Thermal racemization of substituted indolinobenzospiropyrans: Evidence of competing polar and nonpolar mechanisms

Article abstract of DOI:10.1021/ja0001613

A series of 6-substituted indolinobenzospiropyrans were resolved by chiral stationary phase HPLC and rate constants k(rac) for their thermal racemization were measured by circular dichroism spectropolarimetry at 60 °C in three different solvents: cyclohexane, 90:10 hexanes/2-propanol, and acetonitrile. Results show that the spiropyrans undergo thermal racemization most rapidly in acetonitrile, with k(rac) values ranging from 9.3 x 10 ^-5 to >5.0 x 10 ^-3 s ^-1, and least rapidly in cyclohexane, with k(rac) values ranging from 6.8 x 10 ^-6 to 4.6 x 10 ^-4 s ^-1. V-shaped plots of log k(rac) vs Hammett σ(p) constants in 90:10 hexanes/2-propanol and acetonitrile suggest that thermal racemization of the 6-substituted spiropyrans proceed via two competing mechanisms: a polar mechanism involving heterolytic C(sp³)-O bond cleavage with anchimeric assistance from the indoline nitrogen and a nonpolar electrocyclic ring opening mechanism with no anchimeric assistance from the indoline nitrogen. The outcome of this competition appears to be strongly influenced by solvent polarity: plots of log k(rac) vs σ(p) and σ^- in cyclohexane show a near-linear correlation with negative slope, which is consistent with the nonpolar mechanism. However, an increase in solvent polarity results in a shift toward a linear correlation with positive slope, which is consistent with the polar mechanism.

Full text of DOI:10.1021/ja0001613

6594
J. Am. Chem. Soc. 2000, 122, 6594-6600
Thermal Racemization of Substituted Indolinobenzospiropyrans:
Evidence of Competing Polar and Nonpolar Mechanisms
Susan Swansburg, Erwin Buncel, and Robert P. Lemieux*
Contribution from the Department of Chemistry, Queen’s UniVersity, Kingston, Ontario K7L 3N6, Canada
ReceiVed January 14, 2000
Abstract: A series of 6-substituted indolinobenzospiropyrans were resolved by chiral stationary phase HPLC
and rate constants krac for their thermal racemization were measured by circular dichroism spectropolarimetry
at 60 °C in three different solvents: cyclohexane, 90:10 hexanes/2-propanol, and acetonitrile. Results show
that the spiropyrans undergo thermal racemization most rapidly in acetonitrile, with krac values ranging from
9.3 × 10-5 to >5.0 × 10-3 s-1, and least rapidly in cyclohexane, with krac values ranging from 6.8 × 10-6 to
4.6 × 10-4 s-1. V-shaped plots of log krac vs Hammett σp constants in 90:10 hexanes/2-propanol and acetonitrile
suggest that thermal racemization of the 6-substituted spiropyrans proceed via two competing mechanisms: a
polar mechanism involving heterolytic C(sp3)-O bond cleavage with anchimeric assistance from the indoline
nitrogen and a nonpolar electrocyclic ring opening mechanism with no anchimeric assistance from the indoline
nitrogen. The outcome of this competition appears to be strongly influenced by solvent polarity: plots of log
krac vs σp and σ- in cyclohexane show a near-linear correlation with negative slope, which is consistent with
the nonpolar mechanism. However, an increase in solvent polarity results in a shift toward a linear correlation
with positive slope, which is consistent with the polar mechanism.
Introduction
Scheme 1
Indolinobenzospiropyrans (spiropyrans) are one of the most
studied families of organic dyes by virtue of their thermochro-
mic, solvatochromic, and photochromic properties. These
compounds are attractive as functional materials for a wide
variety of applications, including high-density optical data
storage, optical switching, and nonlinear optics.1-3 In solution,
a spiropyran can undergo ring opening to the corresponding
trans-merocyanine, and the position of this equilibrium usually
depends on solvent polarity and on the nature of substituents.
One of the best known spiropyrans is 1′,3′,3′-trimethyl-6-
nitrospiro[2H-1-benzopyran-2,2′-indoline] (1), which undergoes
ring opening to a stable merocyanine form in polar solvents
such as ethanol and/or upon irradiation in the near-UV (Scheme
1). However, much less attention has been paid to spiropyrans
lacking a strong electron-withdrawing group because they tend
to produce photostationary states with a negligible merocyanine
concentration.4 These so-called nonactiVated spiropyrans have
rather limited use in photochromic applications, but they have
been under consideration as potential chiroptical switches for
optically addressed liquid crystal spatial light modulators.5
Most chiroptical switches are photochromic compounds which
can undergo interconversion between two chiral helical forms
of opposite helicities, or between racemic and optically active
forms by photoresolution.6 The only spiropyran chiroptical
switch reported thus far contains a chiral center at C-3′ in
addition to the chiral spiro carbon (2). Switching is achieved
by reversible photoisomerization between the spiropyran form,
which exhibits circular dichroism as a 1.6:1 mixture of two
diastereomers at equilibrium, and the planar merocyanine form,
which exhibits no circular dichroism.7 We are currently
investigating an alternative approach toward a spiropyran
chiroptical switch which consists of photoresolving a nonacti-
vated liquid crystalline spiropyran using circularly polarized light
to reversibly induce detectable chiral bulk properties such as a
cholesteric helical pitch or a spontaneous polarization.5,8 To
undergo photoresolution, a chiral chromophore must undergo
efficient photoracemization, yet maintain its configurational
integrity in the absence of light.9 Photoracemization can be
achieved with nonactivated spiropyrans because the chiral spiro
form undergoes ring opening to a short-lived prochiral mero-
cyanine form which reverts back to the (R) or (S) enantiomers
of the spiro form with equal probabilities. However, in this
paper, we address the issue of configurational stability of
* To whom correspondence should be addressed.
