Investigation of peptoid chiral stationary phases terminated with N′-substituted phenyl-L-proline/leucine amide

Article abstract of DOI:10.1002/cjoc.201201041

Eight peptoid chiral stationary phases (CSPs) terminated with N′-substituted phenyl-L-proline or L-leucine amide were prepared and evaluated under normal phase mode. With 59 racemic analytes, we compared the enantiomeric separations on CSPs terminated with p-methylphenyl, p-chlorophenyl and unsubstituted phenyl. For short peptoid selectors containing only one S-N-(1-phenylethyl) glycine (Nspe) unit, the terminal p-methyl substituent did not affect chiral recognition abilities significantly. In L-proline amide terminated CSPs, p-chloro substituent resulted in obviously inferior selectivity while in L-leucine amide terminated CSPs, it worked much better. Longer peptoid selectors containing two more Nspe units generally performed much better than the shorter ones, due to the great contributions of peptoid chain to chiral recognition. Meanwhile, the effects of the terminal substituent on selectivity were found changed on these CSPs. For CSPs terminated with L-leucine amide, the terminal p-chloro substituent in longer selector no longer produced the best recognition ability; the CSP with unsubstituted phenyl instead performed best. Comparison of these peptoid CSPs varied in terminal substituents and chain length was conducted to gain a better understanding of the chiral recognition mechanism of this type CSP and promote the development of more useful CSPs. Copyright

Full text of DOI:10.1002/cjoc.201201041

FULL PAPER
DOI: 10.1002/cjoc.201201041
Investigation of Peptoid Chiral Stationary Phases Terminated
with N'-Substituted Phenyl-L-proline/leucine Amide†
Wu, Haiboa(吴海波)
Song, Guangjuna(宋广军)
Ke, Yanxiong*,a(柯燕雄)
Liang, Xinmiaoa,b(梁鑫淼)
a School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
b Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China
Eight peptoid chiral stationary phases (CSPs) terminated with N'-substituted phenyl-L-proline or L-leucine am-
ide were prepared and evaluated under normal phase mode. With 59 racemic analytes, we compared the enantio-
meric separations on CSPs terminated with p-methylphenyl, p-chlorophenyl and unsubstituted phenyl. For short
peptoid selectors containing only one S-N-(1-phenylethyl) glycine (Nspe) unit, the terminal p-methyl substituent did
not affect chiral recognition abilities significantly. In L-proline amide terminated CSPs, p-chloro substituent re-
sulted in obviously inferior selectivity while in L-leucine amide terminated CSPs, it worked much better. Longer
peptoid selectors containing two more Nspe units generally performed much better than the shorter ones, due to the
great contributions of peptoid chain to chiral recognition. Meanwhile, the effects of the terminal substituent on se-
lectivity were found changed on these CSPs. For CSPs terminated with L-leucine amide, the terminal p-chloro sub-
stituent in longer selector no longer produced the best recognition ability; the CSP with unsubstituted phenyl instead
performed best. Comparison of these peptoid CSPs varied in terminal substituents and chain length was conducted
to gain a better understanding of the chiral recognition mechanism of this type CSP and promote the development of
more useful CSPs.
Keywords chiral stationary phase, peptoid, enantiomeric separation, proline amide, leucine amide
Introduction
Ph
O
Ph
O
O
O
O
O
O
O
H
HN
N
N
N
Si
Nowadays, the separation of enantiomers on chiral
stationary phases (CSPs) by high-performance liquid
chromatography (HPLC) has been an attractive method
for analysis and preparation of enantiomers.[1,2] In the
last two decades or so, CSPs have evolved a lot based
on the pioneering works by Davankov, Pirkle, Okamoto,
Blaschke, Allenmark, Hermansson, Armstrong, Gaspar-
rini, and Lindner.[2,3] Especially CSPs based on poly-
saccharide,[4-6] protein,[7-10] cyclodextrin[11,12] and mac-
rocyclic antibiotics[13,14] were most widely used today.
