption, especially when they are used as stationary or pseudo-stationary phases in

chiral chromatographic separation, such as thin-layer chromatography, high-performance liquid chromatography, gas

chromatography and capillary electrophoresis.

2012 Elsevier Ltd. All rights reserved.

Keywords: Carbon nanotube; Enantioseparation; Magnetic nanomaterial; Mesoporous silica; Metal nanomaterial; Metal-organic framework;

Nanomaterial; Organic polymer; Stationary phase

Abbreviations: AuNP, Gold nanoparticle; b-CD, b-cyclodextrin; BSA, Bovine serum albumin; CE, Capillary electrophoresis; CEC, Capillary

electrochromatography; CNT, Carbon nanotube; EOF, Electroosmotic flow; GC, Gas chromatography; HPLC, High performance liquid

chromatography; HP-b-CD, Hydroxypropyl-b-cyclodextrin; MNP, Magnetic nanoparticle; MOF, Metal-organic framework; MWCNT, Multi-walled

carbon nanotube; SPR, Surface-plasmon resonance; STM, Scanning tunneling microscope; SWCNT, Single-walled carbon nanotube; TLC, Thin-layer

chromatography; XRD, X-ray diffraction

1. Introduction

Chirality, which refers to the property of a

molecule or a system not identical to its

mirror image, has been confirmed to be

related to the origin of life [1,2]. In

chemistry, chirality is used to describe the

lack of a symmetric plane in molecules.

This property exists in various types of

molecules, including chiral drugs, aminoacids, carbohydrates, DNAs and proteins.

These chiral compounds, especially chiral

drugs, often exhibit remarkably different

effects in pharmacological activity, trans-

port mechanism, metabolism pathway

and toxicity. Taking thalidomide as an

example, the R-(+)-enantiomer is an

effective sedative, whereas the S-(-)-enan-

tiomer was found to cause fetal abnor-

malities. So obtaining enantiomeric pure

compounds is significantly important, but

it is still a big challenge because of the

identical physical and chemical properties

of enantiomers in an achiral environment.

Although great success has been attained

in asymmetric synthesis, enantioselective

reactions are still restricted to the use of

enantiomeric pure materials (e.g., chiral

substrates, chiral auxiliary and chiral

catalysts) [3]. The development of more

efficient enantioseparation techniques istherefore greatly desired for obtaining

pure enantiomers, monitoring asymmetric

reactions and ensuring quality control of

chiral drugs.

Chiral separation has been developed for

several decades, but the separation theory

is still based on the three-point interac-

tion [4], which was pointed out by

Dalgliesh in 1952. The theory states that

at least three configuration-dependent

points are needed for the recognition

Cuilan Chang, Xin Wang,

Yu Bai, Huwei Liu*,

Beijing National Laboratory for

Molecular Sciences, the Key

Laboratory of Bioorganic

Chemistry and Molecular

Engineering of Ministry of

Education, Institute ofAnalytical Chemistry, College

of Chemistry and Molecular

Engineering, Peking University,

Beijing 100871, China

*Corresponding author.

Tel.: +86 10 62754976;

Fax: +86 10 62751708;

E-mail: [email protected],

Trends in Analytical Chemistry, Vol. 39, 2012 Trends

0165-9936/$ - see front matter 2012 Elsevier Ltd. All rights reserved. doi:http://dx.doi.org/10.1016/j.trac.2012.07.002 195
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between chiral selectors and enantiomeric analytes, and

one of them must be an enantioselective interaction. The

final enantiomeric separation comes from multiple syn-

ergetic interactions, including electrostatic, ion ex-

change, hydrogen bonding, inclusion complex,

hydrophobic, p-p, dipole-dipole, and steric interactions.

Based on the above theory, many efficient chiral selec-tors with multiple interaction sites (e.g., proteins, poly-

saccharide, cellulose, cyclodextrins and their derivatives)

have been used as stationary phases or pseudo-station-

ary phases in thin-layer chromatography (TLC), high-

performance liquid chromatography (HPLC), gas

chromatography (GC) and capillary electrophoresis (CE)

through chemical bonding or physical coating.

Recently, Wards et al. [5] published a critical review

on chiral separation, which concluded that the devel-

opment of monolithic chiral stationary phases, ionic li-

quid phases and derivatized cyclodextrin phases would

be the trend in this field. However, these conventional

chromatographic or electromigration techniques are re-stricted by their low efficiency, high cost and poor uni-

versality. Alternatively, nanomaterials with large

surface-to-volume ratio and specific physical and

chemical properties attracted more and more attention

in recent years for their potential application in this field.

