Molecular rotors: synthesis and evaluation as viscosity sensors

Article abstract of DOI:10.1016/j.tet.2010.01.093

It has been shown that compounds containing the p-N,N-dialkylaminobenzylidene cyanoacetate motif can serve as fluorescent non-mechanical viscosity sensors. These compounds, referred to as molecular rotors, belong to a class of fluorescent probes that are

Full text of DOI:10.1016/j.tet.2010.01.093

Tetrahedron 66 (2010) 2582–2588
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Molecular rotors: synthesis and evaluation as viscosity sensors
,
Jeyanthy Sutharsan a, Darcy Lichlyter b, Nathan E. Wright a, Marianna Dakanali a, Mark A. Haidekker b
,
*
,
Emmanuel A. Theodorakis a
*
a Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, USA
b Faculty of Engineering, University of Georgia, Athens, GA 30602, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
It has been shown that compounds containing the p-N,N-dialkylaminobenzylidene cyanoacetate motif
can serve as fluorescent non-mechanical viscosity sensors. These compounds, referred to as molecular
rotors, belong to a class of fluorescent probes that are known to form twisted intramolecular charge-
transfer complexes in the excited state. In this study we present the synthesis and spectroscopic
characterization of these compounds as viscosity sensors. The effects of the molecular structure and
electronic density of these rotors to the emission wavelength, fluorescence intensity, and viscosity
sensitivity are discussed.
Received 20 November 2009
Received in revised form
22 January 2010
Accepted 26 January 2010
Available online 1 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
group of environment-sensitive fluorescent probes.17 These probes,
referred to as molecular rotors, are known to form twisted intra-
Variations in fluid viscosity are associated with a variety of
functions and diseases both at the cellular1 and organismal level.2
For instance, cell membrane viscosity depends on the chemical
composition of the bilayer and must have optimum values for the
proper function of various membrane bound enzymes and re-
ceptors.3 Consequently, changes of membrane viscosity affect cel-
lular signaling pathways and are associated with a variety of
disorders, such as cardiovascular disease,4 cell malignancy,5 and
Alzheimer’s disease.6 In a similar fashion, changes in the viscosity
of blood, plasma or lymphatic fluids have been linked to diabetes,7
hypertension,8 infarction,9 and aging.10
The importance of membrane viscosity in cellular biology and
physiology led to the development of several methods for quanti-
tative measurements. Among them are included mechanical
methods, where the lipids and proteins are tested in a cone-and-
plate viscometer or a capillary viscometer.11 However, these
methods are limited by the large sample size and are not effective
in measuring real-time changes.12 Alternatively, fluorescence-
based methods benefit from the rapid response time and good
spatial resolution of the fluorescent probes.13 Techniques based on
fluorescence anisotropy14 (FA) and fluorescence recovery after
photobleaching15 (FRAP) are commonly used in biological mea-
surements but suffer from the need of specialized instruments,
high energy light and limited spatial resolution.16 An alternative
method for measuring viscosity is based on the use of a special
molecular charge-transfer (TICT) complexes in the excited state
producing a fluorescence quantum yield that is dependent on the
surrounding environment.18 The chemical structure of the molec-
ular rotors contains an electron donor unit in conjugation with an
electron acceptor unit (D-p-A motif). Following photoexcitation,
this motif has the unique ability to relax either via fluorescence
emission or via an internal non-radiative molecular rotation. This
internal rotation occurs around the
s-bonds that connect the
electronically rich -system with the donor and acceptor groups
p
and can be modulated by the microenvironment of the probe.19 For
instance, if such rotation is hindered due to the high viscosity of
their microenvironment, the relaxation occurs via an increased
fluorescence emission. In contrast, in solvents of low viscosity the
relaxation proceeds mainly via a non-radiative pathway. Overall,
this property results in a fluorescence emission whose quantum
yield is proportional to the viscosity of the environment.
Figure 1 shows the chemical structures of two commonly used
molecular rotors based on the julolidine scaffold: 9-(dicyanovinyl)-
julolidine (DCVJ)20 and 9-(2-carboxy-2-cyano)vinyl-julolidine
N
N
CN
CO2H
NC
DCVJ (1)
NC
CCVJ (2)
* Corresponding authors. Tel.: þ1 858 822 0456; fax: þ1 858 822 0386; e-mail
Figure 1. Representative structures of molecular rotors based on the julolidine
scaffold.
address: etheodor@ucsd.edu.
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.093

J. Sutharsan et al. / Tetrahedron 66 (2010) 2582–2588
2583
(CCVJ).21 TICT formation takes place by photoinduced electron
transfer from the julolidine nitrogen to one of the nitrile groups
with subsequent intramolecular rotation around the julolidine–
vinyl bond. Over the past years we have been exploring the appli-
cability of molecular rotors, containing the N,N-dialkylaniline
motif,22 as sensors for various biological and engineering applica-
tions.23 The subject of this investigation was to evaluate whether
and how changes in the chemical structure of the molecular rotors
can change the emission wavelength, fluorescence intensity, and
sensitivity of the viscosity measurements.
methoxy naphthaldehyde 8 with 8 equiv of lithiated piperidine.25
Condensation of 6, 8, and 9 with methyl 2-cyanoacetate (4a)
afforded rotors 7, 10, and 11, respectively, in excellent yields.
