Sensor array composed of "clicked" individual microcantilever chips

Article abstract of DOI:10.1002/adfm.201000729

A simple technique is described to functionalize a small library of microcantilever (MC) chips presenting varied headgroups. A generic azide monolayer, bound to the MC surface, can be coupled with various alkynes using efficient "click" chemistry. This me

Full text of DOI:10.1002/adfm.201000729

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Sensor Array Composed of “Clicked” Individual
Microcantilever Chips
François P. V. Paoloni, Sven Kelling, Juzheng Huang, and Stephen R. Elliott*
cannot be tolerated for many applica-
tions. For example, microcantilevers with
receptor layers presenting a copper-doped
carboxylic acid headgroup have been pro-
A simple technique is described to functionalize a small library of microcan-
tilever (MC) chips presenting varied headgroups. A generic azide monolayer,
bound to the MC surface, can be coupled with various alkynes using efficient
“click” chemistry. This method is compatible with many functional groups,
and novel headgroups are introduced on the MC surface by means of alkynes
synthesized via a one-step reaction. The surface “click” reaction reduces
greatly the effort that would be required to synthesize and purify the corre-
sponding functional thiols. This technique represents a convenient comple-
mentary tool for Phase-Shifting Interferometric Microscopy (PSIM) read-out
that has been developed in our group. The affinity of these surface coatings
towards different solvents can be estimated by measuring the deflection of
the cantilevers. A proof-of-concept sensor composed of four individual MC
chips presenting different headgroups can unambiguously discriminate the
fingerprint response of a nerve-gas simulant from other solvent vapors.
posed as potential candidates for nerve-
gas sensing,[7] but these are also sensitive
to exposure to solvents and changes of
pH.
It has been proposed that an array of
different receptors could be able to rec-
ognize certain molecules, even without
highly selective interactions, in analogy to
the olfaction mechanism in mammals.[8]
For example, colorimetric arrays com-
posed of metalloporphyrins and dyes have
been used to differentiate volatile organic
compounds (VOCs).[9] Also, solvent-vapor
recognition has been recently achieved
by principal component analysis of the
response of an array of six microcanti-
levers functionalized with thin polymer films.[6f] Simultaneous
monitoring of the cantilevers was achieved by means of a piezo-
electric readout in that study.
1. Introduction
The large variety of species that can be detected, on binding
to receptor layers on the surface of microcantilevers by
subsequent surface-stress-induced static deflections or
adsorbate-mass-induced changes in the resonant vibrational
frequency, demonstrates the versatility of MCs as chemical
and biological sensors.[1] This technique is extremely sensi-
tive and the detection of single-base mismatches,[2] absence
of single hydrogen bonding sites,[3] ions,[4] hydrogen,[5] and
volatile organic compounds (VOC)[6] have all been reported.
Cantilever-based chemical sensors are limited, however, by
the availability of coatings that interact exclusively and selec-
tively with the analyte of interest. Unlike biomolecules, small
organic compounds can lack a chemical “handle” that allows
their selective recognition based on the lock-and-key prin-
ciple. Therefore, some chemical sensors are susceptible to
several compounds, resulting in possible false positives that
The functionalization of individual microcantilevers
in arrays with several distinct receptor coatings generally
requires the use of micropipette or microfabrication tools that
prevent the rapid screening of novel surface coatings. There-
fore, most reports describe MC chips decorated with a single
type of coating that gives redundant information and limits
the miniaturization of the sensing devices. We have recently
reported an optical method to determine simultaneously the
entire bending profile of several cantilevers, belonging to
independent chips, based on a Twyman–Green interferom-
eter.[10] Phase-shifting interferometric microscopy (PSIM) uses
a single light source and it is suitable for microcantilevers
arrays. This readout system can be used in combination with
an innovative low-volume measuring cell designed for up to
four individual standard chips. In the present configuration,
the system requires only minimum alignment and allows the
rapid replacement of MC chips.
“Pick and Mix” arrays of cantilevers can therefore be built
from individual chips. This has the advantage that each chip can
be functionalized with a different monolayer simply by immer-
sion using conventional laboratory glassware. Also, if a canti-
lever becomes damaged, or if its coating proves to be unsuit-
able for the application of interest, it is possible to replace this
single MC chip while keeping the other sensor chips in place.
This PSIM readout capability offers researchers without access
to microfabrication tools the possibility to design complex
Dr. F. P. V. Paoloni, Dr. S. Kelling, Mr. J. Huang, Prof. S. R. Elliott
Department of Chemistry
University of Cambridge
Lensfield Road, CB2 1EW, UK
E-mail: sre1@cam.ac.uk
Dr. F. P. V. Paoloni
Division of Polymer & Materials Chemistry
Lund University
22100 Lund, Sweden
DOI: 10.1002/adfm.201000729
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S
N3
2
R
R
R
R
N
1
R
N
N
N
N
N
N
N
N
N3
N3
N3
N3
N
N
N
Scheme 1. Cartoon representation of the general functionalization of surface using “click” chemistry.
receptor-coated microcantilever arrays, and to test and optimize
them rapidly.
the bending response of the microcantilevers upon exposure
to different solvent vapors. Combined with a PSIM read-out,
the screening of different headgroups can be achieved rapidly
and arrays of microcantilevers can be designed by combining
individual chips without access to specialized microfabrication
tools.