Nanomaterials, with at least one dimension in the

range 1100 nm, have become more and more popular

in modern science. Due to the techniques of controllable

synthesis of nanomaterials [6], they are widely used in

efficient separation [7,8], sensitive measurement [9] and

selective catalysis [10,11]. As demonstrated by Zhang

et al. [12,13], the usage of nanomaterials provided spe-cial opportunities for the development of selective, stable

and efficient techniques in separation science. There are

several advantages of using nanomaterials in enantio-

separation and related techniques. First, nanomaterials

can be easily modified with chiral selectors and used as

enantioselective adsorbents, especially chiral stationary

or pseudo-stationary phases. Second, nanomaterials can

increase column capacity, separation selectivity, stability

and efficiency for chiral chromatographic separation.

Third, nanomaterials, with unique surface-plasmon

resonance (SPR) properties, can facilitate the develop-

ment of simple, rapid and sensitive sensors for chiral

recognition.In general, there are two main ways to prepare

enantioselective nanomaterials. One is post modification

of achiral nanomaterials using chiral selectors, and the

other is synthesis of nanomaterials using chiral tem-

plates. The enantioselective nanomaterials are expected

Figure 1. (a) Chiral chromatographic separation; and, (b) enantioselective adsorption.

Trends Trends in Analytical Chemistry, Vol. 39, 2012

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to interact with every enantiomer, forming locally-chiral

structures according to different interaction mechanisms

(e.g., van der Waals dispersion, short-range repulsions,

and hydrogen-bonding interaction). The different sta-

bility of the two diastereomeric complexes is the basis of

enantioseparation. Fig. 1 describes the scheme of

nanomaterials for chiral chromatographic separationand enantioselective adsorption.

In this review, we focus on the applications of various

functionalized nanomaterials in enantioseparation,

which work through their specific enantioselective

adsorption, especially used as stationary or pseudo-sta-

tionary phases in chiral chromatographic columns (e.g.,

TLC, HPLC, GC and CE). Table 1 sets out applications of

both traditional and novel nanomaterials, including

mesoporous silica, organic polymers, metal-organic

frameworks (MOFs), metal nanoparticles (NPs), mag-

netic nanoparticles (MNPs), carbon nanotubes (CNTs)

and well-oriented chiral nanolayers.

2. Mesoporous silica nanomaterials

Mesoporous silica materials have been widely used in

separations because of their stability, fast mass exchange

and high thermal resistance [14]. The diversity of prep-

aration and modification makes silica-based chiral

nanomaterials promising in enantioseparation and

enantioselective adsorption or release.

Silica nanomaterials could be used as the support for

chiral selectors to increase the phase ratio by non-

covalent coating or chemical bonding. Physical coatingis commonly used due to its simplicity and convenience.

Dong et al. [15] immobilized crystalline mesoporous sil-

ica NPs onto the inner wall of a capillary, and then used

them as the support for cellulose derivative through

hydrogen bonding. Due to the increased surface area

inside the capillary column, the silica-NP-modified cap-

illary offered much higher enantioselectivity for eight

pairs of enantiomers than a bare capillary with the same

coating.

In most cases, chemical bonding is more stable and

robust than physical coating. Lee et al. [16] synthesized

antibody-based silica-NT membranes for enantiomeric

drug separations. These silica NTs were synthesized

within the pores of alumina films, and then the antibody

was attached to the inner walls of the NTs through

chemical bonding. The enantiomer separation was

realized through selective binding of drug enantiomers

and antibodies with different affinities. The selective

coefficient, a, which was defined as the ratio of two

enantiomers content, could be as high as 2.0 0.2.

Apart from the post-chiral modifications by chiral

selectors, the template-based approach [17] was well

recognized for the direct preparation of chiral silica-

based nanomaterials. The templates could be chiral

surfactants, chiral/achiral block copolymers and chiral

complexes.

Fireman-Shoresh et al. [18] prepared chiral silica

nanomaterials by doping or imprinting the chiral sur-

factant. These chiral nanomaterials exhibited good

enantioselectivities with the chiral selective factors in the

range 1.221.34 for three pairs of model enantiomers.Similarly, chiral mesoporous silica, synthesized by

using a chiral block copolymer of polyethylene oxide and

DD/LL-aspartic acid as the template [19], showed high

enantioselectivity toward valine enantiomers with a

chiral selective factor of 7.52.