The synthesis of molecular rotor 14, in which the donor and
acceptor groups are conjugated through a thiophene scaffold, is
shown in Scheme 3. Commercially available aldehyde 12 was
converted to the piperidine derivative 13 in 72% yield.26 Knoeve-
nagel condensation of 13 with 4a produced 14 in 90% yield.
2. Results
2.1. Synthesis of molecular rotors
The synthesis of all molecular rotors was accomplished in one
step by Knoevenagel condensation of 1 equiv of the appropriate
aldehyde with 1.1 equiv of malonic acid derivative 4. This reaction
was catalyzed by piperidine (10%) and was completed within 8 h.24
The synthesis of rotors based on the phenyl scaffold is illustrated in
Scheme 1. In most cases, the desired product 5 crystallized out of
methanol (Table 1).
Scheme 3. Reagents and conditions: (a) 1.0 equiv aldehyde, 1.0 equiv piperidine,
0.1 equiv p-TsOH, toluene, 120 ꢀC, 24 h, 72%; (b) 1.0 equiv 13, 1.1 equiv 4a, 0.1 equiv
piperidine, MeOH, 50 ꢀC, 8 h, 90%.
The synthesis of molecular rotor 18, containing two methoxy
groups ortho to the acceptor unit, is shown in Scheme 4. Treatment of
1-bromo-2,4-dimethoxybenzene (15) with sodium amide in the
presence of diethylamine produced, via the formation of an aryne
intermediate, aniline 16 in 85% yield.27 Formylation of 16 under
Vilsmeier conditions, followed by condensation of the resulting al-
dehyde 17 with 4a produced compound 18 in 53% combined yield.28
CO2Me
R
OMe
Br
(a)
NaNH2
MeO
OMe
Scheme 1. Reagents and conditions: 1.0 equiv 3, 1.1 equiv 4, 0.1 equiv piperidine,
MeOH, 50 ꢀC, 8 h.
CN
OMe
(c)
MeO
NHEt2
(85%)
MeO
(81%)
Table 1
N
Structures and yields of rotors 5a–5m
N
16: R= H
15
Cmp #
R1
R2
E1
E2
Yield (%)
(b)
18
17: R= CHO
5a
5b
5c
5d
5e
5f
5g
5h
5i
OMe
NH2
NH2
H
H
H
H
H
H
H
OMe
OMe
Me
H
H
H
CN
CN
CN
CN
CN
CN
CO2Me
CN
CN
CN
CN
SO2Ph
CN
CO2Me
CO2Me
CN
CO2Me
CN
SO2Ph
CO2Me
SO2Ph
CO2Me
CO2Me
CO2Me
SO2Ph
CO2Me
84
87
65
89
91
92
17
81
89
86
67
7
Scheme 4. Reagents and conditions: (a) 1 equiv 15, 10 equiv NaNH2, 75 equiv NHEt2,
25 ꢀC, 24 h, 85% (b) 1.0 equiv 16, 2.0 equiv DMF, 1.1 equiv POCl3, 2 M NaOH, 8 h, 65%;
(c) 1.0 equiv aldehyde, 1.1 equiv cyanomethylester, 0.1 equiv piperidine, MeOH, reflux,
50 ꢀC, 8 h, 81%.
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NEt2
2.2. Spectroscopic characterization of molecular rotors
5j
5k
5l
In principle a good molecular rotor should have the following
properties: (a) a large Stokes shift that will provide good separation
between the excitation and emission light; (b) a tunable emission
wavelength that can be modified as a function of the chemical
structure and can be optimized for a specific application and; (c)
high brightness, which translates to a high overall emission quantum
yield; and (d) high sensitivity, which translates to bigger changes in
emission quantum yield as a function of changes in viscosity.
As indicated above, two excited-state deactivation pathways
exist for molecular rotors, the non-radiative intramolecular rota-
tion and the fluorescent emission. The viscosity of the solvent in-
fluences the rate of the non-radiative intramolecular rotation that
subsequently influences the fluorescence quantum yield.29 Fo¨rster
and Hoffmann found a nonlinear relationship between fluorescent
NMe2
NBu2
5m
72
The synthesis of molecular rotors based on the naphthalene
scaffold is illustrated in Scheme 2. The p-substituted naph-
thaldehyde 9 was prepared by treatment of commercially available
quantum yield FF and viscosity
h
as described in Eq. 1:30
log FF ¼ C þ xlog
h
(1)
where x is a dye-dependent constant and C is an empirical pro-
portionality constant. Furthermore, fluorescence emission intensity
(IF) and quantum yield (FF) are proportional. With steady-state
fluorescence, Eq. 1 can be reformulated as a power law Eq. 2:
IF
¼
a
$
hx
(2)
Scheme 2. Reagents and conditions: (a) 1.0 equiv aldehyde, 1.1 equiv a-cyanomethy-
is 10C multiplied with predominantly
lester, 0.1 equiv piperidine, MeOH, 50 ꢀC, 8 h; (b) 8.0 equiv piperidine, benzene/HMPA:
where the new constant
a
1:1, 0 ꢀC, 8.0 equiv n-BuLi, 0 ꢀC, 15 min, then 1.0 equiv aldehyde, 25 ꢀC, 12 h, 35%.