The synthesis of compounds able to form monolayers is
time consuming, resulting in a limited number of headgroups
being readily available. Instead, we propose here to function-
alize receptor coatings on microcantilever chips by “click”
chemistry. The copper-catalyzed Huisgen cycloaddition between
an azide and an alkyne (CuAAC)[11] is orthogonal to most func-
tional groups, proceeds to high yield under mild conditions and
without significant formation of side-products. This synthetic
tool has been widely adopted by polymer and material chem-
ists.[12] “click” reaction on gold surfaces (e.g., coating MCs) can
be achieved by the formation of an azide monolayer followed
by addition of an alkyne,[13] or by coupling of an alkyne surface
with an organoazide.[14] A recent comparison of these methods
suggested that the first route leads to greater coverage of the
surface.[15] Also, it greatly reduces the handling of organic
azides that must be considered as potentially hazardous, explo-
sive and toxic compounds.[16] As in the case of solid-supported
synthesis, performing the “click” reaction on the surface limits
the purification effort that would be necessary if this was car-
ried out before the monolayer formation.
In this report, we describe the preparation of a library of
receptor-coated microcantilever chips by “click” reactions.
Bis(11-azido undecanyl)disulfide 1 is used for the formation of
azide monolayers on gold surfaces. Individual chips are func-
tionalized by reactions with different alkynes, as shown in
Scheme 1. Several simple alkynes are commercially available
and two simple methods to synthesize novel alkyne derivatives
are described. The alkynes used in this study were designed to
present a wide variety of functional groups that could take part
in the formation of non-covalent interactions, once immobilized
on the surface of microcantilever chips. This technique reduces
greatly the synthetic effort necessary to the preparation of such
library of microcantilever chips. The affinity of these receptor
surfaces for several solvents was evaluated by determining
2. Results
2.1. Synthesis of Azide-Terminated Disulfide and Alkyne
Compounds
The azide-terminated disulfide 1 was synthesized in three steps.
Bis(11-hydroxyundecanyl)disulfide was obtained by oxidation
of 11-mercaptoundecanol with N-chlorosuccinimide. It was
converted to bis(11-methanesulfonate undecanyl)disulfide by
reaction with mesyl chloride in the presence of triethylamine.
Nucleophilic substitution of the mesylate groups by sodium
azide gave bis(11-azidoundecanyl)disulfide 1.
Novel alkynes (Figure 1) were synthesized in one step by
reaction of alcohol derivatives with propargyl bromide in the
presence of base, or by ester formation in the presence of EDC
and DMAP. All compounds were obtained in good yield after
purification by column chromatography, and their structures
were confirmed by proton and 13C NMR, FT–IR and elemental
analysis.
2.2. “Click” Reaction of Simple Alkynes
Azide-terminated monolayers on gold-coated glass micro-
scope slides were prepared by immersion overnight in 1 mM
ethanol solution of 1. Loosely bound molecules were removed
by washing the substrate with ethanol and hexane. The “click”
CF3
F3C
F3C CF3
O
OH
CF3
CF3
OH
O
O
OH
O
OH
2
3
4
5
O
O
O
O
Cl
Cl
CF3
N
O
O
O
O
O
O
O
O
6
7
8
9
10
Figure 1. Alkyne derivatives synthesized in this study.
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T a b le 1 . Maximum amplitude of microcantilever bending upon injec-
tion of solvent vapors. The position of the tip of the cantilever is given
in nm.
reactions of receptor layers on microcantilevers presenting
azide groups with 4-pentynoic acid, N,N dimethylaminopro-
pyne, 3-butynol and 9-decyne were performed in a mixture of
isopropanol and water in the presence of copper sulfate and
sodium ascorbate. After reaction, the catalyst and excess of
alkyne were removed by washing the substrate extensively with
ethanol, followed by water, ethanol and hexane. Sessile drop
contact angles with water were determined. The surfaces pre-
senting a polar head group were found to be hydrophilic (car-
boxylic acid = 43.8 1.1°;. N,N dimethylamine = 27.1 1.0°;
alcohol = 36.8 1.4°). The surface presenting a ‘clicked’ alkane
was hydrophobic (83.1 2.3°).
Surface coating
Toluene
−336
−164
−450
166
Ethanol
−673
−197
−360
220
DMMP
−302
324
2
3
4
−178
344
5
6
119
166
279
7
192
182
176
8
−89
185
289
9
7
−48
18
2.3. Surface Functionalization of Microcantilevers
10
−136
41
42
216
COOH/Cu2+
ODT
184
314
The chips used in this study had two rectangular 500 μm long
single-crystal Si cantilevers pre-coated with gold on the top side
(Nanoworld, TL2Au). They were mounted on a custom-made
clamp to minimize the risk of damaging the cantilever when
manipulating the chips. Prior to surface functionalization, the
cantilever chips were cleaned by successive washing with 1 N
HCl, water, ethanol, hexane and ethanol. A library of chips was
obtained by carrying out the “click” reaction with a set of dif-
ferent alkynes 2–10. Another set of chips presenting a carboxylic
acid head group was obtained by immobilization of 4-pentynoic
acid, followed by immersion in a solution of copper sulfate.
Finally, an alkane-coated chip was obtained by functionalization
with octadecanethiol (ODT) without using “click” chemistry.
187
692
386
technique by material scientists that do not possess a chemical
background. Disulfides can also form monolayers on gold and
we have developed a simple method to synthesize bis(11-azido
undecanyl)disulfide 1 to introduce the azide group in the last
step. Firstly, commercially available 11-mercaptoundecanol was
oxidized to avoid the competitive reaction between the thiol and
alcohol in subsequent steps. Then, the alcohol was converted
to a mesylate group. Large amounts of this intermediate com-
pound can be prepared and stored for prolonged periods of
time. Finally, the compound was reacted with sodium azide,
which afforded 1 at 34% overall yield. When the last step of the
synthesis was performed on a 50 mg scale, it was found that this
compound could be purified easily by passing through a pad of
silica gel in a Pasteur pipette. This results in enough material
to functionalize several gold-coated substrates and ensures that
freshly prepared 1 is systematically used.