(1) Photochromism; Brown, G. H., Ed.; Wiley: New York, 1971.
(2) Photochromism-Molecules and Systems; Du¨rr, H., Bouas-Laurent, H.,
Eds.; Elsevier: Amsterdam, 1990.
(3) Feringa, B. L.; Jager, W. F.; de Lange, B. Tetrahedron 1993, 49,
8267.
(4) Keum, S.-R.; Lee, K.-B.; Kazmaier, P. M.; Buncel, E. Tetrahedron
Lett. 1994, 37, 1015.
(5) (a) Swansburg, S.; Choi, Y.-K.; Keum, S.-R.; Buncel, E.; Lemieux,
R. P. Liq. Cryst. 1998, 24, 341. (b) Keum, S. R.; Lee, M.-J.; Swansburg,
S.; Buncel, E.; Lemieux, R. P. Dyes Pigments 1998, 39, 383.
(6) (a) Burnham, K. S.; Schuster, G. B. J. Am. Chem. Soc. 1999, 121,
10245. (b) Huck, N. P. M.; Jager, W. F.; de Lange, B.; Feringa, B. L. Science
1996, 273, 1686. (c) Suarez, M.; Schuster, G. B. J. Am. Chem. Soc. 1995,
117, 6732. (d) Feringa, B. L.; Huck, N. P. M.; van Doren, H. A. J. Am.
Chem. Soc. 1995, 117, 9929.
(7) Eggers, L.; Buss, V. Angew Chem. Int. Ed. Engl. 1997, 36, 881.
(8) For examples of photoresolution in a nematic liquid crystal phase,
see refs 6a,b.
(9) Rau, H. Chem. ReV. 1983, 83, 535.
10.1021/ja0001613 CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/29/2000

Racemization of Substituted Indolinobenzospiropyrans
J. Am. Chem. Soc., Vol. 122, No. 28, 2000 6595
Scheme 2
Recently, we reported the synthesis and characterization of
a spiropyran derivative (4) which forms monotropic nematic,
smectic A, and smectic C liquid crystal phases.5a Compound 4
was resolved by chiral phase HPLC but it could not be used as
a liquid crystal chiroptical switch, or as a chiral dopant in liquid
crystal hosts, due to its configurational instability. CD measure-
ments have shown that the optical activity of 4 decays following
spiropyrans as potential candidates for photoresolvable liquid
crystalline chiroptical switches.
Few studies on the configurational stability of indolinoben-
zospiropyrans have been carried out so far. Zaichenko and co-
workers measured free energies of activation for the inversion
of configuration (∆G‡inv) of a series of spiropyrans 3 at 25 °C
by dynamic NMR spectroscopy in deuterated DMSO and
correlated those values to Hammett σp constants for substituents
R1 and R3, and to Taft σ* constants for substituent R2.10 The
results are consistent with a rate-determining heterolytic cleavage
of the C(sp3)-O bond to give a zwitterionic cisoid intermediate
that can rapidly invert and close back to the spiropyran of
opposite configuration, as shown in Scheme 2. Accordingly,
the lowest ∆G‡ value (17 kcal/mol) was obtained for a
first-order kinetics with a half-life of 2.4 h at 60 °C in 90:10
hexanes/2-propanol, a solvent of relatively low polarity.14 To
increase the barrier to thermal racemization, we have introduced
an alkenyloxy substituent at the 6-position of the indolinoben-
zospiropyran (5), which makes heterolytic ring opening less
favorable by destabilizing a developing negative charge on the
benzopyran oxygen. The terminal alkene also enables the
addition of the spiropyran to a side-chain polysiloxane liquid
crystal. Surprisingly, CD measurements have shown that 5
undergoes thermal racemization 10 times faster than 4 under
the same conditions!14 To explain this unusual result, we have
investigated the effect of substituents on the rate of thermal
racemization of the indolinobenzospiropyrans 1 and 6a-l using
solvents that are less polar than those used in previous studies
(vide supra).10,11 In this paper, we report the measurements of
rate constants for racemization (krac) of 1 and 6a-l by CD
spectropolarimetry in three different solvents and correlations
of the krac values with Hammett σp and σ- constants. These
results strongly suggest that the thermal racemization of
indolinobenzospiropyrans proceeds via competing polar and
nonpolar mechanisms, and that the outcome of this competition
is a function of solvent polarity.
inv
spiropyran with substituents R2 ) R3 ) NO2, which stabilize
the negative charge buildup on the oxygen, and the highest
∆G‡inv value (25.2 kcal/mol) was obtained for a spiropyran with
a single substituent R1 ) NO2, which destabilizes the positive
charge buildup on nitrogen.
Mannschreck and co-workers resolved several spiropyrans
and spirooxazines by chiral phase HPLC on microcrystalline
triacetylcellulose and measured their ∆G‡inv by on-line circular
dichroism (CD) using methanol and ethanol as solvents.11
Although this study did not focus on substituent effects, the
∆G‡ values reported for indolinobenzospiropyrans are con-
inv
sistent with those obtained by Zaichenko and co-workers. A
more systematic investigation of substituent and solvent effects
on ∆G‡ of chiral 2H-chromene systems, which model the
inv
benzopyran half of indolinobenzospiropyrans, was carried out
by polarimetry using samples resolved preparatively by chiral
phase HPLC on triacetylcellulose.12,13 As with indolinoben-
zospiropyrans, substituent effects on ∆G‡ in polar solvents
inv
are consistent with a polar mechanism in which the C(sp3)-O
bond is cleaved heterolytically in the transition state of the rate-
determining step. In the case of 7,8-benzo-2-benzyloxy-2H-
chromene, ∆G‡inv (60 °C) was shown to increase with solvents
of decreasing polarity (e.g., ∆G‡inv(ethanol) ) 102.8 kJ/mol and
∆G‡inv(n-hexane) ) 105.9 kJ/mol).
