Chiral discrimination of enantiomers with a self-assembled monolayer of functionalized β-cyclodextrins on Au surfaces

Article abstract of DOI:10.1016/S0040-4039(02)00267-8

A facile synthetic route to mercaptyl functionalized β-cyclodextrins was devised and self-assembled onto the gold electrodes of a quartz crystal microbalance (QCM) to afford a durable sensor capable of chiral discrimination of enantiomers.

Full text of DOI:10.1016/S0040-4039(02)00267-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2863–2866
Chiral discrimination of enantiomers with a self-assembled
monolayer of functionalized b-cyclodextrins on Au surfaces
Siu-Choon Ng,* Tong Sun and Hardy S. O. Chan
Department of Chemistry, National University of Singapore, Lower Kent Ridge Road, Singapore, 119260
Received 13 December 2001; revised 29 January 2002; accepted 7 February 2002
Abstract—A facile synthetic route to mercaptyl functionalized b-cyclodextrins was devised and self-assembled onto the gold
electrodes of a quartz crystal microbalance (QCM) to afford a durable sensor capable of chiral discrimination of enantiomers.
© 2002 Published by Elsevier Science Ltd.
Molecular host–guest recognition systems have
attracted significant attention in recent years.1 It
becomes evident that researchers in this area are
increasingly interested in the potential applications of
these systems in chemical sensors and molecular elec-
tronics.2 Among synthetic host molecules, cyclodextrin
(CD) has emerged as an ideal candidate for this pursuit
due to its well-defined molecular cavity and its ability
to accommodate a variety of guest molecules.3 It is
necessary for cyclodextrin to be confined or immobi-
lized on the surface of a substrate such as the Au
surface at the device level. Therefore, several routes for
the synthesis of dialkyl sulfide- and alkanethiol-substi-
tuted cyclodextrins forming self-assembled monolayers
(SAMs) on Au and Ag have been reported. Rojas et al.1
immobilized native b-CD molecules on a gold surface
through thiol moieties directly linked to the b-CD
molecule. Nelles et al.4 reported the immobilization
kinetics of b-CD through mono- or multithiol linkers.
More recently, Beulen et al.5 developed synthetic routes
to introduce short and long dialkyl sulfides onto the
primary side of a-, b-, and g-CDs. However, it is
apparent that these synthetic routes were invariably
applied to native CDs whilst a systematic approach
towards dialkyl sulfide- or thiol-modified functionalized
CDs was not reported.
The present work reports on a facile synthetic approach
to structurally well-defined mercaptyl functionalized b-
CDs. Subsequently, self assembly onto an Au surface of
a quartz crystal microbalance (QCM) afforded a
durable enantioselective coating which was applicable
for the chiral discrimination of enantiomers.
Scheme 1 depicts the synthetic route to mercaptyl func-
tionalized b-CD from (6A-azido-6A-deoxy)heptakis(2,3-
Scheme 1. Reagents and conditions: (i) imidazole/Ph3P/I2/DCM (dry); (ii) potassium phathalimide/DMF (dry)/D; (iii) CH3COSH/
hexane (dry)/UV; (iv) NH2NH2·H2O/MeOH/reflux; (v) PPh3/CO2/THF (dry).
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00267-8

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S.-C. Ng et al. / Tetrahedron Letters 43 (2002) 2863–2866
di-O-functionalized)-6B,6C,6D,6E,6F,6G -hexa-O-func-
tionalized-b-CD (1). The synthesis of (1) has been
reported previously,6 thus the crucial part of the whole
scheme relies on the availability of mercaptyl-alkylamines
of different lengths, NH2(CH2)nSH (2). With n=2,
commercially available cysteamine was used directly. For
n>2, a facile route was derived for the synthesis of
6-(v-mercaptyl)-hexanamine (2b) and 11-(v-mercaptyl)-
undecanylamine (2c) using a modified Gabriel reaction7
followed by a photoaddition reaction8 and then a depro-
tection step which conveniently cleaved both protective
groups in one step (step iv). Coupling of (1) and the thiol
linker (2) was accomplished using a Staudinger reaction
under mild conditions and the expected products (3) were
obtained.9 Table 1 summarizes the respective yields of
these mercaptyl b-CD derivatives, in which R=methyl,
pentyl, and benzoyl, respectively. The formation of the
carbamido moiety in these compounds was evident from
the 13C NMR resonance at ca. l 159 ppm.