The alkynes synthesized in this study were designed to
confer a wide range of properties to the corresponding surfaces.
To limit the effort dedicated to their synthesis, it was decided
to prepare these compounds in a single step. A series of com-
pounds was obtained in moderate to good yield by reaction of
propargyl bromide with phenol derivatives (Figure 1). Alkynes
presenting a phenol moiety (2, 3, 4, and 5) are both hydrogen-
bond acceptors and donors. Also, it has been reported that the
hexafluoroisopropanol and 4-(hexafluoropropyl)phenol moiety
found in 3 and 5 interacts selectively with organophosphates.[17]
It was expected, therefore, that the corresponding surfaces
could serve as nerve-gas sensors. Three electron-rich aromatic
compounds that can take part in weak π–π stacking were also
synthesized (6, 7 and 8). Alternatively, the alkyne moiety can
be introduced through the formation of an ester bond, using 4-
pentynoic acid or 4-butynol. Reaction of 3-(hydroxymethyl)pyri-
dine with 4-pentynoic acid in dichloromethane, in the presence
of DMAP and EDC, gave 9 in excellent yield. While the forma-
tion of ether linkages is preferable as they are not susceptible
to hydrolysis, this route can be preferred in case of incompat-
ibility of the alcohol derivative with propargyl bromide. Finally,
the aliphatic diester 10 was synthesized in excellent yield by
esterification of 4-butynol with monomethyl succinate, under
2.4. Response of Microcantilevers to Solvent Vapors
The microcantilevers’ responses were characterized by their
bending behavior when exposed to solvent vapors. Solvent
vapors were generated by bubbling nitrogen gas through a bottle
of solvent under constant gas flow. Chips were mounted in the
PSIM read-out system and exposed to one-minute long injec-
tion of several vapors that were repeated three times. With the
PSIM optical readout technique, the entire profiles of all moni-
tored cantilevers are obtained simultaneously. In the present
study, only the position of the tip of the cantilever is reported
for clarity. The affinity of all the cantilevers was determined for
toluene, ethanol and DMMP, and the bending responses are
summarized in Table 1. The response of selected cantilevers
was also determined for dichloromethane and acetone.
3. Discussion
Compounds that possess a thiol and an azide group at each end
of a linear aliphatic chain have the ability to form azide-termi-
nated monolayers on gold. In previous reports, the synthesis of
11-azidoundecane-1-thiol was carried out in four steps that all
involved the handling of organic azides.[13a] This maximizes the
risks associated with the handling of this class of compounds.[16]
Also, organic azides are known to degrade with time and such
compounds cannot be stored for prolonged periods of time.
This limits the practical adoption of the “click” functionalization
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similar conditions. This route can be applied to compounds
presenting a carboxylic acid moiety, considerably expanding the
scope of alkyne derivatives that can be synthesized in a single
step.
determine the absolute position of the cantilever as a result of
drift in the baseline. This was occasionally observed during our
work and is suspected to be an artifact caused by gradual release
of residual stress in the microcantilever surface coating. This
baseline drift had no influence on the direction of the response
of the cantilevers on exposure to a given solvent vapor. When the
cantilever was exposed again to ethanol after 20 minutes,
the amplitude of the downward bending was only half that of
the first peak. This suggests that this solvent interacts strongly
with the receptor surface through hydrogen bonding. Full
recovery of the amplitude could be obtained by drying the
chip under a stream of nitrogen overnight. After exposure to
acetone, the cantilever returned to its original position in ca.
10 minutes. Ethanol has a greater affinity for the receptor surface
as it is both a hydrogen-bond donor and acceptor, while acetone
is a hydrogen-bond acceptor. Dichloromethane does not interact
specifically with the receptor surface and desorption of loosely
interacting molecules was rapid. Finally, dimethyl methylphos-
phonate (DMMP), a simulant for sarin, gave a distinctive ten-
sile stress (upward bending) which could be readily identified
from that of other solvents. Organophosphonates are capable
of accepting multiple hydrogen bonds and it is suspected that
a single molecule of DMMP interacts with several neighboring
hexafluoroisopropanol sites.
The sensitivity of this technique is limited by the thickness
of the monolayers and by the possible low density of functional
groups. Indeed, the amplitude of the deflections observed in
this study are smaller than in previously reported systems using
thick polymeric coatings.[6e,6f] It has been shown that a granular
surface morphology, obtained by plasma polymerization, greatly
enhances the response and a MC coated with polyacrylonitrile
showed a reversible response to naphthalene at 40 °C with a
limit of detection of 1 ppb.[6e] The technique described in
this study allowed the rapid screening of novel headgroups
that could be adapted for functional polymer brushes or bulk
polymer coatings.
Gold-coated microscope slides were functionalized with sev-
eral commercially available alkynes and contact-angle meas-
urements were performed. As expected, surfaces presenting a
carboxylic acid, alcohol or amine headgroup were hydrophilic,
while the substrate ‘clicked’ with the alkane was hydrophobic.
This suggests, in a qualitative manner, that the surfaces were
successfully modified. The efficiency of the surface “click”
reaction has been demonstrated by several groups.[13,14] In par-
ticular, a comparative study confirmed the suitability of the
condition chosen in our report.[15] Microcantilever chips were
functionalized with alkynes 2-10 and 4-pentynoic acid using the
“click” reaction and another chip was decorated with ODT.