Results
Synthesis and Resolution. Most of the spiropyrans used in
the kinetics experiments were obtained by condensation of
2-methylene-1,3,3-trimethylindoline (7) with the corresponding
5-substituted salicylaldehyde, as shown in Scheme 3. The
spiropyrans 6j and 6k were obtained from the corresponding
carboxylic acid. The spiropyrans 1 and 6a-l were resolved by
(10) Zaichenko, N. L.; Marevstev, V. S.; Arsenov, V. D.; Cherkashin,
M. I. Bull. Acad. Sci. USSR, DiV. Chem. Sci. 1987, 36, 1518.
(11) Leiminer, A.; Stephan, B.; Mannschreck, A. Mol. Cryst. Liq. Cryst.
1994, 246, 215.
(12) Harie´, G.; Samat, A.; Guglielmetti, R.; Van Parys, I.; Saeyens, W.;
De Keukeleire, D.; Lorenz, K.; Mannschreck, A. HelV. Chim. Acta 1997,
80, 1122.
(14) A detailed investigation of the kinetics of racemization, including
measurements of Arrhenius parameters in polar and nonpolar solvents, will
be published elsewhere.
(13) Loncar-Tomaskovic, L.; Mintas, M.; Trotsch, T.; Mannschreck, A.
Enantiomer 1997, 2, 459.

6596 J. Am. Chem. Soc., Vol. 122, No. 28, 2000
Swansburg et al.
Scheme 3
vs σp for eight spiropyrans gives a V-shaped correlation which
is slanted toward electron-withdrawing substituents, as shown
in Figure 2. In this solvent, the nitro-substituted spiropyran 1
racemized so rapidly that we were unable to obtain an accurate
value of krac; the corresponding data point in Figure 2 represents
an estimated lower limit. In contrast, a plot of log krac vs σp in
cyclohexane (Figure 3) shows the opposite trend: electron-
donating groups increase the rate of racemization to a much
greater extent than electron-withdrawing groups. Some of the
electron-withdrawing groups actually slow the rate of racem-
ization relative to X ) H. As a result, the V-shape correlation
gives way to a moderately linear correlation with a negative
slope. A comparative analysis of these data reveals that the
increase in solvent polarity results in a increase in krac for all
spiropyrans, and that the increase in krac is more substantial when
X is electron withdrawing, as shown in Figure 4 for five
representative examples.
semi-prep chiral phase HPLC. Baseline resolution was achieved
using a Daicel Chiralcel OJ column with either 90:10 hexanes/
ethanol or 90:10 hexanes/2-propanol as eluant. Each resolved
enantiomer was characterized by CD spectropolarimetry. Re-
solved enantiomeric pairs gave CD spectra with the expected
mirror image relationship and maximum ellipticities at wave-
lengths in the range of 241-255 nm.
Thermal Racemization. The thermal racemization of spiro-
pyrans according to Scheme 2 is treated as a reversible first-
order reaction starting from one enantiomer in optically active
form. By applying a steady-state approximation, it can be shown
that:
Rate constants for racemization of spiropyrans with electron-
withdrawing substituents were also correlated to σ- constants.
As shown in Figure 5, the plots of log krac vs σ- in 90:10
hexanes/2-propanol and acetonitrile give very good linear
correlations with positive slopes (R2 ) 0.980 and 0.977,
respectively). However, in cyclohexane, the plot of log krac vs
σ- appears to be scattered, although a reasonably good linear
correlation with negative slope can be found (R2 ) 0.932) if
one ignores the data point for X ) NO2, as shown in Figure 6.
These results are consistent with one mechanism predominating
in 90:10 hexanes/2-propanol and acetonitrile and another
mechanism predominating in cyclohexane except for spiropyran
1 which contains the strongest electron-withdrawing substituent.
k1 ) krac
(1)
where k1 is the rate constant for cleavage of the C(sp3)-O bond
and krac is the rate constant for racemization of the spiropyran.12
Rate constants for racemization krac at 60 ( 0.1 °C were
measured by CD spectropolarimetry in 90:10 hexanes/2-
propanol, acetonitrile, and cyclohexane. For each spiropyran,
the ellipticity (θ) of an enantiomerically enriched solution was
measured at the wavelength of maximum ellipticity (λCD) every
5-20 s over a minimum of 3 half-lives and the krac value was
derived from a plot of ln θt vs time according to eq 2, where θ0
and θt are ellipticities at times t ) 0 and t * 0. Three
reproducible runs were performed in each solvent. The krac data
are shown in Table 1 and the errors represent two standard
deviations.
Dependence of krac on Solvent Polarity. We evaluated the
effect of solvent polarity on krac for three representative
spiropyrans, 1, 6a, and 6e, using a form of the Grunwald-
Winstein equation (eq 3 ) where Y is the solvent ionizing power
ln θt ) -kract + ln θ0
(2)
log krac ) mY + c
(3)
Throughout the course of each experiment, the spiropyran
solution was kept in the cavity of the spectropolarimeter under
constant exposure to the excitation beam. To rule out the
contribution of a photochemical mechanism to spiropyran
racemization in the cavity of the spectropolarimeter, the thermal
racemization of 6a in 90:10 hexanes/2-propanol was followed
by measuring the ellipticity of the sample every 3 min and
removing the sample from the path of the excitation beam
between measurements. A plot of ln θt vs t gave a krac value of
1.0 × 10-3 s-1, which is the same, within experimental error,
as that obtained in the standard experiment, i.e., 0.93 × 10-3
s-1. None of the spiropyrans used in this study appear to form
any significant amount of colored trans-merocyanine that is
detectable to the eye in the three solvents used (over the course
of a kinetic run).