Peptoids, as a class of non-natural, sequence- and
length-controlled polymers were investigated a lot as
peptide mimics in the last two decades.[15,16] Consider-
ing peptoid with α-chiral aromatic side chains usually
adopt helical conformation[17-19] and it has some struc-
tural similarities with selector of polyacrylamide based
CSP,[20,21] we have been interested in developing pep-
toid based CSPs recently and reported a new type of
CSPs based on peptoids containing S-N-(1-phenylethyl)
glycine (Nspe) units for the first time.[22] Subsequently,
we modified the terminal group of peptoid selector in
N
N
Ph
Ph
Ph
CSP 1
Ph
Ph
O
O
O
O
O
O
H
H
N
N
Si
N
N
N
N
H
O
O
Ph
CSP 2
Figure 1 Structures of stationary phases CSPs 1 and 2.
order to improve the application spectrum of peptoid
CSPs.[23] By introducing new chiral blocks as the ter-
minal moity of chiral selector, the enantioselectivities of
peptoid CSPs were improved efficiently. Figure 1 gives
the structures of previously reported CSP 1 and CSP 2
terminated with N'-phenyl-L-proline/leucine amide,
which exhibited apparent chiral recognition (separation
factor≥1.05) for 34 and 35 analytes out of the 59 tested
racemates. Considering that introducing electron-dona-
*
E-mail: key@ecust.edu.cn; Tel.: 0086-021-64250622; Fax: 0086-021-64250622
Received October 24, 2012; accepted December 2, 2012; published online December 13, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201201041 or from the author.
Dedicated to the 60th Anniversary of East China University of Science and Technology.
†
Chin. J. Chem. 2012, 30, 2791—2797
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Wu et al.
FULL PAPER
Methods
ting/withdrawing substituents on aryl rings in selector
can usually affect chiral recognitions significantly,[24-29]
we introduced p-methyl or p-chloro group on the termi-
nal phenyl group of peptoid selector terminated with
N'-phenyl-L-proline/leucine amide in this study. The
influences of these substituents on selectivities of pep-
toid CSPs were investigated.
Test racemates (TR-1-TR-59, Supporting Informa-
tion) used for chiral separation evaluation were dis-
solved in HPLC grade ethanol to form about 1 mg/mL
concentration.
For chromatographic evaluations, the column tem-
perature was held constantly at 20 ℃, and the flow rate
was 0.8 mL/min. The injection volume was 1 μL. The
UV detection wavelengths were set at 220 nm.
Experimental
The retention factor (k) was determined by (tr－t0)/t0,
in which tr is retention time of analytes and t0 is dead
time. Specifitcally, k values of the first and second
eluting enantiomers were defined as kA and kB, respec-
tively. The separation factor α was calculated by kB/kA.
Resolution factor (Rs) is equal to 1.18×[(trB −trA)/(W1/2A
＋W1/2B)], where trA and trB are the retention times of the
first and second eluting enantiomers, respectively, and
W1/2 is the peak width at half height. t0 was measured
with 1,3,5-tri-t-butylbenzene as void volume marker.
Apparatus
All the chromatographic separations were performed
on Waters HPLC system consisting of 515 HPLC pump,
7725i manual injector, model 1500 column heater and
2489 UV/Visible detector (USA).
Columns were made in our laboratory by dispersing
the modified silica gel into methanol and packing them
into stainless steel columns (150 mm×4.6 mm I.D.,
purchased from Max Stevenson, Berlin, Germany).
1H NMR identifications were carried out on a Bruker
400 (Germany) at a temperature of 25 ℃. All 1H
chemicals shifts are reported relative to tetramethylsi-
lane. Elemental analysis (EA) was measured on an ele-
mentar vario EL III (Germany).