The bending response of the four cantilevers belonging to
two chips decorated with 3 upon repeated one-minute long expo-
sures to toluene vapor is shown in Figure 2. The amplitude and
direction of the bending of all four cantilevers was essentially
identical over repeated exposures to toluene, demonstrating the
reproducibility and uniformity of the “click” functionalization.
The interaction of toluene molecules with the microcantilever
surface resulted in a compressive stress and the maximum
amplitude of the bending was reached in less than 10 seconds.
When the first injection of toluene was completed, evaporation
of the loosely bound molecules during an N2 purge resulted in
a fast partial recovery of the original position of the tip of the
cantilevers. Toluene molecules involved in π–π stacking with the
surface were desorbed in a second slow step, as demonstrated
by the slow return of the cantilevers to their original position
that took over a minute. It was found that ethanol, acetone and
dichloromethane all gave rise to compressive stress, translated
in downward bending (Figure 3). The variations of maximum
amplitudes might arise from differences in the boiling point
and vapor pressure of the solvents, and from their affinity for
the microcantilever receptor surfaces through the formation of
non-covalent interactions. After exposure to vapor, the rate of
return of the cantilever to its original position was character-
istic for each solvent. In the case of ethanol, it was difficult to
In this study, the method used to produce the vapor of solvents
did not allow control of the concentration of the analyte. For cer-
tain application such as nerve gas detection, it is less important
to avoid false positives but determining the exact concentration
N2
300
N2
200
N2
100
0
-100
Toluene
-200
Toluene
Toluene
1000
-300
0
500
1500
2000
2500
3000
3500
4000
time (s)
Figure 2. Response of four individual microcantilevers from two sensor chips, decorated with 3, upon repeated exposure to toluene vapor. Traces with
solid lines are from different cantilevers from one sensor chip and traces with dashed lines are from different cantilevers from another sensor chip.
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6
9
-424 0.8493
-279.150705
7
10
12
14
17
19
21
24
26
28
300
300
-30.671725
7
-443 0.21
N
-421 1.43484
-278.565161
2
(b)
(a)
-30.642011
10 -440 0.43
12 -438 0.35
200
200
-419 1.38476
-278.615243
-277.699324
-277.120241
-276.801828
11
-29.746279
Acetone
-417 2.30068
13
16
18
20
23
25
27
30
32
34
100
100
-29.174069
14 -436 -0.2
17 -433 0.54
19 -431 0.67
21 -429 1.18
24 -426 0.87
-414 2.87976
-29.266109
0
0
-412 3.19817
-29.35138
Ethanol
-410 3.91009
-276.089908
-275.452057
-276.529941
-275.993421
-100
-100
-29.483495
-407 4.54794
-200
-30.534592
-200
-405 3.47006
N2
-29.779742
26 -424 1.01
-300
-300
-403 4.00658
-30.477333
28 -422 1.86
1600
0
400
800
1200
1600
-400 4.47279
-275.527209
1200
31
33
35
0
400
800
-30.886738
-30.777425
-30.319202
31 -419 2.02
-398 5.06291
-396 5.46846
-274.93709
time (s)
time (s)
33 -417 2.2
35 -415 1.7
-274.531539
300
-3896.77779
-273.222211
-272.276059
42 -358
45 -355
47 -353
50 -350
52 -348
54 -346
57 -343
59 -341
61 -339
63 -337
300
200
100
0
(c)
45 -405 1.57
47 -403 2.32
1.566006
2.323226
2.512887
1.303887
0.898555
1.027478
1.929321
2.144568
1.99056
(d)
-3867.72394
N2
200
-3847.44215
-272.557846
DCM
100
49 -401 2.51
52 -398 1.3
54 -396 0.9
56 -394 1.03
-38214.3389
-265.66107
-265.138001
-265.160954
-264.792475
-264.41435
-37914.862
0
-37714.839
-100
-100
-200
-37515.2075
DMMP
59 -391 1.93
-37315.5857
-200
61 -389 2.14
63 -387 1.99
-37016.4788
-263.521245
N2
-300
-300
0
-36817.3703
-262.62971
0
400
800
1200
1600
400
800
1200
1600
65 -385 2.41
68 2 2 24
2.406666
2 243 54
-36617.6765
-36318.3349
-3618.8198
-262.323524
-261.665095
66 -334
68 -332
71 -329
70 -380 1.67
1.666843
time (s)
time (s)
-261.180208
Figure 3. Response of a microcantilever functionalized with 3 upon exposure to (a) ethanol, (b) acetone, (c) dichloromethane and (d) dimethyl
methylphosphonate vapors.
of extremely toxic substances is not essential. It was envisaged
to group the coatings based exclusively on the bending direction
(compressive or tensile) of their stress responses. The canti-
levers decorated with ODT and those functionalized with pen-
tynoic acid, 5, 6 and 7 exhibited upward tensile bending when
exposed to all solvents. The chip presenting the carboxylic acid
headgroup and doped with Cu2+ ions exhibited the weakest
response against toluene of this group, as this coating is not
aromatic. Its response to DMMP was significantly stronger than
to the other solvents, and it has been shown previously that this
coating can interact with organophosphates.[7] However, the
response is not exclusive and this microcantilever sensor alone
is not sufficient to differentiate the nature of the vapors. This
represents a major obstacle to the adoption of microcantilever
sensors for security applications. For example, ethanol is one
of the main components of perfumes, and it is present in food
and drinks which would lead to repeated false positives that
cannot be tolerated. The microcantilevers functionalized with a
simple phenol group (2 and 4) gave a downward bending when
exposed to all three solvents, suggesting that in the case of the
microcantilever decorated with the receptor 5, the headgroups
are probably dominated by the hydrophobic moiety rather than
by the hydroxyl group. Finally, for the chip functionalized with
8 and 10, exposure to toluene gave rise to a tensile stress, while
ethanol and DMMP induced compressive stress.