Free Energy Relationships. Rate constants for racemization
of the spiropyrans 1 and 6a-l were correlated initially to
Hammett σp constants for substituents X.15 In 90:10 hexanes/
2-propanol, a plot of log krac vs σp does not give a linear
correlation, as shown in Figure 1. Instead, it confirms our
preliminary observations that both electron-donating and electron-
withdrawing substituents increase the rate of racemization. The
relatively symmetric V-shaped plot suggests that thermal
racemization in 90:10 hexanes/2-propanol proceeds via two
competing mechanisms, with one mechanism predominating
when X is electron withdrawing and the other predominating
when X is electron donating. In acetonitrile, a plot of log krac
and m is a measure of the dependence of krac on solvent
polarity.16 Rate constants krac were measured by CD spectropo-
larimetry at 30 ( 0.1 °C in acetonitrile/water mixtures and
plotted versus the corresponding Y values.17 The solvent
mixtures ranged in proportion from 90:10 to 60:40 acetonitrile/
water.
In the case of the unsubstituted spiropyran 6e, a plot of log
krac vs Y gave an excellent linear fit (R2 ) 0.998) with a slope
m of 0.76, which indicates a relatively strong dependence of
krac on the solvent polarity. A similar plot was obtained for the
6-dimethylaminospiropyran 6a (R2 ) 0.988), although the slope
m of 0.53 indicates a lesser dependence of krac on solvent
polarity, as shown in Figure 7. The 6-nitrospiropyran 1, as well
as other electron-deficient spiropyrans such as 6k and 6l,
racemized too rapidly in acetonitrile/water for any meaningful
data to be acquired. The krac data for 6a and 6e in acetonitrile/
water were also correlated to Reichardt’s solvent parameter ET,
which gave linear fits of lesser quality (R2 ) 0.958 and 0.941)
with slopes of 0.61 and 0.46, respectively, as shown in Figure
8. The ET parameters were measured for each solvent mixture
using Reichardt’s dye (2,6-diphenyl-4-(2,4,6-triphenylpyridinio)-
phenolate).18
(16) Winstein, S.; Grunwald, E.; Jones, H. W. J. Am. Chem. Soc. 1951,
73, 2700.
(17) Bentley, T. W.; Dau-Schmidt, J.-P.; Llewellyn, G.; Mayr, H. J. Org.
Chem. 1992, 57, 2387.
(15) Hansch, C.; Leo, A.; Taft, R. W. Chem. ReV. 1991, 91, 165.
(18) Reichardt, C. Angew. Chem., Int. Ed. Engl. 1979, 18, 98.

Racemization of Substituted Indolinobenzospiropyrans
J. Am. Chem. Soc., Vol. 122, No. 28, 2000 6597
Table 1. Rate Constants krac for Thermal Racemization of Indolinobenzospiropyrans 1 and 6a-l Measured in 90:10 Hexanes/Isopropanol,
Acetonitrile and Cyclohexane at 60 °C
a
104 krac (s-1
)
CD (nm)b
X
σp
σ- c
90:10 hexanes/IPA
acetonitrile
cyclohexane
c
compd
λ
1
254
251
254
242
253
241
249
255
243
242
250
250
242
NO2
NMe2
OMe
Me
p-MeOC6H4
H
CtCC4H9
I
0.78
-0.83
-0.27
-0.17
-0.08
0
0.03
0.18
0.23
0.23
1.27
7.9 ( 2.0
9.3 ( 2.0
7.2 ( 1.0
1.4 ( 0.5
0.95 ( 0.07
0.63 ( 0.30
1.0 ( 0.4
0.7 ( 0.2
0.52 ( 0.07
0.56 ( 0.10
2.2 ( 0.7
1.8 ( 0.4
3.3 ( 0.5
>50
0.62 ( 0.39
4.6 ( 0.9
6a
6b
6c
6d
6e
6f
6g
6h
6i
19 ( 2
12 ( 3
3.4 ( 0.7
3.5 ( 0.5
0.77 ( 0.11
1.3 ( 0.04
2.0 ( 0.1
0.23 ( 0.03
0.54 ( 0.01
0.53d
0.27
0.25
0.19
0.70e
0.75f
1.00
Br
Cl
0.93 ( 0.03
1.2 ( 0.3
6j
6k
6l
C(O)NHPh
CO2Ph
CN
0.41
0.44
0.66
9.0 ( 1.0
22 ( 2
0.098 ( 0.029
0.068 ( 0.020
a Error is (2 standard deviations. b Wavelength for CD measurements. c From ref 15. d Value for X ) CtCH used. e Value for X ) C(O)NMe2
used. f Value for X ) CO2Me used.
Figure 1. Plot of log krac vs σp for the thermal racemization of
spiropyrans 1 and 6a-l in 90:10 hexanes/2-propanol at 60 °C. Error
bars represent (2 standard deviations.
Figure 3. Plot of log krac vs σp for the thermal racemization of
spiropyrans 1 and 6a-c,e,f,h,k,l in cyclohexane at 60 °C. Error bars
represent (2 standard deviations.
Figure 2. Plot of log krac vs σp for the thermal racemization of
spiropyrans 1 and 6a-c,e,f,h,k,l in acetonitrile at 60 °C. The data point
for 1 (X ) NO2) is a lower limit estimate. Error bars represent (2
standard deviations.
Figure 4. Plot of log krac vs σp for the thermal racemization of
spiropyrans 1 and 6a,b,e,l in 90:10 hexanes/2-propanol (triangles),
acetonitrile (squares), and cyclohexane (circles) at 60 °C. The data point
for 1 (X ) NO2) in acetonitrile is a lower limit estimate. The error
bars are omitted for clarity.