Results and Discussion
The CSPs were synthesized according to the previ-
ously reported method by replacing the initial material
aniline with p-methyl/chloro aniline and controlling the
peptoid chain at a certain length. The structures of the
chiral selectors were shown in Figure 2. Among these
stationary phases, CSPs 3—5 and CSPs 6—8, respec-
tively, terminate with L-proline amide and L-leucine
amide wherein the phenyl group bonded to nitrogen is
substituted by p-methyl or p-chloro group or unsubsti-
tuted. CSPs 9 and 10, compared with CSPs 7 and 8,
have two more Nspe units. Elemental analysis results
and calculated selectors loading of these CSPs are
showed in Table 1.
When the terminal phenyls in these CSPs were sub-
stituted by electron-donating or electron-withdrawing
group, the substituent changed not only the electronic
nature of phenyl ring directly but also the polarity of the
amide group via an inductive effect. Electron-with-
drawing substituent on phenyl will strengthen the acid-
ity of NH proton of terminal amide group while elec-
tron-donating substituent can increase the electron den-
sity at the carbonyl oxygen of the terminal amide group.
Table 2 gives the chemical shifts of the terminal NH
proton in chiral organosilanes of CSPs 3—8, which sup-
ports the above supposal. We can find that p-methyl
substituent resulted in down shifts of 1H NMR signal of
NH proton while p-chloro substituent led to up shifts.
Thus, the substituent may affect retention behavior and
enantioselectivity of CSP by changing the π-π interac-
tion, hydrogen bonding interaction or dipole-dipole in-
teraction between selectand and selector.
UPLC-ESI-LC/MS analysis was performed by Wa-
ters ACQUITY UPLCTM system with a Quattro Micro
MS operating in ESI＋ mode (Waters, USA). Separation
was carried out on ACQUITY UPLC BEH C8 column
(1.7 μm, 50 mm×2.1 mm i.d.) (Waters, Ireland).
Chemicals and reagents
Chloroacetyl chloride, sodium carbonate, potassium
carbonate, acetone, and toluene were purchased from
Shanghai Lingfeng Chemicals Co., Ltd. (China).
L-Proline, L-leucine, aniline, p-aminotoluene and
p-chloroaniline were purchased from Alading Reagent
(Shanghai) Co., Ltd. (China). Methanol and dichloro-
methane were purchased from Shanghai Heqi Chemi-
cals Co., Ltd. (China). S-α-Phenylethylamine was pur-
chased from Shanghai Hanhong Chemicals Co., Ltd.
(China). HPLC-grade spherical silica gel (5 μm particle
size; 10 nm pore size; 300 m2/g surface area) was pur-
chased from Fuji Silysia Chemical Ltd. (Japan). HPLC
grade n-hexane, 2-propanol, trifluoroacetic acid (TFA)
and triethylamine (TEA) were purchased from Tedia
(USA). Triethoxy(3-isocyanatopropyl) silane was do-
mestic reagents and purified by distillation before use.
Analytes were obtained from commercial suppliers
or prepared according to relative references. Chiral sta-
tionary phases CSP 1 and CSP 2 were prepared in our
previous work.
Preparation of CSPs 3—10
According to the preparation of CSP 1 and CSP 2 in
our previous paper,[23] other CSPs in this study were
prepared similarly. Details are available in Supporting
Information.
The 59 racemic analytes used to evaluate CSPs 1 and
2 were also tested on CSPs 3—10 in this study. The
number of separations with α≥1.05 on each column is
summarized in Figure 3. Chromatographic data of some
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2791—2797

Investigation of Peptoid Chiral Stationary Phases Terminated with N'-Substituted Phenyl-L-proline/leucine
O
O
O
O
O
O
H
H
O
O
O
H
N
N
Si
N
HN
N
N
Si
N
N
H
O
O
O
R
CSP 3, R = H
CSP 4, R = CH3
CSP 5, R =Cl
CSP 6, R = H
CSP 7, R = CH3
CSP 8, R =Cl
R
O
O
O
H
H
N
N
N
Si
O
N
N
N
O
H
O
O
O
R
CSP 9, R = CH3
CSP 10, R = Cl
Figure 2 Structures of stationary phases CSPs 3—10.