mercaptyl b-CD molecule (i.e. M3a=1517.2 g/mol) con-
firms the formation of the AuꢀS covalent bond between
the mercaptyl b-CD molecule and the Au substrate.11
A study of the gas phase chiral discrimination of enan-
tiomers by immobilized b-CD monolayers was carried out
using an AT-cut 10 MHz quartz crystal microbalance
(QCM). Compounds (3a)–(5c) were immobilized on the
surface of the Au electrodes of a QCM, and the surface
concentration of the immobilized b-CD host molecules
was calculated according to the equation:12 Df=(2.26×
10−6) f02 (Dm/A) and summarized in Table 2.
The influence of the thiol linker length (n) on the surface
concentration of immobilized b-CD monolayers was well
reflected in SAM (3a) and (3c), where the longer thiol
linker (n=11) affords compound (3c) which is more
densely packed in the monolayer.
The chiral discrimination experiment was carried out in
a home-made pulse measuring system using pre-dried N2
as carrier gas, at 200 ml/min.13 The coated QCM sensors
were exposed to the same concentration of (+)-methyl
lactate and (−)-methyl lactate analytes at 25 0.1°C. Their
respective time-course signals were recorded and are
plotted in Fig. 1.†
Immobilization of mercaptyl b-CDs (3a)–(5c) on the Au
surface was achieved using established procedures.10
Subsequently, XPS studies of the Au surface revealed the
presence of the elements C, N, O and S. Moreover, the
presence of a broad peak with binding energy at ca. 162
eV for the S2p environment is consistent with the presence
of an AuꢀS moiety due to self-assembly of the thiols on
the Au surface.4 Further corroborative evidence of the
successful immobilization of these b-CD derivatives on
the Au surface was obtained from positive 10 KeV Ar
TOF-SIMS spectra (Table 2). The presence of two distinct
groups of fragments at molecular mass [M+Au]+ and
[M+AuꢀS]+, where M is the molecular mass of the
As can be seen, the responses of the QCM sensors due
to the inclusion complexation of the analyte molecule by
the b-CD monolayer are reproducible. Moreover, the
responses towards the respective chiral forms of methyl
lactate are similar but differ in the extent of frequency
reductions (Df ), reflecting the differences in the binding
affinity of the b-CD monolayers towards the respective
enantiomer.14 All four b-CD monolayers depict higher
binding affinity towards the (+)-methyl lactate than the
(−)-form.
Table 1. Yields of mercaptyl functionalized persubstituted
b-CD derivatives
Compd
n
Yield (%)
Amongst the b-CD SAMs, (3c) depicts better chiral
discrimination as measured by the chiral discrimination
factor, hR/S,‡ than (3a) corresponding to the increase in
the surface concentration of the immobilized permethy-
lated b-CD molecules on the Au surface.
2a
2b
2c
3a
3b
3c
4c
5c
2
6
11
2
–
82
87
19
25
34
29
30
6
11
11
11
The more crowded b-CD cavity in the molecular struc-
tures of (4c) and (5c) probably enhances the non-covalent
interactions between the interior cavity and the
Table 2. Immobilization of mercaptyl functionalized b-CD derivatives on the Au electrodes of a QCM
SAMs
3a
3c
4c
5c
Surface concentration (×1011 mol/cm2)
TOF-SIMS
6.90
8.98
1807
1839
4.91
3.44
[M+AuꢀS]+a
[M+Au]+
1679
1713
1910
1.114
2931
2963
3160
1.145
3609
3641
3840
1.178
[M+Au2]+
hR/S
1.125
a m/z, M is the molecular mass of the mercaptyl functionalized b-CD molecule, e.g. M3a=1517.2 g/mol.
† Lab Crystal Oscillator and AT-cut 10 MHz quartz plates were purchased from International Crystal Manufacturer Inc., Oklahoma City, OK.