Discussion
Our study has revealed a remarkable contrast in the effect of
solvent polarity on the rate of racemization as a function of
substituents. Thus, the rate of racemization of spiropyrans with
electron-donating substituents is much less sensitive to solvent
polarity than that of spiropyrans with electron-withdrawing
groups. In going from acetonitrile to cyclohexane, krac for 6a
(X ) NMe2) decreases only by a factor of 4 whereas krac for 6l
(X)CN) decreases by more than two orders or magnitude. These
observations are consistent with the correlations of log krac with
Grunwald-Winstein and Reichardt solvent parameters (Figures
7 and 8) and suggest that two mechanisms are operative in the
thermal racemization of the spiropyrans. An examination of the

6598 J. Am. Chem. Soc., Vol. 122, No. 28, 2000
Swansburg et al.
Figure 5. Plot of log krac vs σ- for the thermal racemization of
spiropyrans 1 and 6f-l in 90:10 hexanes/2-propanol at 60 °C (filled
circles) and spiropyrans 1 and 6f,h,k,l in acetonitrile at 60 °C (open
circles). Error bars represent (2 standard deviations.
Figure 8. Plot of krac vs Reichardt’s solvent parameter ET for the
thermal racemization of spiropyrans 6a (circles) and 6e (squares) in
acetonitrile/water mixtures at 30 °C. The error bars are omitted for
clarity.
The symmetrical V-shaped correlation obtained in 90:10
hexanes/2-propanol (Figure 1) suggests that the two mechanisms
are evenly matched in this solvent and that the competition is
controlled primarily by substituent effects. An increase in solvent
polarity, from 90:10 hexanes/2-propanol to acetonitrile, causes
a general increase in krac, which is most pronounced for
spiropyrans with electron-withdrawing substituents (Figure 2),
thus resulting in a distortion of the V-shape correlation toward
a possible linear correlation with positive slope (i.e., domination
of one mechanism regardless of substituent effects). Unfortu-
nately, we were unable to further test this hypothesis due to
the lack of transparency of more polar solvents in the 241-
255 nm range, although we know from the work of Zaichenko
et al. that a positive linear correlation was found in DMSO.10
However, a further decrease in solvent polarity, from 90:10
hexanes/2-propanol to cyclohexane, produced the opposite
effect: a general decrease in krac, which is most pronounced
for spiropyrans with electron-withdrawing substituents (Figure
3), thus resulting in a distortion of the V-shape correlation
toward a linear correlation with negative slope (i.e., domination
of the other mechanism regardless of substituent effects). These
results are consistent with a competition between the well-
established polar mechanism shown in Scheme 2 and a
“nonpolar” mechanism in which there is relatively little charge
separation in the transition state.
Figure 6. Plot of log krac vs σ- for the thermal racemization of
spiropyrans 1 and 6f,h,k,l in cyclohexane at 60 °C. The data point for
X ) NO2 is omitted in the least-squares fit. Error bars represent (2
standard deviations.
In the polar mechanism, ring opening proceeds via a transition
state in which there is a significant amount of charge separation
by virtue of anchimeric assistance from the indoline nitrogen.
The polar transition state is stabilized by polar solvents and the
developing negative charge on the benzopyran oxygen is
stabilized by electron-withdrawing substituents at the 6-position.
This stabilizing effect is described more explicitely by σ-
constants, as shown by the very good correlation found between
log krac and σ- in acetonitrile and 90:10 hexanes/2-propanol
(Figure 5).
Under most circumstances reported thus far in the literature,
i.e., polar solvents and electron-withdrawing substituents at the
6- and 8-positions, the polar mechanism appears to be the
predominant, if not the exclusive pathway for thermal racem-
ization of spiropyrans. However, under circumstances which
disfavor charge separation in the transition state, i.e., nonpolar
solvents and electron-donating substituents which destabilize a
developing negative charge on the benzopyran oxygen, a
nonpolar mechanism appears to be predominant. For this
mechanism, we propose an electrocyclic ring opening to a
Figure 7. Plot of krac vs Grunwald-Winstein solvent ionizing power
Y for the thermal racemization of spiropyrans 6a (circles) and 6e
(squares) in acetonitrile/water mixtures at 30 °C. The error bars are
omitted for clarity.
three log krac vs σp plots (Figures 1-3) in order of increasing
solvent polarity, from cyclohexane to acetonitrile, also suggests
that the latter has a strong influence on the outcome of a
competition between the two mechanisms.

Racemization of Substituted Indolinobenzospiropyrans
J. Am. Chem. Soc., Vol. 122, No. 28, 2000 6599
Scheme 4
least rapidly in cyclohexane, with krac values ranging from 6.8
× 10-6 to 4.6 × 10-4 s-1. Plots of log krac vs Hammett σp and
σ- constants suggest that thermal racemization of the spiropy-
rans proceed via two competing mechanisms: a polar mecha-
nism involving heterolytic C(sp3)-O bond cleavage with
anchimeric assistance by the indoline nitrogen, and a nonpolar
electrocyclic ring-opening mechanism with no anchimeric
assistance by the indoline nitrogen. The outcome of this
competition appears to be strongly influenced by solvent
polarity: plots of log krac vs σp and σ- in cyclohexane give a
near-linear correlation with negative slope, which is consistent
with the nonpolar mechanism, and an increase in solvent polarity
results in a shift toward a linear correlation with positive slope,
which is consistent with the polar mechanism. Overall, these
results suggest that 6-substituted indolinobenzospiropyrans are
configurationally too labile, regardless of the nature of the
substituent, to be useful as photoresolvable chiroptical switches.