To some extent, it was not easy to obtain the chiral

block copolymers and chiral surfactants, hence the

synthesis of chiral NPs using achiral block copolymers

and conventional surfactants provided new insight. Guo

et al. [20] synthesized chiral silica-based porous mate-

rials using a conventional achiral surfactant and a chiral

cobalt complex as co-template. These chiral silica

nanomaterials were successfully used for enantioselec-tive release of chiral drugs due to the chiral interactions

between enantiomers and the chiral nanomaterials.

Molecular imprinting [21], a technique to create

template-shaped cavities in polymer matrices with

memory of the template molecules to be used in molec-

ular recognition, presents a novel approach for prepar-

ing chiral silica nanomaterials, which possess high

affinity and selectivity for a given target molecule. Fire-

man-Shoresh et al. [22] synthesized silica-based chiral

template-molecule-imprinted sol-gel thin films and

measured the selective adsorption properties. Due to the

high configuration match between the cavity and theadsorbed molecules, adsorption of a preferred enantio-

mer was obtained and non-specific adsorption was

remarkably suppressed.

However, this traditional hydrolytic sol-gel technology

often suffers the problems associated with cracking and

shrinking of the beds during the drying process [23]. To

overcome these limitations, Wang et al. [24] developed a

novel room-temperature ionic liquid (RTIL)-mediated,

non-hydrolytic sol-gel methodology for the preparation

of silica-based molecular imprinting materials with the

template of (S)-naproxen. RTILs with low vapor pressure

could assist in reducing gel shrinkage, and their high

ionic strength could increase the aggregation rate. With

these chiral nanomaterials as the stationary phase in

capillary eletrochromatography (CEC), the resolution

between (S)-naproxen and (R)-naproxen reached 3.96

under optimized conditions.

3. Organic polymer nanomaterials

Recently, the synthesis of polymer NPs with controlled

characteristics has become an appealing topic [25]. Due

to their easy processability, good permeability, diverse




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composition and satisfactory stability over a wide range

of pH, polymer nanomaterials, including traditional

polystyrene to novel core/shell NPs, have been exten-

sively used in chiral separation techniques.

Polystyrene is one of the most widespread polymeric

NPs appreciated for its excellent stiffness and good pro-

cessability. Na et al. [26] dispersed polystyrene NPs intothe running buffer of CE employing hydroxypropyl-

b-cyclodextrin (HP-b-CD) as chiral selector to study the

chiral separation of propranolol. Polystyrene NPs pro-

vided a large surface for HP-b-CD adsorption and en-

hanced the interaction between HP-b-CD and solutes,

leading to higher separation efficiency at low HP-b-CD

concentrations. The effects of polystyrene were most

pronounced especially when the concentration of NPs in

the running buffer was much less than that of the sol-

utes. Above a certain concentration, further increase of

NPs resulted in counteraction because of conglomera-

tion. However, the buffer containing polystyrene NPs

was not always superior to that without polystyreneNPs. For example, in the buffer without polystyrene NPs,

the enantiomer resolution did not change remarkably as

pH increased from 2.14 to 3.73, whereas it was obvi-

ously influenced and decreased dramatically above pH

2.50 for the buffer containing polystyrene NPs.

When used in chiral separation, in situ polymerized

molecularly imprinted polymers (MIPs) are still limited

by the severe peak broadening and tailing caused by the

slow dynamic process [27,28]. Boer et al. [29] developed

a chiral separation method using NP-sized MIPs as a

free-moving pseudo-stationary phase in CE to minimize

these undesirable effects. They prepared

100-nmspherical MIP particles and used them for the enantio-

separation of ephedrine. With a partial filling technique,

the ephedrine enantiomers were separated with accept-

able efficiency, and the band broadening was reduced

because of the smaller size of the NPs. Also, by incor-

porating two different templates during the preparation

process, a multiple-template method was developed to

increase the binding capability of MIPs [30]. The affinity

for the targets was strongly affected by the relative

amounts of the two templates. Using a partial-filling

technique in CE, the enantiomers of propranolol and

ropivacaine were simultaneously separated using the

multiple-template method. However, these MIPs are bulk

materials and have to be triturated to desired sizes. Yin

et al. [31] synthesized S-propranolol-imprinted NTs in

the pores of anodic aluminum oxide to avoid trituration.

These molecularly-imprinted NTs can be used for con-

trolled release of target chiral drug with high capacity

and good site accessibility.