The time-course frequency signals were monitored by TF830 universal frequency counter and recorded by PC.
‡ hR/S=Dfmax-R/Dfmax-S. Dfmax-R, Dfmax-S standing for the maximum frequency reductions of a QCM while exposed to the respective enantiomeric
analyte.15

S.-C. Ng et al. / Tetrahedron Letters 43 (2002) 2863–2866
2865
methyl lactate were successful. It was found that the
perbenzoylated b-CD monolayer depicted the best
enantiomeric discriminatory ability towards methyl lac-
tate. Further investigations on the host–guest interac-
tions between chiral ligands and the monolayers are
currently underway.
Acknowledgements
The authors thank the National University of Singa-
pore for financial support through the research grant
R-143-000-156-112. Tong Sun is grateful to NUS for
the award of a research scholarship.
References
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Phys. Chem. B 1998, 102, 9940–9945.
3. (a) Li, S.; Purdy, W. C. Chem. Rev. 1992, 92, 1457; (b)
Szejtli, J.; Osa, T. Comprehensive Supramolecular Chem-
istry, Vol. 3, Cyclodextrins Elsevier: Oxford, 1996.
4. (a) Nelles, G.; Weisser, M.; Back, R.; Wohlfart, P.;
Wenz, G.; Mittler-Neher, S. J. Phys. Chem. 1996, 100,
17893–17900; (b) Nelles, G.; Weisser, M.; Back, R.;
Wohlfart, P.; Wenz, G.; Mittler-Neher, S. J. Am. Chem.
Soc. 1996, 118, 5039–5046.
5. Beulen, M. W.; Bu¨gler, J.; Jong, M. R.; Lammerink, B.;
Huskens, J.; Scho¨nherr, H.; Vancso, G. J.; Boukamp, B.
A.; Wieder, H.; Offenha¨user, A.; Knoll, W.; Veggel, F. C.
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6. Melton, L. D.; Slessor, K. N. Carbohydr. Res. 1971, 18,
29–51.
7. Lange, G. L.; Gottardo, C. Synth. Commun. 1990, 20,
1473–1476.
8. Ulman, A. Thin Films: Self-Assembled Monolayers of
Thiols; Academic Press: London, 1998; Vol. 24, pp. 6–13.
9. Zhang, L. F.; Wong, Y. C.; Chen, L.; Ching, C. B.; Ng,
S. C. Tetrahedron Lett. 1999, 40, 1815–1817.
10. Troughton, E. B.; Bain, C. D.; Whitesides, G. M.; Nuzzo,
R. G.; Allara, D. A.; Porter, M. D. Langmuir 1988, 4,
365–370.
Figure 1. Chiral discrimination of four QCM sensors towards
(+)-methyl lactate and (−)-methyl lactate. (a) 3a; (b) 3c; (c) 4c;
(d), 5c. Temp. 25 0.1°C; carrier gas N2, 200 ml/min; sample
injection, 2.0 ml.
11. Van Vaeck, L.; Adriaens, A.; Gijbels, R. Mass Spectrom.
Rev. 1999, 18, 1–22.
12. Czanderna, A. W.; Lu, C. Applications of Piezoelectric
Quartz Crystal Microbalances; Elsevier: New York, 1984;
pp. 114–118.
included methyl lactate molecules, thus affording
improved chiral discrimination: hR/S-5c>hR/S-4c>hR/S-3c
despite the decreased surface concentration of the
immobilized derived b-CD molecules.
13. O’Sullivan, C. K.; Guilbault, G. G. Biosensors Bioelec-
tron. 1999, 14, 663–669.
14. Henke, C.; Steinem, C.; Janshoff, A.; Steffan, G.; Luft-
mann, H.; Sieber, M.; Galla, H.-J. Anal. Chem. 1996, 68,
3158–3169.
15. Bodenho¨fer, K.; Hieriemann, A.; Seemann, J.; Gauglitz,
G.; Koppenhoefer, B.; Go¨pel, W. Anal. Chem. 1997, 69,
3058–3071.