Scheme 5
quinoid intermediate which does not involve formal participation
of the indoline nitrogen, as shown in Scheme 4. The ring-opened
quinoid intermediate can then undergo rapid conformational
inversion, followed by ring closure to the other enantiomer. This
electrocyclic ring-opening mechanism should proceed via a
different transition state structure, with different conformational
degrees of freedom, than in the polar mechanism even though
the quinoid intermediate may be viewed as an extreme canonical
form of the zwitterionic intermediate.
Experimental Section
1
General. H and 13C nuclear magnetic resonance (NMR) spectra
were obtained in deuterated chloroform, deuterated DMSO, or deuter-
ated acetone on Bruker ACF-200 and Avance 300 spectrometers.
Chemical shifts are reported in δ (ppm) relative to tetramethylsilane.
Low-resolution EI mass spectra were obtained using a Fisons VG
Quattro triple quadrupole mass spectrometer; peaks are reported as m/z
(percent intensity relative to base peak). High-resolution EI mass spectra
were obtained by the University of Ottawa Regional Mass Spectrometry
Centre. Melting points were measured using a Uni-Melt Thomas-Hoover
melting point apparatus and are uncorrected. Semi-prep chiral HPLC
resolutions were performed on a system consisting of a Waters 501
HPLC pump, a Supelguard C18 LC-Si guard column (2 cm × 4.0 mm
i.d.), a semi-prep Daicel Chiracel OJ chiral stationary phase column
(25 cm × 10 mm i.d.), and a D-Star DWW-10 variable-wavelength
UV detector. Hexanes/ethanol (90:10) and hexanes/2-propanol (90:10)
mixtures were used as eluant (3 mL/min). Circular dichroism (CD)
spectra were recorded on a Jasco J-715 spectropolarimeter in hexanes/
2-propanol (90:10), cyclohexane, acetonitrile, and acetonitrile/water
mixtures. Temperature control for the kinetics measurements was
achieved using a water-jacketed quartz cell (0.1 cm path length) and a
NESLAB RTE-111 Bath/Circulator with microprocessor control.
Interestingly, the rate of racemization of the electron-rich
spiropyran 6a (X ) NMe2) does show a moderate dependence
on solvent polarity, which suggests that racemization by the
“nonpolar” mechanism proceeds via a transition state with some
degree of charge separation. The charge distribution in the
transition state for electrocyclic ring opening of a spiropyran
with an electron-donating substituent (i.e., X ) NMe2) may be
modeled by the canonical forms shown in Scheme 5, in which
the developing partial positive charge para to C-6 would be
stabilized by an electron-donating substituent via a π-polariza-
tion effect; the latter is otherwise insulated from conjugative
interaction with the para carbon.19 This would be consistent
with the negative slope of the log krac vs σp and σ- plots obtained
in cyclohexane. In these two plots, the rate constant for
compound 1 (X ) NO2) does not fit the observed trend, which
suggests that the polar mechanism still contributes to some
extent to thermal racemization in cyclohexane when a very
strong electron-withdrawing group is present. The V-shaped
correlations obtained in the more polar solvents suggest that
the nonpolar mechanism predominates when X is electron
donating, but gives way to the polar mechanism when X is
electron withdrawing. In highly polar solvents such as DMSO,
the nonpolar mechanism appears to be completely suppressed
in favor of the polar mechanism.
Materials. All reagents and chemicals were obtained from com-
mercial sources and used without further purification unless otherwise
noted. Toluene was distilled over Na/benzophenone under nitrogen,
and CH2Cl2 was distilled over P2O5 immediately prior to use. Hexanes
for chiral HPLC resolutions was distilled over molecular sieves.
2-Methylene-1,3,3-trimethylindoline (7) was obtained from Aldrich.
5-(N,N-Dimethylamino)salicylaldehyde (8), 5-iodosalicylaldehyde (9),
and 5-cyanosalicylaldehyde (10) were prepared according to literature
procedures.20-22 The spiropyrans 1, 6b,23 6c,24 6e, 6g,25 6h, 6i, and
1′,3′,3′-trimethylspiro[2H-1-benzopyran-2,2-indoline]-6-carboxylic acid
(11) were prepared according to the method of Keum et al. and shown
to have the expected physical and spectral properties.26 6-(4-Methoxy-
phenyl)-1′,3′,3′-trimethylspiro[2H-1-benzopyran-2,2-indoline] (6d) was
provided by Prof. S.-R. Keum. All spiropyrans were purified by
recrystallization from either spectral grade hexane or acetonitrile after
filtration through 0.45 µm PTFE syringe filters prior to resolution by
chiral phase HPLC.
Summary
Indolinobenzospiropyrans are under investigation as potential
liquid crystalline chiroptical switches based on the principle of
photoresolution. One of the basic requirements of such materials
is that they must be configurationally stable in the absence of
light. Hence, rates of thermal racemization for a series of
6-substituted indolinobenzospiropyrans were measured by CD
spectropolarimetry at 60 °C in three solvents of varying polarity.
Results show that the 6-substituted spiropyrans 1 and 6a-l
undergo thermal racemization most rapidly in acetonitrile, with
krac values ranging from 9.3 × 10-5 to >5.0 × 10-3 s-1, and
(20) Ando, M.; Emoto, S. Bull. Chem. Soc. Jpn. 1978, 51, 2433.
(21) Pavia, M. R.; Cohen, M. P.; Dilley, G. J.; Dubuc, G. R.; Durgin, T.
L.; Forman, F. W.; Hediger, M. E.; Milot, G.; Powers, T. S.; Sucholeiki,
I.; Zhou, S.; Hangauer, D. Bioorg. Med. Chem. 1996, 4, 659.
(22) Suzuki, Y.; Takahashi, H. Chem. Pharm. Bull. 1983, 31, 1751.