Table 1 Element analysis data and chiral selector loading for
Table 3 Chiral resolution results on CSPs 3—5a
CSPs
Structure
CSP
KA
α
Rs
Mp
Selector loading/(mmol•g－
)
1
CSP
C/% H/%
6.01 1.20
9.89 1.57
6.37 1.22
6.71 1.34
7.28 1.44
9.13 1.54
6.94 1.33
N/%
0.92
1.37
0.96
1.10
1.37
1.48
0.94
1.05
CSP 3
CSP 4
CSP 5
CSP 6
CSP 7
CSP 8
CSP 9
0.16
0.24
0.17
0.20
0.24
0.26
0.11
0.12
CSP 3 2.31 1.22 2.31
CSP 4 3.12 1.25 2.23
CSP 5 1.76 1.07 0.64
A
A
A
OH
OH
TR-1
Br
Br
CSP 10 9.34 1.64
CSP 3 2.26 1.30 2.93
CSP 4 3.50 1.34 2.97
CSP 5 1.63 1.08 0.73
A
A
A
OH
OH
Table 2 Chemical shift of the terminal NH proton in chiral
organosilane of peptoid CSP
TR-3
CSP CSP 3 CSP 4 CSP 5 CSP 6 CSP 7 CSP 8
δ
9.42
9.30
9.46
8.69
8.50
8.91
CSP 3 2.53 1.04
CSP 4 3.51 1.09 1.01
CSP 5 2.66
—
B
B
B
typical separations on CSPs terminated with proline
amide and leucine amide are displayed in Table 3 and
Table 4, respectively.
OH
OH
By comparing the separation data of the CSPs ter-
minated with proline amide (CSPs 3—5), we can find
that CSP 4 containing an electron-donating methyl sub-
stituent on the terminal phenyl group showed similar
enantiorecognition ability with CSP 3. Among the 59
tested racemates, CSP 3 and CSP 4, respectively, sepa-
rated 15 and 16 compounds. It is probably because that
the unsubstituted phenyl in CSP 3 could also play the
role of a π-donor site as methyl phenyl in CSP 4 during
chiral recognition process.
—
—
TR-5
Br
CSP 3 1.82 1.13 1.11
CSP 4 2.36 1.19 1.42
CSP 5 1.84 1.10 1.04
B
B
B
OH
OH
Br
TR-6
CSP 5 containing electron-withdrawing chlorine
substituent on the terminal phenyl group exhibited much
worse performance than CSPs 3 and 4. Only 6 out of the
59 analytes were separated by CSP 5 with lower separa-
tion factors, such as separations of TR-1, TR-3, TR-6,
TR-57 and TR-59 listed in Table 3. A possible reason
for this is that the terminal NH proton in CSP 5 with its
CSP 3 6.78 1.08 1.04
CSP 4 3.58 1.11 0.95
C
D
C
TsHN
NHTs
CSP 5 7.82 1.03
—
TR-10
Chin. J. Chem. 2012, 30, 2791—2797
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Wu et al.
FULL PAPER
Continued
Continued
Structure
CSP
KA
α
Rs
Mp
Structure
CSP
KA
α
Rs
Mp
CSP 3 1.40 1.27 0.93
CSP 4 1.79 1.35 1.38
A
A
A
CSP 3 2.48 1.26 1.56
CSP 4 2.84 1.20 1.09
CSP 5 2.05 1.11 0.82
E
E
E
O
AcHN
NHAc
H2N HN
S
CSP 5 1.78
~1
—
O
TR-11
CF3
F3C
CSP 3 6.01 1.08 0.97
CSP 4 7.65 1.09 1.05
C
C
C
TR-59
O
O
a
N
N
A, H/I＝70/30; B, H/I＝95/5; C, H/I＝90/10; D, H/I/TFA＝
90/10/0.1; E, H/I/TFA/TEA＝80/20/0.2/0.1. H and I refer to
n-hexane and isopropanol, respectively.