instrument factors and dye concentration. The constants a and x

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J. Sutharsan et al. / Tetrahedron 66 (2010) 2582–2588
can be determined experimentally by measuring the peak emission
intensity in solvents of different viscosities and fitting a regression
phenyl (Table 2, compounds 5a, 5b, 5d) and naphthyl systems
(Table 2, compounds 10, 11). Moreover, the extent of conjugation
between the donor and the acceptor group influences significantly
the emission wavelength and increases the Stokes shift. This effect
is evident when we compare rotor 5d (emission max¼460, Stoke
shift¼44) with 11 (emission max¼598, Stoke shift¼151). On the
other hand, the alkyl side chains of the nitrogen have no signifi-
cant effect on the excitation and emission wavelengths (Table 2,
compounds 5d, 5k, 5m). Similarly, minimal changes are observed
between the different acceptor groups (Table 2, compounds 5d,
5e, 5f) and between differentially substituted phenyl rings (Table
2, compounds 5d, 5i, 5j).
line into the logarithms of the data points. Notably,
a is a compar-
ative metric for the dye’s overall brightness and the slope x is
a measure for the change of the intensity with viscosity, that is, the
dye’s viscosity sensitivity. A possible interpretation of the regres-
sion’s y-intercept
a is the logarithm of the emission intensity at
a viscosity of 1 mPa s. We therefore use the scaled y-intercept
a,
given in 1000 photon counts per second, as a relative metric of
brightness. Finally, the Stokes shift was calculated as the difference
between emission and excitation wavelength. Table 2 summarizes
these properties for the synthesized rotors.
Although the size of the alkyl side chain of the nitrogen does not
influence the viscosity sensitivity (all slope numbers are between
0.51 and 0.55) they do affect the brightness of the dye as shown by
the y-intercept data (Table 2: 5b¼50, 5d¼85, 5k[127, and
5m¼200). Replacement of the nitrile group by a methyl ester or
phenyl sulfonyl motif resulted in increase of the emission quantum
yield (Table 2, compounds 5c, 5e, 5f). These results can be explained
by considering the effect of these changes to the overall dipole
moment of the probes. It is known that, upon excitation, the TICT
probes assume a planar and dipolar quinoid structure (B), the sta-
bility of which is affected by the dipole moment and charge dis-
tribution (Fig. 4). Thus, changes in the molecular structure that
stabilize the excited state lead to an increase of the fluorescence
intensity. It should be noted that a similar increase of fluorescence
has been observed with a series of dialkylaminobenzonitriles and
has been explained based on the dipole moment.33
An increase in the brightness is also observed when the phenyl
group of 5d or 5f is functionalized with an additional methoxy
substituent (rotor 5i or 5h, respectively). Similarly, the more elec-
tronically rich thiophenyl group of rotor 14 is brighter than 5d.34
These results suggest that increasing the electron density be-
tween the donor and acceptor units leads to an increase of fluo-
rescence. This electronic effect can, however, be compromised by
steric effects.35 The steric congestion due to substitution at the
periphery of the phenyl ring can destabilize the planar structure (B)
of the excited state. Along these lines, compound 18 is among the
least bright dyes despite the presence of the two electronically
donating methoxy groups. Similar effects have been recorded in
a series of methoxy-substituted stilbenes.35,36
It is also interesting to compare the naphthyl compounds 7 and
11. The presence of the donor and acceptor groups along the long
axis of naphthalene of rotor 11 increases significantly the Stokes
shift and intensity, as compared to 7. This can be explained by
considering that substituents along the long axis of naphthalene
decrease significantly the lowest singlet excited state.37 This results
to an increase of the energy gap between that excited state and the
TICT states rendering the compound more bright but less sensitive
to environmental changes. On the other hand, substituents along
the short axis of naphthalene, such as in rotor 7, decrease the
second lowest excited state and thus increase the coupling of this
state with the TICT states.37
Table 2
Fluorescent properties and viscosity profile of molecular rotors
Cmp # Excitation Emission Stokes
Viscosity
Sensitivity x
R2
Brightness
y-intercept a
l
(nm)
l
(nm)
shift
1
2
470
431
321
423
430
440
447
436
393
448
450
448
443
419
443
466
373
447
470
433
503
489
404
460
460
484
485
486
485
480
480
491
486
470
488
532
476
598
492
461
33
58
83
37
30
44
38
50
92
32
30
43
43
51
45
66
103
151
22
28
0.542
0.543
0.359
0.553
0.425
0.535
0.538
0.531
0.519
0.477
0.528
0.614
0.554
0.440
0.512
0.521
0.403
0.223
0.517
0.562
>0.98
70
147
7
50
24
85
61
146
17
295
99
43
127
22
200
18
81
822
112
11
>0.99
>0.99
>0.99
> 0.99
>0.99
>0.98
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.99
>0.98
>0.99
>0.99
>0.99
5aa
5ba
5ca
5db
5e
5f
5g
5h
5ia
5j
5k
5l
5m
7a
10
11
14
18
a
Average of N¼2.
Average of N¼4.
b
Excitation and emission spectra of selected molecular rotors are
shown in Figure 2. To allow better comparison, the spectra were
normalized so that the emission from the highest viscosity is unity.