(23) Hosangadi, B. D.; Thakur, S. K. Synthesis 1997, 1137.
(24) Hinnen, A.; Audic, C.; Gautron, R. Bull. Chem. Soc. Fr. 1968, 2066.
(25) Cho, Y. J.; Rho, K. Y.; Keum, S. R.; Kim, S. H.; Yoon, C. M.
Synth. Commun. 1999, 29, 2061.
(26) (a) Keum, S.-R.; Lee, K.-B.; Kazmaier, P. M.; Manderville, R.;
Buncel, E. Magn. Reson. Chem. 1992, 30, 1128. (b) Keum, S.-R.; Hur,
M.-S.; Kazmaier, P. M.; Buncel, E. Can. J. Chem. 1991, 69, 1940.
(19) Reynolds, W. F. Prog. Phys. Org. Chem. 1983, 14, 165.

6600 J. Am. Chem. Soc., Vol. 122, No. 28, 2000
Swansburg et al.
Purification of Copper(I) Iodide. A mixture of copper(I) iodide
(5.3 g), saturated KI (25 mL), and activated charcoal was stirred for 3
h, then filtered through Celite. Water was added to the filtrate to
precipitate the CuI, which was collected by filtration and washed with
water, ethanol, and ether (3 × 20 mL each). The purified CuI was
dried under vacuum and stored in a desiccator in the dark.
7.57-7.30 (m, 2H), 7.21-7.04 (m, 4H), 6.92-6.54 (m, 4H), 6.50 (d,
1H, J ) 2.2 Hz), 5.76 (d, 1H, J ) 10.4 Hz), 2.72 (s, 3H), 1.29 (s, 3H),
1.16 (s, 3H); MS m/z 396 (M+, 19), 304 (73), 261 (16), 159 (100), 144
(59); HRMS calcd for C26H24N2O2 396.1838, found 396.1833.
Phenyl 1′,3′,3′-trimethylspiro[2H-1-benzopyran-2,2-indoline]-6-
carboxylate (6k). The procedure used for the preparation of 6j was
repeated with 112 mg of 11 (0.35 mmol) and 94 mg of phenol (1 mmol)
6-(N,N-Dimethylamino)-1′,3′,3′-trimethylspiro[2H-1-benzopyran-
2,2-indoline] (6a). A solution of 8 (35 mg, 0.21 mmol) and 2-meth-
ylene-1,3,3-trimethylindoline (7, 60 mg, 0.35 mmol) in EtOH (3 mL)
was refluxed for 3 h. After cooling, the solution was concentrated and
the solid residue purified by chromatography on silica gel (90:10
hexanes/EtOAc) to give 42 mg (63%) of 6a as a pink solid: mp 105-
1
to give 54 mg (39%) of 6k: mp 141-142 °C; H NMR (200 MHz,
CDCl3) δ 7.98-7.93 (m, 2H), 7.45-7.37 (m, 2H), 7.28-7.15 (m, 4H),
7.08 (d, 1H, J ) 7.2 Hz), 6.96-6.86 (m, 2H), 6.78 (d, 1H, J ) 8.2
Hz), 6.54 (d, 1H, J ) 7.4 Hz), 5.77 (d, 1H, 10.4 Hz), 2.74 (s, 3H),
1.30 (s, 3H), 1.18 (s, 3H); 13C NMR (50 MHz, CDCl3) δ 164.7, 159.1,
151.1, 147.9, 136.4, 132.3, 129.4, 129.3, 128.9, 127.7, 125.7, 121.8,
121.5, 121.3, 120.3, 119.5, 118.7, 115.2, 106.9, 105.6, 52.0, 28.9, 25.9,
20.0; MS m/z 397 (M+, 8), 304 (100), 261 (22), 158 (38), 144 (75);
HRMS calcd for C26H23NO3 397.1768, found 397.1678.
1
108 °C; H NMR (200 MHz, CDCl3) δ 7.22-7.02 (m, 2H), 7.03 (d,
1H, J ) 7.2 Hz), 6.48 (d, 1H, J ) 6.8 Hz), 5.70 (d, 1H, J ) 10.6 Hz),
2.92 (s, 6H), 2.69 (s, 3H), 1.26 (s, 3H), 1.13 (s, 3H); 13C NMR (50
MHz, CDCl3) δ 148.4, 147.0, 145.2, 137.0, 129.8, 127.5, 121.5, 120.0,
118.9, 115.7, 115.3, 112.0, 106.7, 103.7, 51.6, 41.9, 30.0, 29.0, 25.9,
20.3; MS m/z 320 (M+, 29), 305 (9), 161 (67), 159 (100), 144 (49);
HRMS calcd for C21H24N2O 320.1889, found 320.1907.
6-Cyano-1′,3′,3′-trimethylspiro[2H-1-benzopyran-2,2-indoline] (6l).
The procedure used for the preparation of 6a was repeated with 60 mg
of 7 (0.35 mmol) and 36 mg of 10 (0.25 mmol) to give 55 mg (74%)
5-(1-Hexynyl)salicylaldehyde (12). This reaction wa carried out on
a Schlenck line. A round-bottom flask containing 9 (1.01 g, 4.1 mmol),
CuI (41 mg, 0.22 mmol), and (Ph3P)2PdCl2 (0.168 g, 0.24 mmol) was
evacuated and flushed with Ar (3×). Degassed toluene (5 mL) and
diisopropylamine (5 mL) were added by syringe and stirred at room
temperature. After 10 min, 1-hexyne (0.58 g, 7.1 mmol) was added
dropwise by syringe and the mixture was stirred under Ar overnight.