Similar to silica-based nanomaterials, chiral organic

nanomaterials could also be obtained through template-

based methods. Chiral mesoporous polypyrrole NPs were

prepared using a chiral block copolymer of polyethylene

oxide as the template [32]. After extracting the template,

the chiral resolution toward racemic valine and alanine

was confirmed by circular dichroism and optical polar-

imetry. As the chiral block copolymers were limited by

their species and preparation, novel helical poly(phen-

ylacetylene) was designed with bulky crown ether as

pendant [33]. This polymer showed high sensitivity to

chiral amino acid and could detect an extremely smallenantiomeric imbalance in a-amino acids (less than

0.005% enantiomeric excess of alanine).

Hybrid materials consisting of organic and inorganic

building blocks, especially core/shell NPs, could combine

the advantages of the individual components. In some

cases, using silica as the shell can protect the core from

aggregation and minimize the environmental influences.

Chen et al. [34] reported chiral hybrid NPs consisting of

an optically active helical polyacetylene core and a silica

shell. The hybrid NPs possessed large optical activities,

arising from the helical core, and at the same time, the

silica shell provided desirable protection for the core. The

chiral recognition ability was confirmed by enantiose-lective crystallization of amino-acid enantiomers. Re-

cently, the same group improved the preparation

method and obtained hollow two-layered chiral NPs [35]

by removing the optically active helical polymer. These

hollow NPs exhibited low density, high stability, good

dispersity and considerable enantioselectivity toward

racemic alanine.

4. Metal-organic frameworks

Metal-organic frameworks (MOFs), known as a sub-classof the coordination polymers, are crystalline materials

generated by the association of metal ions and organic

ligands [36]. They have emerged as a promising type of

material for their potential applications in gas storage,

separation and catalysis due to their fascinating struc-

tures [37,38]. In recent years, many chiral MOFs, syn-

thesized by incorporating enantiomerically pure

homochiral building blocks and occasionally achiral

building blocks, have been used in enantioselective sep-

aration [36,38].

Xiong et al. [39] first reported a homochiral 3D zeolite-

like MOF, which was prepared by treating chiral bridging

ligand quitenine with Cd(OH)2, for the enantioselective

adsorption of racemic 2-butanol. The single-crystal

X-ray diffraction (XRD) study performed on the complex

of chiral MOFs(S)-2-butanol clearly revealed that (S)-2-

butanol was wrapped in the chiral cavities of the

network. After being heated to a suitable temperature,

(S)-2-butanol could be completely removed, and the ee

value of the desorbed (S)-2-butanol was estimated to be

as high as 98.2%.

Bradshaw et al. [40] recently reported several homo-

chiral MOFs whose enantioselective sorption strongly

depended on guest size. For example, the binaphthol


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guest was enantioselectively adsorbed onto MOFs with

an enantiomeric excess of 8.3%, while no enantioselec-

tion toward ethyl-3-hydroxybutyrate, terpenes menth-

one and fenchone was observed. Also, many other chiral

MOFs with high enantioselectivity were synthesized

using amino-acid backbones or cyclic clusters with en-

zyme-like chiral cavities [4143]. Moreover, creatinghomochiral MOFs from the achiral building blocks for

the resolution of racemic molecules was always a great

challenge. In 2006, Xiong et al. [44] prepared chiral

MOFs by unstirred crystallization [45] of achiral building

blocks, and described the enantiomeric resolution of

racemic 2-butanol. This work provided new insight into

the enantioseparation methods by chiral MOFs.

Compared with enantioselective adsorption, chiral

chromatographic separation is more efficient. Nuzhdin

et al. [46] developed a column chromatography with

chiral MOFs as the chiral stationaryphase. A 33-cm chiral

column was prepared by loading a glass tube (8 mm inner

diameter) with the suspension of chiral MOFs. The modelracemic compounds were directly loaded onto the top of

the column, and complete baseline separation of sulfoxide

was achieved. They studied the separation mechanism by

introducing electro-withdrawing substituents in the aro-

matic ring of sulfoxides. The results revealed that both the

sorption constants and ees of sorption were decreased due

to the reduced coordinating ability of the sorbate induced

by the electronic effects.

Padmanaban et al. [47] also developed a chiral HPLC

column employing highly ordered chiral MOFs as the

stationary phase for enantioseparation. Usually, these

MOF-packed columns could not provide high resolutionbecause of the considerable diffusion resistance of bulky

packing. As a result, the MOF-coated capillary chiral

column was recently developed. Xie et al. [48] prepared

chiral open-tubular columns for high-resolution GC

separation of chiral compounds. The chiral MOF with a

single-handed helical structure was coated onto the

capillary by the dynamic coating method. After being

heated, the single-stranded helices lost water molecules

and cross-linked to a chiral open framework, which was

critical for subsequent chiral separation. The columns

showed excellent selectivity and possessed good recog-

nition ability toward a wide range of organic compounds

(e.g., racemates, isomers, alkanes and alcohols).