The dashed line represents an excitation acquisition for each de-
rivative while solid lines are the emission spectra in different
mixtures of ethylene glycol and glycerol of varying viscosity (given
in mPa s). A high glycerol content increases the solvent viscosity
leading to an increase in the quantum yield of the fluorescence
emission.
As shown in Eq. 2, there is a power law relationship between
viscosity and emission quantum yield. Figure 3 represents peak
emission intensities taken from Figure 2 and drawn over viscosity
in a double-logarithmic scale. The slope and the y-intercept provide
the desired metrics for sensitivity and brightness.
3. Discussion
Theoretical studies by Fo¨rster and Hoffmann30 have predicted
that the maximum viscosity sensitivity of a molecular rotor is 0.66
assuming that the deexcitation of this molecule takes place pre-
dominantly via intramolecular rotation. In solvents with the vis-
cosity range used in our study, this prerequisite is met. In most
cases the viscosity sensitivity of the molecular rotors was found to
be between 0.4 and 0.6. It is interesting to observe that most
chemical modifications that increase the fluorescence intensity
result in a decrease of the viscosity sensitivity. In fact, compound
18, one of the least bright dyes of this study, exhibits one of the
highest sensitivity values. On the other hand, naphthalene-based
rotor 11 is the brightest dye but has the smallest value of viscos-
ity sensitivity. This suggests that a dye that exhibits low intensity at
In terms of chemistry, all rotors are characterized by a small
molecular weight (less than 500), a facile one- to two-step syn-
thesis from commercially available materials and a good solubility
in the solvents of interest. With the exception of the low yielding
condensation reaction for the formation of 5g and 5l, all yields
were high. Their chemical structure is defined by the presence of
an electron donor group (oxygen or nitrogen) that is in conjuga-
tion with an electron acceptor group (nitrile, methyl ester of
phenyl sulfone). Replacing the amino group with a weaker elec-
tron donor, such as the methoxy group,31 induces a blue shift to
both the excitation and emission maxima in accordance to pre-
vious published results.32 This effect is manifested in both the

J. Sutharsan et al. / Tetrahedron 66 (2010) 2582–2588
2585
Figure 2. Normalized fluorescence excitation and emission spectra for compounds 5a, 5d, 7, 10, 11, and 14.
A
D
A
D
A
B
Figure 4. Mesomeric structures of a TICT probe. Upon photoexcitation, the ground-
state structure (A) is converted to a dipolar quinoid structure (B).
a low viscosity can increase its viscosity related intensity faster, and
thus have a higher sensitivity, as compared to a bright dye.
4. Conclusions
In this study we examined the effects of the chemical func-
tionalities of molecular rotors to the fluorescence profile, bright-
ness and viscosity sensitivity. The excitation and emission maxima
for these compounds can be tuned by the extent of conjugation
between the electron donor and electron acceptor groups. In ad-
dition, the brightness of these dyes can be tuned by modifying the
Figure 3. Emission intensities of rotors 5a, 5d, 7, 10, 11, and 14 in mixtures of ethylene
glycol/glycerol (emission maxima in Table 2) drawn over the viscosity of the mixtures
in a double-logarithmic scale.

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J. Sutharsan et al. / Tetrahedron 66 (2010) 2582–2588
electron density between the electron donor and electron acceptor
groups and by the presence of alkyl side chains on the donor group.
Moreover, chemical changes that increase the brightness of a mo-
lecular rotor, lead to a decrease of its viscosity sensitivity. The un-
derstanding of the effect of the chemical structure to the
fluorescence profile should help the rational design of molecular
rotors that are optimized for a specific application.
93.7, 52.6; HRMS calcd for C11H10N2O2 (MþH)þ 203.0815, found
203.0822.
5.2.3. 2-(4-Aminobenzylidene)malononitrile (5c). Yield 65%; dark
yellow solid; 1H NMR (400 MHz, DMSO)
d 7.97 (s, 1H), 7.72 (d, 2H,
J¼8.8 Hz), 7.02 (s, 2H), 6.66 (d, 2H, J¼8.8 Hz); 13C NMR (100 MHz,
DMSO)
d 159.7, 156.7, 135.1, 119.6, 117.1, 116.3, 114.3, 68.5; HRMS
calcd for C10H7N3 (M)þ 169.0634, found 169.0636.
5. Experimental section
5.1. General notes
5.2.4. (E)-Methyl 2-cyano-3-(4-(dimethylamino)phenyl) acrylate
(5d). Yield 89%; yellow solid; 1H NMR (400 MHz, CDCl3)
d
8.06 (s,
1H), 7.92 (d, 2H, J¼9.0 Hz), 6.68 (d, 2H, J¼9.1 Hz), 3.87 (s, 3H), 3.10
(s, 6H); 13C NMR (100 MHz, CDCl3)
d 165.0, 155.0, 153.9, 134.3, 119.5,
6-Methoxy-2-naphthaldehyde 8 was purchased from Alfa
Aesar. The rest of the reagents were obtained (Aldrich, Acros) at
highest commercial quality and used without further purification
except where noted. Air- and moisture-sensitive liquids and so-
lutions were transferred via syringe or stainless steel cannula.