In summary, Scheme 1 depicts a facile synthetic route
for the synthesis of mercaptyl functionalized b-CD
derivatives. Analytical data for compounds (2)–(5) is
detailed in Ref. 16. These can be self-assembled onto
the Au electrodes of a QCM. The application of these
structurally defined b-CD monolayers for the study of
gas phase chiral discrimination of enantiomers of

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S.-C. Ng et al. / Tetrahedron Letters 43 (2002) 2863–2866
52.67; H, 7.94; N, 1.78; S, 2.03; found: C, 52.71; H, 7.79;
N, 1.76; S, 1.92%.
16. Analytical data for compounds 2–5:
6-(v-Mercapto)-hexanamine (2b): IR (cm−1) 3382 (N–H
str), 2940 (C–H str), 2502 (S–H str), 1595 (–NH2 def),
(6A-v-Mercapto-undecanylureado-6A-deoxy)heptakis(2,3-
di-O-methyl)-6B,6C,6D,6E,6F,6G-hexa-O-methyl-b-cyclo-
dextrin (3c): IR (cm−1) 3396 (N–H str), 2928 (C–H str),
1659 (CꢁO str, urea), 1039 (C–O–C str). 13C NMR
1
1065 (C–NH2 str); H NMR (CDCl3, 300 MHz) l (ppm)
2.66 (m, 2H, CH2
NH2), 1.67 (m, 2H, CH2
(t, J=7.2 Hz, 1H, SH
); 13C NMR (CDCl3, 75 MHz) l
(ppm) 41.9 (NH2CH2–), 38.9, 33.4, 29.0, 28.2 (–(CH2)4–),
26.3 (–CH2–SH); accurate MS m/z calcd 133.0925, found
6
–SH), 2.49 (t, J=7.2 Hz, 2H, CH2
6 –
6
–CH2–NH2), 1.41 (m, 6H), 0.96
(CDCl3, 75 MHz) l (ppm) 159.02 (NH–C
(C-1), 81.64 (C-2), 81.35 (C-3), 80.26 (C-4), 71.85 (C-6b),
70.97 (C-5), 67.68 (C-6a), 61.14 (H3CO–C3), 58.83
(H3CO–C6), 58.36 (H3CO–C2), 41.27 (–NHCH2–),
40.36–26.80 (–(CH2)9–), 24.44 (–CH2–SH); ESI-MS m/z
6 O–NH), 98.70
6
6
6
6
6
6
6
6
133.0921.
11-(v-Mercapto)-undecanylamine (2c): IR (cm−1) 3372
(N–H str), 2920 (C–H str), 2510 (S–H str), 1595 (–NH2
6
6
calcd 1643.6, found 1666.1 for [M+Na]+; elemental analy-
sis calcd C, 54.05; H, 8.22; N, 1.70; S, 1.95; found: C,
54.4; H, 7.82; N, 1.29%; S, 1.70%.
1
def.), 1065 (C–NH2 str); H NMR (CDCl3, 300 MHz) l
(ppm) 2.66 (t, J=7.2 Hz, 2H, CH2
Hz, 2H, CH2–NH2), 1.59 (m, 2H, CH2
1.40 (m, 17H); 13C NMR (CDCl3, 75 MHz) l (ppm) 42.0
(NH2CH2–), 39.1, 33.9, 33.6, 29.3, 29.1, 28.9, 28.4, 28.2,
26.8 (–(CH2)9–), 24.5 (–CH2–SH); accurate MS m/z calcd
203.1708, found 203.1705.