5. Metal nanomaterials

In recent years, chiral metal NPs have shown various

unexpected advantages in asymmetry catalysis [4952],

chiral separation [5355] and enantioselective detection

[56,57]. Here, we mainly discuss the reports about metal

nanomaterials applied in chiral separation or enantiose-

lective detection. For the applications on asymmetry

synthesis, readers can refer to the recent reviews [5860].

Gold NPs (AuNPs) are very attractive in nanotech-

nology [6163] due to their ease of preparation, con-

trollable particle size, narrow size distribution, good

solubility in buffer and convenient modification via the

Au-S bond. Dispersing chiral selector-modified AuNPs in

running buffer to act as the chiral pseudo-stationary

phase in CE is easy. Yang et al. synthesized thiolatedbCD modified AuNPs and dispersed them in running

buffer for chiral separation of enantiomers [53]. Efficient

baseline separation with theoretical plate numbers up to

2.4 105 and chiral separation resolution up to 4.7 was

achieved with very low concentration of thiolated bCD

modified AuNPs. The corresponding concentration of

thiolated bCD modified AuNPs in the running buffer

was only 0.300.53 mM, which was much lower than

the optimum concentration of 15 mM if pure bCD was

used. These results indicated that thiolated bCD-modi-

fied AuNPs can provide sufficient interaction with the

analytes through the increased surface area. This

method was restricted from repeated use as the runningbuffer had to be updated during experiments. Hence, the

same group developed another enantioselective CE

method by immobilizing the thiolated b-CD-modified

AuNPs onto the inner wall of a capillary [54]. The fused-

silica capillary was first coated with positively-charged

poly(diallydimethylammonium chloride), and then the

negatively-charged thiolated b-CD-modified AuNPs were

assembled onto the capillary by electrostatic interaction.

The capillary column constructed had high stability,

steady electroosmotic flow (EOF) mobility over a wide pH

range 3.09.2 and good column-to-column reproduc-

ibility.Chiral-modified AuNPs could also be chemically

bonded to the pre-derivatized capillary by the Au-S bond,

to get a more stable separation performance. Generally,

the capillary or the microchannel was pre-derived with

(3-mercaptopropyl)-trimethoxysilane to provide thiol

groups, and then chiral-modified AuNPs could be linked

onto the surface by the Au-S bond. Based on this

chemistry, a chip-based enantioselective CE employing

bovine serum albumin (BSA)-modified AuNPs as chiral

stationary phase was developed [55]. Compared with the

untreated capillary, the incorporation of AuNPs greatly

increased the phase ratio and favored the generation of

sufficient EOF via the negatively-charged citrate. This

micro-device exhibited excellent enantiomeric selectivity

and good run-to-run repeatability in the enantiosepa-

ration of ephedrine and norephedrine. In addition, this

capillary could keep an enantioselective lifetime for more

than 1 month. Similarly, the BSA-modified AuNPs were

also incorporated into a silica monolith and used as

chiral stationary phase for chiral separation [64].

AuNPs were also used for enantioselective adsorption

[56] and recognition [65]. Shukla et al. [56] employed

either DD- or LL-cysteine-modified AuNPs for enantioselec-

tive adsorption of propylene oxide. The enantioselective




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adsorption process was monitored by optical rotation

measurements, which were based on the rotation of

polarized light by (R)- and (S)-propylene oxide being en-

hanced through interaction with AuNPs. The results

demonstrated that LL-cysteine (DD-cysteine)-modified

AuNPs could selectively adsorb the (R)-propylene oxide

((S)-propylene oxide). When exposed to racemic propyl-

ene oxide, the chiral AuNPs selectively adsorbed one

enantiomer and gave an enantiomeric excess in the

solution phase, thereby inducing enantioselective sepa-

ration. Similarly, an electrochemical sensor for enantio-

selective recognition of 3,4-dihydroxyphenylalanine was

developed employing penicillamine-modified AuNPs [65].

With regard to the method discussed above, working

with specific instruments is necessary, so it is still highly

desirable to develop a simple, rapid, sensitive and

instrument-independent method for chiral recognition.