Organic solutions were concentrated by rotary evaporation below
45 ꢀC at approximately 20 mmHg. All non-aqueous reactions were
carried out under anhydrous conditions. Yields refer to chro-
matographically and spectroscopically (1H NMR, 13C NMR) ho-
mogeneous materials, unless otherwise stated. Reactions were
monitored by thin-layer chromatography (TLC) carried out on
0.25 mm E. Merck silica gel plates (60F-254) and visualized under
UV light and/or developed by dipping in solutions of 10% ethanolic
phosphomolybdic acid (PMA) or p-anisaldehyde and applying
heat. E. Merck silica gel (60, particle size 0.040–0.063 mm) was
used for flash chromatography. Preparative thin-layer chroma-
tography separations were carried out on 0.25 or 0.50 mm
E. Merck silica gel plates (60F-254). NMR spectra were recorded on
Varian Mercury 400 and/or Unity 500 MHz instruments and
calibrated using the residual non-deuterated solvent as an in-
ternal reference. The following abbreviations were used to explain
the multiplicities: s¼singlet, d¼doublet, t¼triplet, q¼quartet,
m¼multiplet, br¼broad. High resolution mass spectra (HRMS)
were recorded on a VG 7070 HS mass spectrometer under electron
spray ionization (ESI) or electron impact (EI) conditions. Fluores-
cence spectroscopy data were recorded on a Jobin-Yvon Fluo-
romax-3 instrument.
117.8, 111.7, 93.6, 53.0, 40.2; HRMS calcd for C13H14N2O2 (MþH)þ
231.1128, found 231.1126.
5.2.5. 2-(4-Dimethylaminobenzylidene)malononitrile
(5e). Yield
7.78 (d, 2H,
91%; orange solid; 1H NMR (400 MHz, CDCl3)
d
J¼8.8 Hz), 7.41 (s, 1H), 6.68 (d, 2H, J¼8.9 Hz), 3.14 (s, 6H); 13C NMR
(100 MHz, CDCl3)
d 158.0, 154.1, 133.7, 119.1, 116.0, 114.9, 111.5, 71.3,
40.0; HRMS calcd for C12H11N3 (MþH)þ 198.1026, found 198.1024.
5.2.6. (E)-3-(4-(Dimethylamino)phenyl)-2(phenylsulfonyl) acryloni-
trile (5f). Yield 92%; orange solid; 1H NMR (400 MHz, CDCl3)
d 7.99
(s, 1H), 7.97 (s, 2H), 7.81 (d, 2H, J¼9.1 Hz), 7.62 (m, 1H), 7.55 (m, 2H),
6.65 (d, 2H, J¼9.1 Hz), 3.10 (s, 6H); 13C NMR (100 MHz, CDCl3)
d
154.0, 151.1, 139.6, 134.0, 133.7, 129.3, 127.9, 117.6, 115.0, 111.5,
104.6, 40.0; HRMS calcd for C17H16N2O2S (MþH)þ 313.1005, found
313.1004.
5.2.7. Dimethyl2-(4-(dimethylamino)benzylidene)malonate(5g). Yield
17%; yellow solid; 1H NMR (400 MHz, CDCl3)
d
7.67 (s, 1H), 7.33 (d, 2H,
J¼8.9 Hz), 6.63 (d, 2H, J¼9.0 Hz), 3.88 (s, 3H), 3.81 (s, 3H), 3.03 (s, 6H);
13C NMR (100 MHz, CDCl3)
d 168.4, 165.3, 151.9, 143.5, 131.8, 119.8,
118.9,111.5, 52.4, 52.2, 39.9; HRMS calcd for C14H17O4N (M)þ 263.1155,
found 263.1152.
5.2.8. (E)-3-(4-(Dimethylamino)-2-methoxyphenyl)-2-(phenyl-
sulfonyl) acrylonitrile (5h). Yield 81%; yellow solid; 1H NMR
(400 MHz, CDCl3)
d
8.51 (s, 1H), 8.12 (d, 1H, J¼9.2 Hz), 7.97 (d, 2H,
J¼7.5 Hz), 7.60 (m, 1H), 7.53 (m, 2H), 6.26 (dd, 1H, J¼2.1, 9.2 Hz),
5.2. General procedure for the preparation of molecular
rotors
5.98 (d, 1H J¼2.1 Hz), 3.89 (s, 3H), 3.11 (s, 6H); 13C NMR (100 MHz,
CDCl3)
d 162.1, 156.2, 144.8, 140.2, 133.4, 130.7, 129.2, 127.8, 115.8,
107.9, 105.3, 102.4, 92.6, 55.4, 40.2; HRMS calcd for C18H18N2O3S
To a round bottom flask containing a solution of aldehyde
(5.0 mmol) and methyl 2-cyanoacetate (5.5 mmol) in 20 mL of
methanol was added 0.50 mmol of piperidine and the mixture was
heated at 50 ꢀC. The formation of the product was monitored by TLC
and was completed within 8 h. Note that in certain cases the
product precipitates out of the reaction mixture. The crude mixture
was concentrated under reduced pressure and the product was
collected by a vacuum filtration. Alternatively, the product was
purified via flash chromatography (10–30% ethyl acetate in
hexane).
(MþH)þ 343.1111, found 343.1110.