H
H
O
CSP 5 4.98
~1
—
TR-18
CSP 3 2.53 1.04
CSP 4 3.55 1.05
—
—
—
C
C
C
O
N
H
OH
CSP 5 2.38
—
TR-22
CSP 3 3.27 1.04
CSP 4 3.48 1.04
—
—
—
C
C
C
O
O
Figure 3 The number of separations with α≥1.05 on CSPs
3—10, out of the 59 analytes.
N
H
OH
CSP 5 3.41
—
TR-25
acidity strengthened by chloro substituent on phenyl
group resulted in much stronger hydrogen bonding in-
teraction with nitrogen or oxygen atoms in analytes. The
increased non-enantioselective interactions between
selectand and terminal motif of selector thereby weak-
ened the function of the middle chiral centers in peptoid
selector in chiral discrimination process.
Br
CSP 3 2.69 1.05
CSP 4 3.11 1.05
—
—
—
C
C
C
O
N
H
OH
TR-26
CSP 5 2.82
—
Generally, substituted aryl groups in racemic ana-
lytes can also result in different chromatographic be-
haviors on CSPs.[30-33] In this study, we found that
compound TR-3 containing two more bromo substitu-
ents on naphthyls than TR-1 did not show much differ-
ent retention and resolution on CSP 3; while on CSP 4
and CSP 5, TR-3 retained more and retained less than
TR-1, respectively (Figure 4). It is because that the
π-basic methylphenyl in CSP 4 acted as an attractive π-π
interaction site for TR-3 containing π-acidic bro-
monaphthyls while π-acidic chlorophenyl in CSP 5
caused repulsive π-π interaction with TR-3. Similar
cases also happened to TR-22, TR-25 and TR-26. But
such π-π interactions between selector and selectand did
not result in much difference in selectivity, probably
because that they are not the dominant interactions re-
sponsible for chiral recognitions. Besides, there are
some substituted analytes exhibiting similar trends in
retention and selectivity on CSPs 3—5. For example,
compound TR-6 exhibited higher α values and less re-
tention than TR-5 on all these three CSPs (Figure 5). A
reasonable explanation for this is that the bromo sub-
CSP 3 3.34 1.13 1.44
CSP 4 3.65 1.09 0.54
E
E
E
Ph
NH
N
H
O
CSP 5 3.64
~1
—
TR-54
CF3
CF3
S
CSP 3 2.13 1.09 0.79
E
E
E
HN
N
H
H2N
CSP 4 2.34
CSP 5 1.71
~1
—
—
—
(trans)
TR-55
O
CSP 3 2.99 1.83 6.26
CSP 4 2.98 1.62 5.62
CSP 5 2.54 1.29 2.63
E
E
E
O
N
H
H2N
(trans)
TR-57
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2791—2797

Investigation of Peptoid Chiral Stationary Phases Terminated with N'-Substituted Phenyl-L-proline/leucine
Figure 4 Separations of TR-1 and TR-3 on (a) CSP 3, (b) CSP 4 and (c) CSP-5.
Figure 5 Separations of TR-5 and TR-6 on (a) CSP 3, (b) CSP 4 and (c) CSP-5.
stituents adjacent to the hydroxyls in TR-6 hindered the
hydrogen bonding interactions between selector and
selectand and probably they meanwhile strengthened the
π-π interactions between bromophenyls in TR-6 and the
unsubstituted phenyl in Nspe unit in CSPs 3—5, which
likely contributed to the chiral recognitions.
short selectors could be resolved by corresponding
CSPs based on long selectors with comparable or even
higher α values. The better performance of longer pep-
toid selector in enantioselectivity probably benefited
Table 4 Chiral resolution results on CSPs 6—10 and CSP 2a
From the comparison of CSPs terminated with leu-
cine amide, we found that the terminal phenyl and
p-methylphenyl behaved similarly as well. CSPs 6 and 7,
respectively, showed obvious chiral recognitions for 4
and 3 analytes out of the 59 analytes. However, CSP 8
containing p-chlorophenyl group separated as many as
21 compounds. In addition, no separations on CSPs 6
and 7 were found superior to those on CSP 8 (Table 4).