One of the most urgent challenges is to achieve visual

discrimination of enantiomers by an appropriate color

change. Metal nanomaterial-based colorimetric sensors,

due to their simplicity, high sensitivity and lower cost,

were promising in this field. An ultra-efficient enantio-separation and detection platform for DD- and LL-cysteine

was therefore developed by employing uridine 5-tri-

phosphate-capped AgNPs (Fig. 2) [57]. The aggregation

of 5-triphosphate-capped AgNPs was selectively induced

by DD-cysteine, which allowed the rapid enantiomeric

discrimination of racemic cysteine without any prior

derivatization or specific instruments. After centrifuga-

tion, an excess of the other enantiomer was left in the

solution and resulted in an enantioseparation. Simplicity

and efficiency made this method promising for the

future.

6. Magnetic nanomaterials

Derivatized magnetic NPs (MNPs) with large surface

areas could form complexes with target molecules via

multiple interactions. At the same time, the complexes

could be conveniently separated from the solution by

applying magnetic field [14]. Compared with conven-

tional separation methods, this process is noted for its

speed, simplicity and cost effectiveness. MNPs, immobi-

lized with an appropriate chiral catalyst or chiral selec-

tor, have been successfully used for asymmetric

synthesis [66] and enantioseparation [6770]. Here, we

focus on the work employing chiral selector-modified

MNPs for enantioseparation. MNPs tagged with an

appropriate chiral selector were expected to interact

selectively with a single enantiomer and form complexes,

which were easily removed by an external magnet. The

enantioseparation process is just like enantioselective

fishing.

Ghosh et al. [67] synthesized carboxymethyl-b-cyclo-

dextrin-bonded Fe3O4/SiO2 core-shell NPs, and applied

these MNPs in the enantioselective adsorption of chiralamino acids. Adsorption-equilibrium experiments dem-

onstrated that the adsorption capacities were higher for

LL-enantiomers than the corresponding DD-enantiomers.

But the enantioselective adsorption ability for racemic

solution was not investigated.

Choi et al. [68] developed a method employing race-

mic amino-acid solutions as model compounds for fur-

ther study (Fig. 3). First, MNPs with (S)-chiral selector

(MNPs/(S)-CS) were added into the racemic solution for

enantioselective adsorption. The enantiomeric excess

was evaluated by chiral HPLC and confirmed the

Figure 2. Colorimetric discrimination of LL-cysteine and DD-cysteine using 5-triphosphate-capped Ag nanoparticles [57] (Reprinted with permis-sion from [57], 2012, American Chemical Society).




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enantioselectivity of MNPs/(S)-CS. But the enantioselec-

tivity was not stratified. Consequently, another method

was developed, employing equal non-magnetic silica

particles tagged to the antipode (R)-chiral selector

(MNPs/(R)-CS) and MNPs/(S)-CS at the same time. After

extraction, the MNPs/(S)-CS-enantiomer complexes were

collected by a magnet, while the MNPs/(R)-CS-enantio-

mer complexes were collected by decantation after cen-

trifugation. These results of chiral HPLC separation

demonstrated that the enantioselectivity was improved

when MNPs/(R)-CS was simultaneously used. This

method indicated that the two contrary chiral selectors

Figure 3. The separation of enantiomers using (a) MNPs/(S)-CS only; and, (b) MNPs/(S)-CS and NMPs/(R)-CS at the same time [68] (Reprintedwith permission from [68], 2012, Royal Society of Chemistry).

Figure 4. Preparation procedures and separation mechanism ofb-CD modified Fe3O4 nanoparticles for amino acids enantiomers [69] (Reprintedwith permission from [69], 2012, Royal Society of Chemistry).




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could have some synergistic effects for enantioseparation

and provided a new insight to the development of a high-

efficiency enantioselective method.

In most conditions, washing to retrieve the target

molecules was necessary for further experiments. But

elution made the method complicated, and the organic

solvent was not economic or environmental friendly. Asan alternative, Chen et al. [69] developed a photo-con-

trolled inclusion-and-exclusion method to induce the

release of the adsorbed enantiomers in reverse (Fig. 4).

The chiral selective system also employed b-CD-func-

tionalized Fe3O4 NPs as chiral adsorbents. After extrac-

tion, pure optical enantiomer adsorbed on the NPs was

released via the photo-controlled inclusion-and-

exclusion reactions of azobenzene derivatives with b-CD.

The reversible photo-controlled inclusion-and-exclusion

process enabled recycled use of b-CD-functionalized

Fe3O4 NPs in enantioseparation. It is worth mentioning

that, after repeated use for more than 5 times, b-CD-

modified Fe3O4 NPs still showed good enantioselectivityfor LL-tryptophan, indicating that b-CD-modified Fe3O4NPs were highly applicable in repeated recycling.