Based on the screening of individual chips, it would be pos-
sible to select four chips to build a microcantilever array capable
of sensing and discriminating nerve-gas stimulants from
common solvents. We have recently developed a 4-chip cell that
could be used to build arrays. Using a dedicated measuring cell
holding four chips, the fingerprint response of VOCs, could be
identified using the PSIM readout. A preliminary experiment
showed that an array composed of chips functionalized with 2,
3, 10 and ODT could recognize DMMP and ethanol unequivo-
cally by monitoring the direction of bending of each cantilever
(Figure 4). Toluene, acetone and dichloromethane could be
Figure 4. Bending response of four selected cantilevers when exposed to
toluene, dichloromethane, acetone, ethanol and DMMP.
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washed with water (30 mL), dried with magnesium sulfate, filtered and
evaporated. Purification by column chromatography afforded bis(11-
methanesulfonate undecanyl)disulfide (0.355 g, 63%, Rf = 0.35 in
CH2Cl2) as a white powder, m.p. = 70-72 °C; FT-IR (neat) ν = 2918, 2851,
1473, 1340, 1327, 1166, 1159 cm−1 ; 1H NMR (CDCl3, 400 MHz) δ = 1.21-
1.40 (m, 28 H, CH2), 1.62-1.77 (m, 8 H, CH2), 2.67 (t, J = 7.4 Hz, 4 H,
S-CH2), 2.99 (s, CH3), 4.21 (t, J = 6.6 Hz, 4 H, O-CH2); 13C NMR (CDCl3,
100 MHz) δ = 25.4, 28.5, 29.0, 29.1, 29.2, 29.4, 37.4, 39.2, 70.2; HR-MS
(ESI): calculated for C24H50O6S4 [M+H]+, 585.2382, found 585.2384.
Bis(11-Azido Undecanyl)Disulfide 1: To a stirred solution of bis(11-
methanesulfonate undecanyl)disulfide (0.056 g, 0.1 mmol) in
dimethylformamide (2 mL) was added sodium azide (0.013 g, 0.2 mmol).
After 48 hours, diethyl ether (40 mL) was added and washed twice with
water. The organic layer was dried with magnesium sulfate, filtered and
evaporated. Purification by column chromatography afforded bis(11-
azido undecanyl)disulfide 1 (0.025 g, 55%, Rf = 0.71 in petroleum ether/
ethyl acetate 9:1) as a colorless oil, FT-IR (neat) ν = 2924, 2853, 2091,
differentiated by the relative amplitudes of response. The can-
tilevers decorated with 2 and 10 had a strong response to the
chlorinated solvent, whereas the amplitude of the response to
acetone was significantly greater for 2 than for 10. In the pres-
ence of toluene, the amplitude of the bending of cantilevers
functionalized with 3 and 10 was about half of that observed for
the cantilever decorated with 2.
In future work, we plan to increase the number of simul-
taneously monitored cantilevers and will be using multivariate
statistics techniques, such as principal component analysis, to
increase the conclusiveness of our results. We also plan to com-
pare accuracy and reproducibility of data obtained from limited
time span exposure, as presented here, with saturation data.
1
1464, 1259 cm−1 ; H NMR (CDCl3, 400 MHz) δ = 1.21-1.45 (m, 28 H,
4. Conclusions
CH2), 1.55-1.69 (m, 8 H, CH2), 2.67 (t, J = 7.4 Hz, 4 H, S-CH2), 3.24 (t, J =
7.0 Hz, 4 H, N3-CH2); 13C NMR (CDCl3, 100 MHz) δ = 26.7, 28.5, 28.8,
29.1, 29.2, 29.5, 39.2, 51.5; HR-MS (ESI): calculated for C22H44N6S2
[M+H]+, 457.3142, found 457.3123.
The combination of “click” functionalization of receptor mono-
layers on microcantilevers and phase-shifting interferometric
microscopy readout represents an excellent combination to rapidly
screen the behavior of libraries of novel microcantilever-receptor
coatings. New surface coatings can be designed using simple
chemical reactions, expanding considerably the scope of functional
groups that could be made available to material scientists. Also,
sensor arrays can be built by combining individual ‘clicked’ chips
prepared using exclusively standard laboratory glassware. The
development of chemical sensors for point-of-care medical diag-
nosis or of microcantilever-based logic gates could be envisaged, as
a result of the simplicity and versatility of this technique.
4-Propargyloxyphenol 2: To
a stirred mixture of hydroquinone
(0.220 g, 2.0 mmol) and potassium carbonate (0.138 g, 1.0 mmol) in
dimethylformamide (5 mL) at 60 °C was added propargyl bromide (0.117 g,
1.0 mmol). After four hours, dichloromethane (50 mL) was added, the
organic layer was washed with 10% HCl (30 mL), water (30 mL), dried
with magnesium sulfate, filtered and evaporated. Purification by column
chromatography afforded 4-propargyloxyphenol 2 (0.098 g, 66%, Rf = 0.15
in dichloromethane) as a yellow oil, FT-IR (neat) ν = 3370, 3289, 1702,
1506, 1146, 1375, 1199, 1027, 825 cm−1 ; 1H NMR (CDCl3, 400 MHz) δ =
2.52 (t, J = 2.4 Hz, 1 H, CH), 4.64 (d, J = 2.4 Hz, 2 H, CH2), 5.50 (br, 1
H, OH), 6.80 (m, AA’XX’, 2 H, Ar), 6.88 (m, AA’XX’, 2 H, Ar); 13C NMR
(CDCl3, 100 MHz) δ = 56.7, 75.4, 78.8, 116.0, 116.3, 150.3, 151.5; Analysis
calculated for C9H8O2: C, 72.96; H, 5.44%. Found: C, 71.70; H, 5.40%.
