2
SHUANG ET AL.
applicability, the high‐performance liquid chromatogra-
phy (HPLC) coupling various chiral stationary phases
(CSPs) has developed into one of the most important
methods in the chiral separation, in which the efficient
and versatile CSPs has played a crucial role in this
method.5
They attributed this to the space steric hindrance caused
by the excessive substituents, leading to the congestion
of the CD's rims and incurring difficulty for the CD's cav-
ities to include the analytes.19 Therefore, only relying on
the functionalization is limited in improving the chiral
performance of the CD‐CSPs. A promising alternative is
developing the novel bridged CD‐CSPs.
The most common CSPs derivatized the cellulose‐
based stationary phase, of which the separation capability
mainly depends upon the effects of inclusion, hydrogen
bonding, and ion‐association provided by the ordered
grooves of the polysaccharides.6 For the purpose of
protecting the ordered structure, this type of CSPs is usu-
ally used in a coating manner, with being employed
under the normal phase (NP) mode that uses the non-
aqueous hexane‐isopropanol as the mobile phase.7,8
Therefore, it is relatively insufficient for these cellulose‐
based CSPs in the compatibility of being combined with
electrospray mass spectrometry (ESI‐MS). As we know,
the exploration of the multimode CSPs (MMCSP) has an
important significance.9,10 The cyclodextrin‐based CSPs
(CD‐CSPs),11 characterized by the multimode compatibil-
ity, which is applicable to the reversed phase (RP),12
NP,13 and polar organic (PO) mode,14 have been fre-
quently used in HPLC.
The bridged cyclodextrins is a new kind of supramo-
lecular compounds coupled by two or more native cyclo-
dextrins.21 By bridging two or more cavities with a
functional linker, the bridged cyclodextrins could signifi-
cantly enhance the original binding ability and molecular
selectivity of the native cyclodextrin, thus being exten-
sively used in molecular recognition, asymmetric cataly-
sis, drug‐directed carriers, and artificial mimic
enzymes.22-24 Many studies have confirmed that the bind-
ing constant of the bridged cyclodextrins with guests was
as high as the level of biological enzymes.23 Moreover,
Liu et al24 found that in addition to the synergistic inclu-
sion, the bridging functional linker could also act as a
pseudo‐cavity21 to generate extraordinary effects.
Although the bridged cyclodextrins has attracted great
attention for a long time, few reports can be found in chi-
ral separation. Chang et al25 prepared three diamino‐
bridged bis(β‐CD)‐CSPs and separated different sets of
chiral compounds including aryl alcohols and β‐blockers,
and acquired the encouraging resolutions. Ai et al26 pre-
pared two ureido‐bridged β‐CD CSPs and achieved the
good resolutions for aromatic positional isomers and
dansyl amino acid enantiomers, which supported the syn-
ergistic inclusion of bridged cyclodextrins in separations.
Our research group27 also prepared an ethylenediamino‐
bridged bis(β‐CD)‐CSP to resolved fourteen β‐blocker
drugs, of which exhibited higher resolutions and wider
enantioselectivities than the native CD‐CSP. Obviously,
the bridged CD‐CSPs has a potential applicable value
for chiral separations.
In 1985, Armstrong15 reported the first stable β‐CD‐
CSP and applied a patent. After that, most studies have
focused on the functionalization of CD‐CSPs such as
alkylation, benzoylation, and phenylcarbamated,16-18
which introduced various interaction sites including π‐π
stacking, dipole‐dipole, ion paring, electrostatic attrac-
tion, and steric repulsive for the chiral separation. How-
ever, the performance of CD‐CSPs could be influenced
by the number of substituents on the CD's rims.19 By
far, according to the degree of substitution, the current
derivatization of CD‐CSPs has been divided into
monoderivatization, partial derivatization, and full deriv-
atization. The monoderivatized CD‐CSPs has well‐defined
structures and chromatographic stability, but the single
substituent may be inefficient to improve the
enantioselectivity.20 The partial‐derivatized CD‐CSPs has
suitable substituents, but with incapability to ensure the
number and the position of substituents that caused the
poor chromatographic reproducibility. The full‐
derivatized CD‐CSPs could readily be obtained by adding
excess modifiers. Armstrong research group12,14,17,18 has
prepared a series of fully aromatic‐derivatized CD‐CSPs
and systematically investigated the chiral separation
mechanism of them. They separated a large spectrum of
enantiomers including the derivatized chiral amines,
alcohols, and amino acids. However, the dansyl amino
acids, crown ethers, and some biologically active com-
pounds were not resolved on their phenethyl‐ and
naphthylethyl‐carbamate fully derivatized CD‐CSPs.17
The bridged bis(β‐cyclodextrin) is usually synthesized
by the bifunctional reagents such as diisocyanates,
dicarboxylic acids, and diacid chlorides.22,25,28 But the
steric hindrance and excessive reaction sites (–OH) of
the bulky cyclodextrins would lead to the above‐
mentioned synthetic approaches inclining a lower yield
(5‐15%), thus having to purify by time‐consuming and
complicated process.22 A satisfactory alternative is the
Click Chemistry reaction proposed by Sharpless for the
first time.29 As a powerful, highly reliable and selective
reaction to rapidly synthesize various new compounds,
the [3
+
2] dipolar cycloaddition between
azides/alkynes catalyzed by copper (I) is a primary Click
Chemistry reaction.30
We herein described a new approach to prepare the
triazole‐bridged bis(β‐CD)–bonded CSP (TBCDP) via