The mixture was diluted with toluene and washed with 2 M aqueous
HCl (3×) and brine, dried (MgSO4), and concentrated. The solid residue
was purified by chromatography on silica gel (hexanes) to give 0.50 g
1
of 6l as a pink solid: mp 153-156 °C; H NMR (200 MHz, CDCl3)
δ 7.38-7.33 (m, 2H), 7.24-7.05 (m, 2H), 6.89-6.81 (m, 2H), 6.74
(d, 1H, J ) 8.8 Hz), 6.53 (d, 1H, J ) 7.8 Hz), 5.79 (d, 1H, J ) 10
Hz), 2.71 (s, 3H), 1.30 (s, 3H), 1.12 (s, 3H); MS m/z 302 (M+, 28),
287 (21), 272 (13), 159 (100), 143 (96); HRMS calcd for C20H18N2O
302.1419, found 302.1431.
Kinetics Measurements. All spiropyrans were resolved by semi-
prep chiral phase HPLC with 90:10 hexanes/2-propanol as eluant, except
for 1, 6a, 6c, and 6e which were resolved with 90:10 hexanes/ethanol
as eluant. For kinetics measurements in 90:10 hexanes/2-propanol,
solutions of resolved spiropyrans were collected directly from the HPLC
and transferred to the thermostated CD cell. Sample concentrations were
adjusted when necessary to give CD spectra of acceptable quality (HT
voltage in the 250-400 range). For kinetics measurements in cyclo-
hexane, acetonitrile, and acetonitrile/water, as well as in hexanes/2-
propanol for 1, 6a, 6c, and 6e, solutions of resolved spiropyrans were
collected from the HPLC and the solvent was removed in the dark by
rotary evaporation at room temperature. The resolved samples were
kept under high vacuum for 24 h and redissolved in the appropriate
solvent(s). Rate constants of thermal racemization (krac) were measured
in 90:10 hexanes/2-propanol, cyclohexane, and acetonitrile at 60 ( 0.1
°C, and in acetonitrile/water mixtures at 30 ( 0.1 °C by CD
spectropolarimetry. Solutions of optically active spiropyrans were
allowed to thermally equilibrate for ca. 5 min in the thermostated cell
before the start of data collection. The spectropolarimeter was
programmed to record the ellipticity (θ) of each solution at the
wavelength of maximum ellipticity (see Table 1) every 5 to 20 s,
depending on the rate of racemization, over at least 3 half-lives. Three
separate runs were carried out for each spiropyran. Rate constants krac
were obtained from the slope of ln θ vs time plots.
1
(60%) of 12 as a pale yellow solid: mp 27-28 °C; H NMR (200
MHz, CDCl3) δ 11.00 (s, 1H), 9.82 (s, 1H), 7.58 (d, 1H, J ) 2.4 Hz),
7.51 (dd, 1H, J ) 8.6, 2.0 Hz), 6.89 (d, 1H, J ) 8.6 Hz), 2.38 (t, 2H,
J ) 6.8 Hz), 1.61-1.52 (m, 4H), 0.93 (t, 3H, J ) 7.1 Hz); 13C NMR
(50 MHz, CDCl3) δ 196.1, 160.8, 139.9, 136.6, 120.4, 117.8, 116.1,
89.9, 78.7, 30.8, 22.0, 19.0, 13.6; MS m/z 202 (M+, 34), 187 (26), 173
(19), 159 (100), 145 (53); HRMS (EI) calcd for C13H14O2 202.0994,
found 202.0999.
6-(1-Hexynyl)-1′,3′,3′-trimethylspiro[2H-1-benzopyran-2,2-indo-
line] (6f). The procedure used for the preparation of 6a was repeated
using 112 mg (0.65 mmol) of 7 and 97 mg (0.48 mmol) of 12 to give
6f as an oil that was resolved by chiral phase HPLC without further
purification: 1H NMR (300 MHz, CDCl3) δ 7.18-7.03 (m, 4H), 6.84-
6.76 (m, 2H), 6.59 (d,1H, 8.1 Hz), 6.50 (d, 1H, J ) 7.8 Hz), 5.67 (d,
1H, J ) 10.2 Hz), 2.69 (s, 3H), 2.36 (t, 2H, J ) 6.9 Hz), 1.60-1.41
(m, 4H), 1.26 (s, 3H), 1.14 (s, 3H), 0.92 (t, 3H, J ) 7.2 Hz); 13C NMR-
(75 MHz, CDCl3) δ 154.0, 148.1, 136.6, 133.0, 129.8, 129.0, 127.6,
121.6, 119.9, 118.7, 115.5, 115.0, 106.8, 104.5, 88.5, 80.8, 51.8, 31.0,
28.9, 25.9, 22.0, 20.1, 19.1, 13.6; MS m/z 357 (M+, 11), 159 (100),
144 (26); HRMS (EI) calcd for C25H27NO 357.2093, found 357.2095.
1′,3′,3′-Trimethyl-6-(N-phenylcarboxamide)spiro[2H-1-benzopy-
ran-2,2-indoline] (6j). A solution of 11 (0.102 g, 0.32 mmol), aniline
(0.092 g, 1.0 mmol), DCC (0.078 g, 0.37 mmol), and DMAP (0.016 g,
0.13 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for
several days. The reaction mixture was concentrated and eluted through
a short silica gel column (90:10 hexanes/ethyl acetate). The product
was redissolved in EtOAc, washed with 10% aqueous NaOH (2×) and
water (2×), dried (MgSO4), and concentrated to give 114 mg (90%)
of 6j as an oil: 1H NMR (200 MHz, CDCl3) δ 7.65-7.58 (m, 3H),
Acknowledgment. We are grateful to the Natural Science
and Engineering Research Council of Canada for financial
support of this work, to Prof. Sam-Rok Keum for a generous
gift of compound 6d, and to Ms. Lisa Knight for the synthesis
of compound 11.
JA0001613