Take compound TR-10 as an example, apparently better
separation can be achieved on CSP 8 (Figure 6). In view
of the flexible structure of leucine amide in these CSPs,
we suppose that the terminal amide NH group probably
formed intramolecular hydrogen bonding with neighbor
carbonyl oxygen. The more acidic terminal NH proton
in CSP 8 is expected to facilitate the formation of such
intramolecular hydrogen bond. Accordingly, a more
stable conformation and a chiral cavity could be con-
structed, as illustrated in Figure 4. We believe that this
special structure of CSP 8 afforded its superiorities in
enantioselectivity.
Structure
CSP
KA
α
Rs
—
—
Mp
A
CSP 6
CSP 7
CSP 8
CSP 2
CSP 9
CSP 10
3.02 ~1
3.61 1.03
A
OH
OH
2.53 1.09 1.09
3.18 1.35 1.59
2.92 1.22 2.71
4.51 1.51 4.57
A
B
A
TR-1
A
CSP 6
CSP 7
CSP 8
CSP 2
CSP 9
CSP 10
3.12 1.34 3.40
3.77 1.21 1.84
4.09 1.66 6.14
7.73 2.19 5.29
3.58 1.74 6.22
5.46 2.37 9.34
C
C
C
C
C
C
TsHN
NHTs
TR-10
CSP 6
CSP 7
CSP 8
CSP 2
CSP 9
CSP 10
3.24
3.73
3.84
—
—
—
—
—
—
D
D
D
A
D
D
CSPs 2, 9 and 10 with longer chain length exhibted
much better selectivities than corresponding CSPs
(CSPs 6—8) with shorter peptoid chain. These three
CSPs showed apparent recognitions for 35, 18 and 32
analytes out of the total 59 tested racemates, respec-
tively. Almost all the analytes separated on CSPs with
O
3.11 1.14 0.95
3.72 1.08 1.14
4.68 1.31 4.11
N
H
TR-12
Chin. J. Chem. 2012, 30, 2791—2797
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Wu et al.
FULL PAPER
Continued
Mp
Continued
Rs Mp
Structure
CSP
KA
α
Rs
Structure
CSP
KA
α
CSP 6
CSP 7
CSP 8
CSP 2
CSP 9
CSP 10
5.12 1.06 0.73
4.89 1.05
A
A
A
B
A
A
CSP 6
CSP 7
CSP 8
CSP 2
CSP 9
CSP 10
2.73 1.14 1.61
2.69 1.16 1.59
2.23 1.31 2.73
2.92 1.14 0.82
2.39 1.12 1.38
3.13 1.16 1.32
F
F
F
G
F
F
O
—
O
N
O
4.24 1.15 1.97
3.09 1.20 1.39
4.56 1.10 1.62
5.88 1.21 2.91
H
H2N
(trans)
O
N
H
N
H
O
TR-57
TR-18
CSP 6
CSP 7
CSP 8
CSP 2
CSP 9
CSP 10
2.50
2.55
—
—
—
—
A
A
A
A
A
A
CSP 6
CSP 7
CSP 8
CSP 2
CSP 9
CSP 10
3.28
3.43
2.82
F
F
F
G
F
F
—
—
—
—
—
—
O
2.36 1.08 0.86
3.48 1.12 0.90
O
S
H2N HN
O
N
O
2.53 1.11 0.49
2.76 1.05
3.30 1.07 0.60
H
O
2.55 1.05
—
—
TR-19
TR-58
3.05 1.12 1.60
a A, H/I＝90/10; B, H/I＝80/20; C, H/I/TFA＝80/20/0.1; D, H/I
＝95/5; E, H/I/TFA＝90/10/0.1; F, H/I/TFA/TEA＝80/20/0.2/0.1;
G, H/I/TFA/TEA＝50/50/0.2/0.1. H and I refer to n-hexane and
isopropanol, respectively.