5.2.9. (E)-Methyl 2-cyano-3-(4-(dimethylamino)-2-methoxyphenyl)
acrylate (5i). Yield 89%; orange solid; 1H NMR (400 MHz, CDCl3)
d
8.62 (s, 1H), 8.36 (d, 1H, J¼9.2 Hz), 6.31 (dd, 1H, J¼2.4 9.2 Hz), 6.00
(d, 1H, J¼2.4 Hz), 3.87 (s, 3H), 3.85 (s, 3H), 3.09 (s, 6H); 13C NMR
(100 MHz, CDCl3)
d 165.5, 162.2, 155.9, 148.4, 131.2, 118.6, 109.6,
105.4, 93.1, 91.8, 55.6, 52.8, 40.4; HRMS calcd for C14H16N2O3
(MþH)þ 261.1234, found 261.1235.
5.2.10. (E)-Methyl 2-cyano-3-(4-(dimethylamino)-2-methylphenyl)
5.2.1. (E)-Methyl 2-cyano-3-(4-methoxyphenyl)acrylate (5a). Yield
acrylate (5j). Yield 86%; yellow solid; 1H NMR (300 MHz, CDCl3)
48%; yellow solid; 1H NMR (400 MHz, CDCl3)
d
8.19 (s, 1H), 8.01 (d,
d
8.44 (s, 1H), 8.41 (s, 1H), 6.57 (dd, 1H, J¼2.5, 9.1 Hz), 6.47 (d, 1H,
2H, J¼8.9 Hz), 7.00 (d, 2H, J¼8.9 Hz), 3.92 (s, 3H), 3.90 (s, 3H); 13C
J¼2.3 Hz), 3.87 (s, 3H), 3.07 (s, 6H), 2.43 (s, 3H); 13C NMR (100 MHz,
NMR (100 MHz, CDCl3)
d
163.8, 163.5, 154.6, 133.6, 124.1, 116.1, 114.7,
CDCl3) d 165.3, 153.8, 151.5, 144.0, 131.3, 118.4, 118.2, 113.1, 110.1,
98.6, 55.5, 53.1; HRMS calcd for C12H11NO3 (MþNa)þ 240.0631,
93.5, 53.0, 44.4, 40.2, 20.8; HRMS calcd for C14H16N2O2 (MþH)þ
found 240.0633.
245.1285, found 245.1289.
5.2.2. (E)-Methyl 3-(4-aminophenyl)-2-cyanoacrylate (5b). Yield
5.2.11. (E)-Methyl
2-cyano-3-(4-diethylaminophenyl)
acrylate
8.01 (s,
87%; yellow solid; 1H NMR (400 MHz, CDCl3)
d
8.09 (s, 1H), 7.88 (d,
(5k). Yield 67%; brown solid; 1H NMR (400 MHz, CDCl3)
d
2H, J¼8.7 Hz), 6.69 (d, 2H, J¼8.7 Hz), 4.36 (s, 2H), 3.89 (s, 3H); 13C
1H), 7.88 (d, 2H, J¼9.1 Hz), 6.64 (d, 2H, J¼9.2 Hz), 3.84 (s, 3H), 3.42
NMR (100 MHz, CDCl3) d 164.2, 154.8, 152.8, 134.1, 120.3, 117.1, 114.0,
(q, 4H, J¼7.1 Hz), 1.19 (t, 6H, J¼7.1 Hz); 13C NMR (100 MHz, CDCl3)

J. Sutharsan et al. / Tetrahedron 66 (2010) 2582–2588
2587
d
164.8, 154.4, 151.6, 134.4, 118.6, 117.7, 111.0, 92.4, 52.6, 44.7, 12.4;
(2 mL). The reaction mixture was warmed to room temperature,
left stirring for 12 h and then it was poured into cold 5% aqueous
NaCl (30 mL). The mixture was extracted with diethyl ether
(3ꢁ20 mL), dried over MgSO4, and concentrated. The product was
purified via flash chromatography (20% EtOAc in hexanes) to give
compound 9. Compound 9: 35% yield, yellow solid; 1H NMR
HRMS calcd for C15H18N2O2 (MþH)þ 259.1441, found 259.1430.
5.2.12. 4-(2,2-Bis(phenylsulfonyl)vinyl)-N,N-dimethylaniline
(5l). Yield 2%; yellow solid; 1H NMR (400 MHz, CDCl3)
d 8.45 (s,
1H), 8.02 (t, 4H, J¼7.5 Hz), 7.90 (d, 2H, J¼9.0 Hz), 7.43–7.59 (m, 6H),
6.61 (d, 2H, J¼9.0 Hz), 3.09 (s, 6H); 13C NMR (400 MHz, CDCl3)
(300 MHz, CDCl3) d 10.02 (s, 1H), 8.14 (s, 1H), 7.88–7.73 (m, 2H), 7.67
d
153.6, 151.5, 141.9, 141.7, 137.5, 133.3, 133.0, 128.9, 128.8, 128.7,
(d, 1H, J¼8.6 Hz), 7.32 (dd, 1H, J¼2.5, 9.1 Hz), 7.08 (d, 1H, J¼2.4 Hz),
128.1, 127.2, 117.0, 112.2, 40.0; HRMS calcd for C22H21NO4S2 (MþH)þ
3.42–3.32 (m, 4H), 1.85–1.57 (m, 6H); 13C NMR (100 MHz, CDCl3)
428.0985, found 428.0984.
d 192.2, 152.2, 138.8, 134.7, 131.6, 130.7, 127.5, 126.5, 123.6, 119.7,
109.0, 49.8, 25.8, 24.6; HRMS calcd for C16H17NO (MþH)þ 240.1383,
5.2.13. (E)-Methyl 2-cyano-3-(4-(dibutylamino)phenyl)acrylate
found 240.1387.