1-(hydroxyhexafluoroisopropyl)-4-(propargyloxyhexafluoroisopropyl)
benzene 3: To a stirred mixture of 1,4-bis(2-hydroxyhexafluoroisopropyl)
benzene (0.820 g, 2.0 mmol) and potassium carbonate (0.138 g,
1.0 mmol) in dimethylformamide (8 mL) at 60 °C was added propargyl
bromide (0.117 g, 1.0 mmol). After three and a half hours, diethyl
ether (75 mL) was added, the organic layer was washed with 10%
HCl (50 mL), water (50 mL), dried with magnesium sulfate, filtered
and evaporated. Purification by column chromatography afforded
1-(hydroxyhexafluoroisopropyl)-4-(propargyloxyhexafluoroisopropyl)
benzene 3 (0.378 g, 84%, Rf = 0.52 in dichloromethane) as a white solid,
m.p. = 58-60°C; FT-IR (neat) ν = 3486, 3317, 2963, 1258, 1171, 1154,
1100 cm−1 ; 1H NMR (CDCl3, 400 MHz) δ = 2.59 (t, J = 2.4 Hz, 1 H, CH),
4.27 (d, J = 2.4 Hz, 2 H, CH2), 7.75 (m, AA’XX’, 2 H, Ar), 7.87 (m, AA’XX’,
2 H, Ar); 13C NMR (CDCl3, 100 MHz) δ = 55.4, 76.0, 77.2, 82.8 (m),
122.0 (q, J = 290.0 Hz), 122.4 (q, J = 287.9 Hz), 127.3, 128.4, 129.9,
131.8; Analysis calculated for C15H8F12O2: C, 40.20; H, 1.80%. Found: C,
39.87; H, 1.79%.
2,2-(4-hydroxyphenyl)-(4′-propargyloxyphenyl)propane 4: To a stirred
mixture of bisphenol A (0.456 g, 2.0 mmol) and potassium carbonate
(0.138 g, 1.0 mmol) in dimethylformamide (5 mL) at 60 °C was added
propargyl bromide (0.117 g, 1.0 mmol). After two hours, diethyl
ether (50 mL) was added, the organic layer was washed with 10%
HCl (30 mL), water (30 mL), dried with magnesium sulfate, filtered
and evaporated. Purification by column chromatography afforded
2,2-(4-hydroxyphenyl)-(4’-propargyloxyphenyl propane 4 (0.248 g, 50%,
Rf = 0.29 in dichloromethane) as a colorless oil, FT-IR (neat) ν = 3378,
3286, 2968, 1608, 1508, 1447, 1364, 1297, 1218, 1178, 1027, 1014,
828 cm−1 ; 1H NMR (CDCl3, 400 MHz) δ = 2.51 (t, J = 2.4 Hz, 1 H, CH),
4.66 (d, J = 2.4 Hz, 2 H, CH2), 4.90 (br, 1 H, OH), 6.73 (m, AA’XX’, 2 H, Ar),
6.88 (m, AA’XX’, 2 H, Ar), 7.09 (m, AA’XX’, 2 H, Ar), 7.15 (m, AA’XX’,
2 H, Ar); 13C NMR (CDCl3, 100 MHz) δ = 31.1, 41.7, 55.8, 75.4, 78.8,
114.2, 114.7, 127.8, 128.0, 143.2, 144.1, 153.3, 155.4; Analysis calculated
for C18H18O2: C, 81.17; H, 6.81%. Found: C, 80.41; H, 6.87%.
5. Experimental Section
General Methods and Instrumentation: Solvents were obtained from
Fisher and used without purification. Chemicals were purchased from
Aldrich or Acros and used as received. All reactions were carried out
under a nitrogen atmosphere, unless otherwise noted. Attenuated total
reflectance FT-IR spectra were acquired on a Perkin Elmer Spectrum One
equipped with a Universal ATR accessory. NMR (1H and 13C) spectra were
recorded on 400 MHz Bruker spectrometers. The chemical-shift data for
each signal are given in units of δ (ppm) relative to tetramethylsilane
(TMS) where δ (TMS) = 0, and referenced to the residual solvent
resonances. Splitting patterns are denoted as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet), and br (broad).
Bis(11-Hydroxyundecanyl)disulfide: To
a
stirred solution of
11-mercaptoundecanol (1.022 g, 5.0 mmol) in dichloromethane (20 mL)
was added N-chlorosuccinimide (0.334 g, 2.5 mmol) in dichloromethane
(5 mL). A white precipitate was rapidly formed. After ten minutes, warm
dichloromethane (50 mL) was added and the solution was washed with
water (30 mL). The organic layer was washed with water (30 mL), dried
with magnesium sulfate, filtered and evaporated under reduced pressure
to yield bis(11-hydroxyundecanyl)disulfide (0.996 g, 98% yield) as a
white powder, m.p. = 63-66 °C; FT-IR (neat) ν = 3347, 2917, 2850, 1469,
1
1346, 1055, 1038 cm−1 ; H NMR (CDCl3, 400 MHz) δ = 1.25-1.39 (m,
28 H, CH2), 1.52-1.73 (m, 8 H, CH2), 2.71 (t, J = 7.4 Hz, 4 H, S-CH2),
3.66 (t, J = 6.6 Hz, 4 H, O-CH2); 13C NMR (CDCl3, 100 MHz) δ = 25.7,
28.5, 29.2, 29.4, 29.5, 29.6, 32.8, 39.2, 63.0; HR-MS (ESI): calculated for
C22H46O2S2 [M+H]+, 407.3012, found 407.3026.