CSP 6
CSP 7
CSP 8
CSP 2
CSP 9
CSP 10
3.02
3.99
—
—
—
—
—
A
A
A
A
A
A
H
N
3.00 ~1
5.81 1.09 0.72
3.73 1.03
4.55 1.10 1.39
O
TR-21
—
CSP 6
CSP 7
CSP 8
CSP 2
CSP 9
CSP 10
2.75
2.70
—
—
—
—
A
A
A
A
A
A
O
2.21 1.06 0.75
4.43 1.07 0.73
N
H
OH
TR-22
2.17
—
—
2.76 1.09 1.14
Figure 6 Separations of TR-10 on CSPs 6—8.
CSP 6
CSP 7
CSP 8
CSP 2
CSP 9
CSP 10
2.29
2.26
2.28
—
—
—
—
—
—
C
C
C
C
C
C
O
OH
O
O
O
O
O
H
H
O
4.28 1.10 0.50
2.42 1.05
3.92 1.09 1.25
N
N
N
Si
N
O
H
H
—
O
Cl
TR-37
Figure 7 Possible intramolecular hydrogen bond in CSP 8.
CSP 6
CSP 7
CSP 8
CSP 2
CSP 9
CSP 10
1.87
2.03
D
D
D
D
D
D
—
—
—
—
—
—
—
from their more stable and favorable conformation.
These results demonstrate the important role of peptoid
chain in the chiral discrimination process.
OH
1.92 ~1
Moreover, we noted that the longer peptoid chain
affected the contributions of terminal substituents to
chiral recognitions. CSP 2 with unsubstituted terminal
phenyl group showed the best enantioselectivity and
separated 31 more analytes than CSP 6, while CSP 9
and CSP 10 did not outperform CSP 7 and CSP 8 so
much, with only 15 and 11 more analytes separated,
respectively. Especially, no best separations were ob-
tained on CSP 9. CSP 10 showed the best resolutions
just for several analytes such as TR-1, TR-10, and
TR-12. The main reason for this may be that the pres-
ence of p-methyl and p-chloro substituent perturbed the
2.79 1.06
O
TR-38
1.92
—
2.25 1.06 0.68
CSP 6
CSP 7
CSP 8
CSP 2
CSP 9
CSP 10
6.70
7.45
E
E
C
C
E
E
—
—
—
—
—
—
—
—
O
5.19 1.05
3.53 1.04
HO
O
OH
TR-50
5.91
-
7.05 1.05
2796
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 2791—2797

Investigation of Peptoid Chiral Stationary Phases Terminated with N'-Substituted Phenyl-L-proline/leucine
[8] Haginaka, J. J. Chromatogr. A 2001, 906, 253.
polarity of the amide group via an inductive effect,
which caused that the test racemates characterized with
—OH or —NH— groups interacted with the terminal
motif of selector preferably through hydrogen bonding
interactions, therefore the contributions of peptoid chain
to chiral recognitions were lessened relatively.
[9] Millot, M. C. J. Chromatogr. B 2003, 797, 131.
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Peptoid chiral stationary phases (CSPs) terminated
with L-proline and L-leucine amide were further inves-
tigated via introducing p-methyl and p-chloro substitu-
ents on the terminal phenyl group. The influence of
substituent on selectivity was found varied along with
the terminal amino acid and peptoid chain length. For
the short peptoid selectors containing only Nspe unit,
p-methyl substituent performed similarly with no sub-
stituent. In L-proline amide terminated CSPs, p-chloro
substituent resulted in weakest recognition ability while
in L-leucine amide terminated CSPs, it performed best.
Long peptoid selectors containing three Nspe units out-
performing the short ones demonstrated the important
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L-leucine amide, the terminal unsubstituted phenyl in-
stead showed the best selectivity; p-methylphenyl ex-
hibited no obvious superiority; p-chlorophenyl produced
comparable selectivity with unsubstituted phenyl with
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Chin. J. Chem. 2012, 30, 2791—2797
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
2797