Another solution, packing chiral MNPs into microchip

channels, was developed to achieve complete enantio-

separation [70]. Molecularly-imprinted MNPs, with S-

ofloxacin as the template molecule, were located as

stationary phase in the microchannel of the microfluidic

device. Under optimized conditions, efficient molecular

recognition of ofloxacin enantiomers was achieved in

195 s with good reproducibility and precision. Compared

with a conventional device, the MNPs could be conve-

niently localized to the predetermined position byapplying an external magnetic field, and the length of

the packing zone could be easily tuned by changing the

length of the magnet.

7. Carbon nanotubes

CNTs with good absorbability and electrical properties

have been used in many fields {e.g., electrochemical

biosensors [71] and chromatographic separation [72]}.

Physical studies revealed the existence of chirality in the

structure of CNTs [73], but CNTs alone have not so far

been successfully used in enantioseparation. Theoretical

studies and experimental results showed that CNTs

cannot supply enough energy differences between

enantiomers [74,75], so adding chiral selectors (e.g.,

b-CD) or an achiral assistant was necessary when CNTs

were used for chiral separation.

In general, CNTs are insoluble in most common sol-

vents, due to the aggregation induced by van der Waals

attractions. In order to produce pseudo-stationary pha-

ses in CE, one effective solution was using surfactant-

coated CNTs {e.g., the CE separation of ()-clenbuterol

was performed using b-CD-modified multi-walled CNTs

(MWCNTs) [76]}. Compared with the other three

nanomaterials, b-CD-MWCNTs showed better results,

because MWCNTs formed a network in the running

buffer and presented a larger surface area to allow better

contact with the analytes.

However, the addition of long-chain surfactants was

not always suitable for specific systems. Another solutionwas to cut the single-walled CNTs (SWCNTs) into short

pipes by chemical oxidation in a mixture of concentrated

sulfuric and nitric acids [77]. On the one hand, the

shortened SWCNTs could be well dispersed in distilled

water after ultrasonic agitation, benefiting from the

activated hydrophilic groups on the surface. On the

other hand, the shortened SWCNTs could offer more

carboxylic groups for binding chiral selectors. When the

short SWCNTs were functionalized with BSA to form

BSA-SWCNT conjugates, this showed that, without the

BSA-SWCNT conjugates, no separation of tryptophan

enantiomers was achieved. After the addition of 0.075

0.1 mg/mL of BSA-SWCNT conjugates, baseline sepa-ration was achieved, and the resolution increased along

with the increase of BSA-SWCNT conjugates. Under

optimal conditions, successful separation of tryptophan

enantiomers was achieved in less than 70 s with a res-

olution factor of 1.35, illustrating the acceptable

enantioselectivity of the BSA-SWCNT conjugates.

Similarly, HP-b-CD was successfully bonded to

MWCNTs, and the HP-b-CD-modified MWCNTs were

used as additives in the TLC stationary phase for chiral

separation [78]. Clenbuterol enantiomers were separated

with better resolution. This method could benefit from

the advantages of TLC, including high sample through-put, accessibility and cost effectiveness, to construct a

rapid, robust chiral separation method.

Apart from the above methods, CNTs could be bonded

to the inner wall of a capillary and applied as the support

for chiral selectors. To investigate the effect of SWCNTs

on enantioseparation, Zhao et al. [79] prepared two

capillary columns for GC, one containing the chiral ionic

liquid, and the other containing the complex of chiral

ionic liquid and SWCNTs. Taking 12 racemates as model

compounds, the column with SWCNTs was able to sep-

arate eight chiral compounds, while the column without

SWCNTs was only able to separate four racemates. The

SEM images showed that most of the bonded SWCNTs

were linked end to end and formed a layer with a skeletal

network structure. Therefore, the SWCNT-modified

capillary column possessed a larger surface for the chiral

ionic liquid stationary phase, which enhanced the

interaction between the chiral stationary phases and the

analytes. Compared with dispersal in running buffer, the

chemical-bonding approach provided more stable, reus-

able capillaries.

In addition to the above chiral-modified CNTs, recent

research demonstrated that achiral-modified CNTs also

exhibited ability for chiral recognition. Martnez et al.




10/12

[80] prepared achiral surfactant-coated MWCNTs via

sonication of MWCNTs and SDS until they formed a final

homogeneous phase. The modified MWCNTs were stable

under high electric field and compatible with the detec-

tor. What is more, sonication allowed modifications of

the chiral properties of CNTs. The resulting material was

then used for chiral separation using the partial-fillingtechnique. The enantiomers (+)- and (-)-norephedrine,

(-)-ephedrine and (+)-N-methylephedrine were com-

pletely resolved, demonstrating that the inherent chi-

rality of MWCNTs was amplified through the

modification and sonication. This work demonstrated

the possibility of directly using carbon nanostructures as

chiral selectors for the separation of racemates.