Bis(11-Methanesulfonate Undecanyl)Disulfide: To a stirred solution
of bis(11-hydroxyundecanyl)disulfide (0.407 g, 1.0 mmol) in
dichloromethane (20 mL) and pyridine (0.2 mL) at 0 °C was added
methanesulfonyl chloride (0.252 g, 2.2 mmol). After an hour, the
mixture was stirred overnight at room temperature, and poured in
water (30 mL) and dichloromethane (30 mL). The organic layer was
©
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Adv. Funct. Mater. 2011, 21, 372–379
2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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2,2-(4-hydroxyphenyl)-(4′-propargyloxyphenyl)hexafluoropropane 5: To
a stirred mixture of 4,4′-(hexafluoroisopropylidene)diphenol (0.672 g,
2.0 mmol) and potassium carbonate (0.138 g, 1.0 mmol) in
dimethylformamide(7mL)at60°Cwasadded propargylbromide(0.117g,
1.0 mmol). After three hours, diethyl ether (75 mL) was added, the
organic layer was washed with 10% HCl (50 mL), water (50 mL), dried
with magnesium sulfate, filtered and evaporated. Purification by column
chromatography afforded 2,2-(4-hydroxyphenyl)-(4’-propargyloxyphenyl)
hexafluoropropane 5 (0.348 g, 49%, Rf = 0.36 in dichloromethane) as a
colorless oil, FT-IR (neat) ν = 3305, 2932,1613, 1514, 1238, 1205, 1132
cm−1 ; 1H NMR (CDCl3, 400 MHz) δ = 2.55 (t, J = 2.4 Hz, 1 H, CH), 4.70
(d, J = 2.4 Hz, 2 H, CH2), 5.92 (br, 1 H, OH), 6.83 (m, AA’XX’, 2 H, Ar),
6.96 (m, AA’XX’, 2 H, Ar), 7.25 (m, AA’XX’, 2 H, Ar), 7.33 (m, AA’XX’, 2
H, Ar); 13C NMR (CDCl3, 100 MHz) δ = 55.8, 63.5 (m), 75.9, 78.1, 114.3,
115.0, 124.3 (q, J = 284.7 Hz), 125.6, 126.4, 131.5, 131.7, 155.9, 157.7;
Analysis calculated for C18H12F6O2: C, 57.76; H, 3.23%. Found: C, 57.73;
H, 3.34%.
1.1 mmol) and dimethylaminopyridine (0.006 g, 0.05 mmol) at 0 °C.
The solution was stirred for an hour at 0 °C, then overnight at room
temperature. The organic layer was washed with saturated aqueous
sodium bicarbonate, brine, dried with magnesium sulfate, filtered
and evaporated. After purification by column chromatography,
2-pyridinylmethyl 4-pentynoate 9 (0.185 g, 98%, Rf = 0.31 in diethyl
ether) as a clear oil, FT-IR (neat) ν = 3293, 2925, 1734, 1428, 1158 cm−1 ;
1H NMR (CDCl3, 400 MHz) δ = 1.96 (t, J = 2.7 Hz, 1 H, CH), 2.51 (m,
2 H, CH2), 2.60 (m, 2 H, CH2), 5.16 (s, 2 H, O-CH2), 7.29 (m, 1 H, Ar),
7.69 (m, 1 H, Ar), 8.57 (m, 1 H, Ar), 8.61 (m, 1 H, Ar); 13C NMR (CDCl3,
100 MHz) δ = 14.3, 33.2, 63.9, 69.3, 82.2, 123.5, 131.4, 136.1, 149.7,
171.5; Analysis calculated for C11H11NO2: C, 69.83; H, 5.86; N, 7.40%.
Found: C, 68.72; H, 5.98; N, 7.21%.
3-Butynyl Methyl Succinate 10: To
a
stirred solution of
monomethyl succinate (0.145 g, 1.1 mmol) and 3-butynol (0.070 g,
1.0 mmol) in dichloromethane (10 mL) was added a solution of N-(3-
dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.211 g,
1.1 mmol) and dimethylaminopyridine (0.012 g, 0.1 mmol) in
dichloromethane (1 mL) at 0 °C. The solution was stirred for an hour
at 0 °C, then overnight at room temperature. The organic layer was
washed with saturated aqueous sodium bicarbonate, brine, dried with
magnesium sulfate, filtered and evaporated. After purification by column
chromatography, 3-butynyl methyl succinate 10 (0.155 g, 92%, Rf = 0.66
in ethyl acetate) as a clear oil, FT-IR (neat) ν = 3279, 2957, 1733, 1439,
1321, 1209, 1161 cm−1 ; 1H NMR (CDCl3, 400 MHz) δ = 1.98 (t, J =
2.7 Hz, 1 H, CH), 50 (dt, J = 6.8 Hz, J = 2.7 Hz, 2 H, C-CH2), 2.62 (m,
4 H, CO-CH2), 3.66 (s, 2 H, O-CH3), 4.17 (t, J = 6.8 Hz, 2 H, O-CH2);
13C NMR (CDCl3, 100 MHz) δ = 18.9, 28.8, 29.0, 51.9, 62.3, 69.9, 79.9,
172.0, 172.7; Analysis calculated for C9H12O4: C, 58.69; H, 6.57%. Found:
C, 58.62; H, 6.50%.