6
–SH), 2.50 (t, J=7.2
(6A-v-Mercapto-undecanylureado-6A-deoxy)heptakis(2,3-
di-O-pentyl)-6B,6C,6D,6E,6F,6G-hexa-O-pentyl-b-cyclodex-
trin (4c): IR (cm−1) 3409 (N–H str), 2933 (C–H str), 1670
(CꢁO str, urea), 1043 (C–O–C str); 13C NMR (CDCl3, 75
6
6
–CH2–NH2), 1.26–
6
6
6
MHz) l (ppm) 159.03 (NH–C6 O–NH), 98.76 (C–1), 81.39
(C-2), 81.19 (C-3), 78.94 (C-4), 74.94 (C-5), 71.79 (C-6b),
67.48 (C-6a), 72.42–72.18 (C-1%), 30.78–29.93 (C–2%),
29.31–29.06 (C-3%), 23.67–23.42 (C-4%), 14.87 (C-5%), 39.64
6A-v-Mercapto-ethylureado-6A-deoxy)heptakis(2,3-di-O-
methyl)-6B,6C,6D,6E,6F,6G-hexa-O-methyl-b-cyclodextrin
(3a): IR (cm−1) 3396 (N–H str), 2931 (C–H str), 1668
(CꢁO str, urea), 1040 (C–O–C str); 13C NMR (CDCl3, 75
(–NHC6 H2–), 35.51–24.38 (–(C6 H2)9–), 21.50 (–C6 H2–SH);
ESI-MS m/z calcd 2788.7, found 2789.1; elemental analy-
sis calcd C, 66.82; H, 10.82; N, 0.72; S, 1.16; found: C,
66.49; H, 11.21; N, 1.17; S, 1.02%.
MHz) l (ppm) 158.72 (–NH–C
81.66 (C-2), 80.24 (C-3), 80.02 (C-4), 71.16 (C-6b), 70.83
(C-5), 67.73 (C-6a), 61.11 (H3CO-C3), 58.81 (H3CO–C6),
58.28 (H3CO–C2), 40.82 (–NHCH2–), 25.43 (–CH2–SH);
6 O–NH–), 98.73 (C–1),
(6A-v-Mercapto-undecanylureado-6A-deoxy)heptakis(2,3-
di-O-benzoyl)-6B,6C,6D,6E,6F,6G-hexa-O-benzoyl-b-cyclo-
dextrin (5c): IR (cm−1) 3412 (N–H str), 3069 (Ar–H str),
2922 (C–H str), 1732 (CꢁO str, urea), 1610, 1449 (Ar-
ring), 1043 (C–O str); 13C NMR (CDCl3, 75 MHz) l
6
6
6
6
6
ESI-MS m/z Calcd 1517.4, found 1517.2; elemental analy-
sis calcd: C, 51.45; H, 7.70; N, 1.84; S, 2.11; found: C,
51.54; H, 7.51; N, 1.93; S, 1.95%.
(6A-v-Mercapto-hexanureado-6A-deoxy)heptakis(2,3-di-O-
methyl)-6B,6C,6D,6E,6F,6G-hexa-O-methyl-b-cyclodextrin
(3b): IR (cm−1) 3399 (N–H str), 2930 (C–H str), 1657
(CꢁO str, urea), 1037 (C–O–C str); 13C NMR (CDCl3, 75
(ppm) 166.15, 165.88, 164.82 (Ar–C
6 O–), 158.47 (NH–
C6
O–NH), 127.58, 127.72, 129.43, 129.61, 129.97, 132.16,
132.50 (H-bearing aromatic carbon atoms), 128.21,
128.50, 128.64 (quaternary aromatic carbon atoms) 97.57
(C-1), 77.4 (C-4), 71.33 (C-2 and C-3), 69.99 (C-5), 63.49
MHz) l (ppm) 159.00 (NH–C
(C-2), 81.32 (C-3), 80.22 (C-4), 71.40 (C-6b), 70.84 (C-5),
67.54 (C-6a), 61.18 (H3CO-C3), 58.90 (H3CO–C6), 58.47
(H3CO–C2), 41.22 (–NHCH2–), 38.67, 30.07, 28.99, 28.14
(–(CH2)4–), 26.44 (–CH2–SH); ESI-MS m/z calcd 1573.5;
found: 1596.5 for [M+Na]+; elemental analysis calcd C,
6 O–NH), 98.76 (C-1), 81.66
(C-6b), 63.39 (C-6a), 40.63 (–NHC
6 H2–), 34.01–26.94 (–
6
6
(CH2)9–), 24.57 (–C6 H2–SH); ESI-MS m/z calcd 3445.2,
6
found 3468.1 for (M+Na+); elemental analysis calcd: C,
67.61; H, 5.09; N, 0.81; S, 0.93; found: C, 68.04; H, 4.88;
N, 0.74; S, 0.82%.
6
6
6
6