(5m). Yield 72%; orange solid; 1H NMR (400 MHz, CDCl3)
d 8.04 (s,
1H), 7.91 (d, 2H, J¼9.1 Hz), 6.64 (d, 2H, J¼9.2 Hz), 3.88 (s, 3H), 3.36
5.2.20. 5-(Piperidin-1-yl)thiophene-2-carbaldehyde (13). A 200 mL
round bottom flask containing 5-bromothiophene-2-carbaldehyde
(7.62 g, 400 mmol), piperidine (3.40 g, 400 mmol), toluene (30 mL),
and p-toluene sulfonic acid (0.69 g, 40 mmol) was refluxed for 24 h.
The crude mixture was concentrated and the residue was subjected
to flash chromatography using dichloromethane/ethyl ether/hex-
ane: 1:1:8 to give aldehyde 13. This compound was further crys-
tallized from dichloromethane/hexane. Compound 13: 72% yield,
(m, 4H), 1.60 (m, 4H), 1.37 (m, 4H), 0.97 (t, 6H, J¼7.3 Hz); 13C NMR
(100 MHz, CDCl3) d 164.9, 154.4, 152.0, 134.3, 118.6, 117.8, 111.2, 92.4,
52.6, 50.8, 29.2, 20.1, 13.8; HRMS calcd for C19H26N2O2 (MþH)þ
315.2067, found 315.2056.
5.2.14. (E)-Methyl 2-cyano-3-(4-(dimethylamino)naphthalene-1-yl)
acrylate (7). Yield 98%; yellow solid; 1H NMR (400 MHz, CDCl3)
d
9.07 (s, 1H), 8.51 (d, 1H, J¼8.3 Hz), 8.20 (d, 1H, J¼8.4 Hz), 8.11 (d,
1H, J¼8.4 Hz), 7.61 (m, 1H), 7.55 (m, 1H,), 7.06 (d, 1H, J¼8.3 Hz), 3.96
(s, 3H), 3.05 (s, 6H); 13C NMR (100 MHz, CDCl3)
164.1, 156.7, 151.9,
dark blue solid; 1H NMR (400 MHz, CDCl3)
d 9.51 (s, 1H), 7.47 (d, 1H,
J¼4.4 Hz), 6.06 (d, 1H, J¼4.4 Hz), 3.35 (t, 4H, J¼4.7, 11.0 Hz), 1.73–
1.65 (m, 6H); 13C NMR (100 MHz, CDCl3) 180.4, 168.6, 140.6, 126.6,
104.2, 51.1, 25.1, 23.7; HRMS calcd for C10H13NOS (MþH)þ 196.0791,
found 196.0792.
d
134.2, 130.2, 128.0, 127.6, 126.0, 125.5, 123.3, 121.2, 117.0, 112.7,
100.0, 53.4, 44.8; HRMS calcd for C17H16N2O2 (MþH)þ 281.1285,
found 281.1287.
5.2.21. 4-(Diethylamino)-2,6-dimethoxybenzaldehyde (17). To
a 10 mL round bottom flask containing N,N-diethyl-3,5-dimethox-
5.2.15. (E)-Methyl 2-cyano-3-(6-methoxynaphthalen-2-yl)acrylate
(10). Yield 87%; yellow solid; 1H NMR (400 MHz, CDCl3)
d
8.37 (s,
yaniline27 (99.7 mg, 0.48 mmol) and DMF (150
mL, 0.96 mmol) in
1H), 8.32 (d, 1H, J¼2.4 Hz), 8.18 (dd, 1H, J¼1.8, 8.7 Hz), 7.85–7.79 (m,
DCM (2 mL) was added dropwise POCl3 (82.2 mg, 0.05 mL,
0.54 mmol) and the reaction mixture was stirred at 25 ꢀC for 5 h.
Sodium hydroxide (2 M, 15 drops) was then added until the solu-
tion became neutral causing the color to change to dark blue and
the mixture was stirred at 0 ꢀC for 3 h. The mixture was extracted
with ether (2ꢁ10 mL) and the organic extracts were dried over
MgSO4 and concentrated. The product was purified by flash column
chromatography (50% EtOAc in hexanes). Compound 17: 65% yield,
white crystals; 1H NMR (400 MHz, CDCl3) 10.17 (s, 1H), 5.68 (s, 2H),
3.82 (s, 6H), 3.38 (q, 4H, J¼7.1 Hz), 1.19 (t, 6H, J¼7.1 Hz); 13C NMR
(75 MHz, CDCl3) 186.6, 164.6, 153.9, 105.1, 86.8, 55.9, 55.8, 45.0,
12.9; HRMS calcd for C13H19NO3 (M)þ 237.1359, found 237.1356.