“Click” Reaction on Microcantilevers: Two gold-coated microcantilever
chips (Nanoworld, 10 nm chromium and 30 nm gold)) were mounted on
a custom-made PEEK chip holder and washed successively by immersion
in 1N HCl, water, ethanol, hexane and ethanol. After immersion in a
bis(11-azido undecanyl)disulfide solution (1 mM in ethanol) overnight,
they were rinsed with ethanol, hexane and dried under a stream of
nitrogen. A solution of the desired alkyne (5 mM) in isopropanol and
water (1:1) containing sodium ascorbate (15 mol%) and copper sulfate
(1 mol%) was sonicated for a minute. The azide chips were immersed
in this mixture overnight. After the “click” reaction, the substrates were
rinsed with ethanol, water, ethanol, hexane and dried under a gentle
stream of nitrogen.
1,3-Dimethoxy-5-Propargyloxybenzene 6: To
a stirred mixture of
3,5-dimethoxyphenol (0.154 g, 1.0 mmol) and potassium carbonate
(0.166 g, 1.2 mmol) in dimethylformamide (5 mL) at 60 °C was added
propargyl bromide (0.143 g, 1.2 mmol). After four hours, diethyl ether
(50 mL) was added, the organic layer was washed twice with water
(30 mL), dried with magnesium sulfate, filtered and evaporated.
Purification by column chromatography afforded 1,3-dimethoxy-5-
propargyloxybenzene 6 (0.137 g, 71%, Rf = 0.62 in dichloromethane) as
a white solid, m.p. = 42-43°C; FT-IR (neat) ν = 3238, 3014, 2945, 1594,
1477, 1459, 1377, 1198 cm−1 ; 1H NMR (CDCl3, 400 MHz) δ = 2.52 (t, J =
2.4 Hz, 1 H, CH), 3.76 (s, 6 H, CH3), 4.64 (d, J = 2.4 Hz, 2 H, CH2),
6.12 (m, 3 H, Ar); 13C NMR (CDCl3, 100 MHz) δ = 55.4, 55.9, 75.6, 78.4,
93.8, 159.4, 161.5; Analysis calculated for C11H12O3: C, 68.74; H, 6.29%.
Found: C, 68.71; H, 6.25%.
4-(trifluoromethoxy)propargyloxybenzene 7: To
a stirred solution
of 4-(trifluoromethoxy)-phenol (0.179 g, 1.0 mmol) and potassium
carbonate (0.168 g, 1.2 mmol) in DMF (5 mL) at 60 °C was added
propargyl bromide (0.143 g, 1.2 mmol). After four hours, the mixture was
cooled down to room temperature, diluted with diethyl ether (50 mL)
and washed with water (35 mL). The organic layer was washed with
10% hydrochloric acid (30 mL), twice with water (35 mL), dried with
magnesium sulfate, filtered and evaporated. Purification by column
chromatography afforded 4-(trifluoromethoxy)propargyloxybenzene
7 (0.177g, 82%, Rf = 0.76 in CH2Cl2) as yellow liquid; FT-IR (neat) ν =
3308, 1599, 1506, 1457, 1375, 1258, 1221, 1192, 1157, 1108, 1028 cm−1 ;
1H NMR ( CDCl3, 400 MHz) δ = 2.53(t, J = 2.4 Hz, 1 H, C≡C-H), 4.68
’
(d, J = 2.4 Hz, 2 H, O-CH2), 6.94-7.17 (m, AAXX’, 4 H, Ar); 13C NMR
Acknowledgements
(CDCl3, 100 MHz) δ = 56.2, 75.9, 78.1, 115.8, 121.8, 122.4, 143.4, 156.0;
Analysis calculated for C10H7F3O2: C, 55.56; H, 3.26%. Found: C, 55.49;
H, 3.28%.
The authors thank the UK Home Office for funding.
3,4-dichloropropargyloxybenzene 8: To
a
stirred solution of
Received: April 16, 2010
3,4-dichlorophenol (0.160 g, 0.98 mmol) and potassium carbonate
(0.167 g, 1.2 mmol) in DMF (5.0 mL) at 60 °C was added propargyl
bromide (0.143 g, 1.2 mmol) within 10 minutes. After three and a
half hours, the mixture was cooled down to room temperature, and
diluted with diethyl ether (50 mL) and washed with water (35 mL).
The organic layer was washed with 10% hydrochloric acid (30 mL),
twice with water (35 mL), dried with magnesium sulfate, filtered
and evaporated. Purification by column chromatography afforded
3,4-dichloropropargyloxybenzene 8 (0.139g, 69%, Rf = 0.77 in CH2Cl2) as
a yellow oil; FT-IR (neat) ν = 3298, 2364, 2124, 1592, 1571, 1472, 1375,
1290, 1263, 1218, 1125, 1034, 1020 cm−1 ; 1H NMR ( CDCl3, 400 MHz) δ =
2.56 (t, J = 2.4 Hz, 1 H, C≡C-H), 4.69 (d, J = 2.4 Hz, 2 H, O-CH2), 6.86
(dd, Jm = 2.9 Hz, Jo = 6.0 Hz, 1 H, Ar), 7.10 (d, Jm = 2.9 Hz, 1 H, Ar),
7.36 (d, Jo = 8.9 Hz, 1 H, Ar); 13C NMR (CDCl3, 100 MHz) δ = 56.3,
76.3, 77.6, 114.9, 117.0, 125.0, 130.7, 132.9, 156.5; Analysis calculated
for C9H6Cl2O: C, 53.77; H, 3.01%. Found: C, 53.97; H, 3.07%.
Published online: November 15, 2010
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