8. Well-oriented nanolayers

Many kinds of well-oriented metal solid surfaces, with

modification or not, have the ability of chiral recognitionwhen they interact with chiral molecules [81]. Chiral

surfaces can be classified into two main categories: sur-

faces derived from achiral bulk structures; and, those

produced by chiral molecules self-assembling onto an

achiral surface.

In the first method, a chiral surface was obtained by

cutting single crystals of bulk achiral metals along a

specific crystal face. The periodic arrayed surfaces ob-

tained can be used for chiral recognition. For example,

Au (110) surfaces can adsorb enantioselectively. Con-

sidering the affinity between the thiol group and Au,

cysteine was selected as a model compound [82]. Thescanning tunneling microscope (STM) image showed

that the deposition of LL-cysteine molecules on the Au

(110) surface resulted in the formation of bright pro-

trusions at the sides of the close-packed rows of gold

atoms. The protrusions always existed as pairs, and the

main axis running through the two bright protrusions

was always rotated 20 clockwise with respect to the

close-packed direction. When the DD-cysteine was depos-

ited, similar molecule pairs rotated 20 anticlockwise.

Moreover, for racemic mixtures, the STM images also

showed molecular dimers identical to the previous

measurements. These exclusively homochiral molecular

pairs indicated the chiral recognition ability of the Au

(110) surface. For further studies, Au (111) and Pt (111)

surfaces were also confirmed to be able to adsorb

enantioselectively [83,84].

Another method of obtaining a chiral surface is to

immobilize chiral molecules onto an achiral surface by

self-assembling. The chirality of the surface is derived

from the adsorbed chiral ligands that retain their chi-

rality. Through this method, five molecules, including

LL-cysteine, DD-cysteine, N-acetyl-LL-cysteine, LL-glutathione

and DD-penicillamine, were assembled on a gold surface.

The self-assembled monolayers were used in crystalliza-

tion experiments for supersaturated racemic solutions

and supersaturated solutions with enantiomeric excess.

[85]. Crystallization experiments indicated that, when

starting with racemic solutions, one enantiomer in ex-

cess was obtained, while crystals of the pure enantiomer

were obtained when starting with a solution having an

eevalue of 50%. The results revealed that these chiralself-assembling monolayers had the ability to adsorb

enantioselectively, but this ability was still restricted to

the enantiomeric excess of the solution.

Similarly, many other chiral molecules (e.g., phenyl-

alanine) were also distinguished by this method [86].

Self-assembling of chiral molecules with higher selec-

tivity may improve the enantioselectivity of well-oriented

nanolayers in the future.

9. Conclusions

As an important and universal phenomenon in nature,chirality is related to many significant biological activi-

ties. The development of efficient enantioseparation

technologies is extraordinarily significant for the phar-

maceutical industry and asymmetric synthesis. A wide

range of nanomaterials with large surface area and

specific chemical and physical properties have been used

in enantioseparation, including mesoporous silica, or-

ganic polymers, MOFs, metal NPs, MNPs, CNTs and well-

oriented chiral nanolayers, to improve the selectivity,

stability and efficiency. The chiral recognition of

nanomaterials is realized through enantioselective

adsorption, especially when they are used as stationary/pseudo-stationary phases in chiral chromatographic

(HPLC, TLC and GC) and CE separation.

Although many novel nanomaterials have been ap-

plied in chiral separation and remarkable separations

have been achieved, the mechanism of nanomaterials in

chiral separation remains unclear and untouched in the

literature. The most likely explanation is still based on

the three-point interaction theory, which lacks theo-

retical and experimental illustration and need to be

further investigated. Under the guidance of current

theory, the design and the synthesis of nanomaterials

with high selectivity, stability, reusability and efficiency

are the future orientation of nanomaterials applied in

enantioseparation. Magnetic and metal nanomaterials

will have high potential in this field. Magnetic nanom-

aterials allow fast, convenient separation from the

solution. Metal-based nanomaterials, with unique SPR

properties, are suitable for the development of simple,

rapid and sensitive sensors for chiral recognition.

Acknowledgements

This work was financially supported by the National

Natural Science Foundation of China (Grant No.




11/12

21027012) and the fundamental research funds for the

central universities.

Appendix A. Supplementary data

Supplementary data associated with this article can befound, in the online version, at http://dx.doi.org/

10.1016/j.trac.2012.07.002.

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