2H), 7.21 (dd, 1H, J¼2.5, 8.9 Hz), 7.16 (s, 1H), 3.97 (s, 3H), 3.95 (s,
3H); 13C NMR (400 MHz, CDCl3)
d 163.5, 160.4, 155.3, 137.3, 134.3,
131.1, 128.1, 127.8, 126.8, 126.0, 120.2, 116.1, 105.9, 100.3, 55.5, 55.3;
HRMS calcd for C16H13NO3 (MþNa)þ 290.0788, found 290.0791.
5.2.16. (E)-Methyl 2-cyano-3-(6-piperidin-1-yl naphthalen-2-yl)
acrylate (11). Yield 90%; orange solid; 1H NMR (300 MHz, CDCl3)
d
8.29 (s, 1H), 8.19 (s, 1H), 8.09 (dd, 1H, J¼1.8, 8.8 Hz), 7.74 (d, 1H,
J¼9.2 Hz), 7.64 (d, 1H, J¼8.8 Hz), 7.28 (dd, 1H, J¼2.6, 9.3 Hz), 7.03 (d,
1H, J¼2.2 Hz), 3.93 (s, 3H), 3.39 (t, 4H, J¼5.1 Hz), 1.73–1.66 (m, 6H);
13C NMR (100 MHz, CDCl3)
d 163.9, 155.5, 151.9, 137.7, 134.7, 130.6,
127.2, 126.4, 126.0, 125.6, 119.3, 116.6, 108.3, 98.3, 53.1, 49.3, 25.5,
24.3; HRMS calcd for C20H20N2O2 (MþH)þ 321.1598, found
321.1601.
5.3. General procedure for the determination of spectral
properties
5.2.17. (E)-Methyl 2-cyano-3-(5-(piperidin-1-yl)thiophen-2-yl)acry-
Each viscosity sample was mixed according to column A in
Table 3 shown below. The glycerol (Gly) was heated to ensure more
exact measuring during pipetting. The pre-stained ethylene glycol
late (14). Yield 90%; orange solid; 1H NMR (400 MHz, CDCl3)
d
7.95
(s, 1H), 7.38 (br s, 1H), 6.07 (d, 1H, J¼4.6 Hz), 3.76 (s, 3H), 3.39 (br s,
4H), 1.64 (m, 6H); 13C NMR (100 MHz, CDCl3)
169.2, 165.4, 146.1,
d
(EG) for each sample contained 100 mM of dye resulting in a final
144.1, 119.4, 118.4, 104.8, 61.5, 51.1, 24.8, 23.3; HRMS calcd for
C14H16N2O2S (MþH)þ 277.1005, found 277.1006.
Table 3
Preparation of an ethylene glycol–glycerol viscosity gradient.
A
B
C
5.2.18. (E)-Methyl 2-cyano-3-(4-(diethylamino)-2,6-dimethoxyphenyl)
acrylate (18). Yield 81%; yellow solid; 1H NMR (300 MHz, CDCl3)
Pre-stained EG/EG/Gly volumes (mL)
Viscosity (mPa s)
log viscosity
d
8.47 (s, 1H), 5.72 (s, 2H), 3.86 (s, 6H), 3 .84 (s, 3H), 3.41 (q, 4H,
0.5:0.5:4.0
0.5:1.0:3.5
0.5:1.5:3.0
0.5:2.0:2.5
0.5:2.5:2.0
391.4
258.1
170.2
112.2
74.0
2.593
2.412
2.231
2.050
1.869
J¼7.1 Hz) 1.22 (t, 6H, J¼7.1 Hz); 13C NMR (100 MHz, CDCl3)
d 166.5,
162.6, 153.9, 146.3, 118.0, 101.1, 95.4, 87.0, 55.0, 52.8, 45.2, 12.9;
HRMS calcd for C17H22N2O4 (MþH)þ 319.1652, found 319.1657.
5.2.19. 6-(Piperidin-1-yl)-2-naphthaldehyde (9). To a 50 mL round
bottom flask containing benzene (3 mL), HMPA (3 mL), and piper-
idine (1.65 mL, 16.7 mmol) was added via syringe, at 0 ꢀC, n-BuLi
(1.6 M in hexane, 10.4 mL, 16.7 mmol). After stirring for 15 min, the
reaction mixture was treated with a solution of 6-methoxy-2-
naphthaldehyde (390 mg, 2.09 mmol) in benzene/HMPA 1:1
concentration of 10 mM for each sample. All samples were placed on
rotating mixer for 1 h before pouring into cuvettes for scanning.
Preliminary fluorescent scanning was done on each dye dissolved
in 391.4 mPa s viscosity solvent to determine optimal excitation
and peak emission and slit settings for each molecular rotor

2588
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Financial support by the NIH (1R21RR025358) and the NSF
(CMMI-0652476) is gratefully acknowledged. We thank the Na-
tional Science Foundation for instrumentation grants CHE-9709183
and CHE-0741968. We also thank Drs. A. Mrse and Dr. Y. Su for NMR
spectroscopic and mass spectrometric assistance, respectively.
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Supplementary data
1H and 13C NMR spectra of compounds 5a–5m, 7–11, 13, 14, and
16–18. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2010.01.093.
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