Enantiospecific photochemical transformations under elevated pressure

Article abstract of DOI:10.1002/chem.201203665

Enantiospecific axial-to-point chiral transfer in light-induced transformations was efficient under elevated pressure at high temperatures. Model photoreactions with atropisomeric compounds showed higher enantioselectivity in the photoproducts under eleva

Full text of DOI:10.1002/chem.201203665

FULL PAPER
DOI: 10.1002/chem.201203665
Enantiospecific Photochemical Transformations under Elevated Pressure
Anoklase J.-L. Ayitou,[a] Gaku Fukuhara,[b] Elango Kumarasamy,[a]
Yoshihisa Inoue,*[b] and J. Sivaguru*[a]
Abstract: Enantiospecific axial-to-point chiral transfer in light-induced transforma-
tions was efficient under elevated pressure at high temperatures. Model photore-
ACHTUNGTRENNUNGactions with atropisomeric compounds showed higher enantioselectivity in the
photoproducts under elevated pressure. The ee values in the photoproducts were
rationalized based on the increased stability of optically pure atropisomeric com-
pounds at elevated pressure, even at high temperatures.
Keywords: asymmetric synthesis ·
atropisomerism · enantioselectivity ·
photochemistry · pressure effects ·
Non-biaryl atropisomers
Introduction
retain their absolute configuration, racemization is an inher-
ent characteristic of atropisomeric compounds at elevated
temperature.[9] Uncovering the intricacies[12–17] that are in-
volved in this racemization process is indispensable for un-
derstanding the stereochemical influence of atropisomeric
compounds on asymmetric chemical transformations.[9] Pres-
sure, volume, and temperature constitute a triumvirate of
parameters that can be empirically exploited to study the
dynamics of natural phenomena.[18–25] Variation of one of
these parameters provides an opportunity to understand and
investigate dynamic chemical processes that are influenced
by a change in physical conditions. For isochoric processes,
pressure and temperature are interchangeably used to com-
pute thermodynamic and kinetic parameters.[24–25]
Chiral motifs in nature play a central role in many vital
chemical and biological processes. Recognizing the impor-
tance of chiral compounds, chemists have focused their at-
tention on controlling chirality during synthetic chemical
transformations. One of the main classes of compounds that
has gained considerable attention in recent years for the de-
velopment of new and effective asymmetric synthetic proce-
dures[1] is atropisomeric compounds, which possess axial
chirality that originates from restricted bond rotation.[2–8]
One of the inherent issues with atropisomeric molecules is
their propensity to racemize at elevated temperature.[9]
Hence, in spite of being an effective chiral scaffold at room
temperature, axially chiral molecules can easily lose their
original absolute configuration, which is a significant limita-
tion to their use in chemical transformations that require
high reaction temperatures.[10]
Recently, we have been exploring[26–31] the use of non-
biaryl axially chiral chromophores to achieve stereoselectivi-
ty during photoreactions (6p-photocyclization,[26–31] photo-
chemical H-abstraction,[26–31] [2+2]-photocycloaddition[26–31]
and 4p-photochemical ring closure[26–31]) in solution and
have achieved high enantioselectivity (>90% ee) in the
photoproducts. In those studies, we showed that effective
chiral transfer was dependent on the reaction tempera-
ture.[26–31] To evaluate the potential of axially chiral chromo-
phores for application in reactions that require elevated
temperature, it became critical to also investigate the effect
of pressure, because pressure and volume affect one another
when the temperature is kept constant.[24–25] Herein, we have
performed detailed investigations on axial-to-point chiral
transfer during photochemical transformations (Scheme 1)
under elevated pressure. Our results indicate that elevated
pressure inhibits/suppresses the racemization of non-biaryl
atropisomeric chromophores, thereby leading to enhanced
enantiomeric excess (ee) in the photoproducts. To show the
general applicability of pressure in the stabilization of axial
chirality, as well as its use in enantiospecific photoreactions,
we have comparatively investigated three different atropiso-
meric systems, that is, a-oxoamide 1a, 2-pyridone 1b, and
acrylanilides 1c–1e (Scheme 1).
For atropisomeric compounds, the interconversion be-
tween left- and right-handed structural forms can be manip-
ulated by external stimuli, such as temperature, which influ-
ence the extent of hindered single-bond rotation.[11] Whereas
point chiral compounds (in which the chiral center is de-
fined on a tetrahedral carbon atom or on another atom)
[a] A. J.-L. Ayitou, E. Kumarasamy, Prof. Dr. J. Sivaguru
Department of Chemistry and Biochemistry
North Dakota State University
1231 Albrecht Blvd., Fargo, ND 58103 (USA)
Fax : (+1)701-231-8831
E-mail: sivaguru.jayaraman@ndsu.edu
[b] Dr. G. Fukuhara, Prof. Dr. Y. Inoue
Department of Applied Chemistry
Osaka University
2-1 Yamada-oka, Suita, Osaka 565-0871 (Japan)
Fax : (+81)6-6879-7923
E-mail: inoue@chem.eng.osaka-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203665.
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4327

Table 1. Enantiospecific photochemical reactions of a-oxoamide 1a and
2-pyridone 1b under different pressures in MeCN at 708C.[a]
Entry
Compound[b]
t [h]
ee [%] (photoproduct)[c]
0.1 MPa
20 MPa
100 MPa
1
2
3
(ꢁ)-1a
(+)-1a
(ꢁ)-1b
2
2
1
17 (A)
16 (B)
4 (B)
29 (A)
30 (B)
18 (B)
–
–
27 (B)
[a] The samples were placed inside a pressure cell that was equipped
with sapphire windows. Irradiation was performed by using an optical
fiber that contained a light source from a Xe lamp. The values are an
average of two runs and carry an error of ꢀ20%, owing to experimental
limitations of handling the samples at elevated pressure and temperature
in the cell. [b] (+) and (ꢁ) denote the sign of the optical rotation of the
reactant. [c] A and B refer to the elution order of the enantiomers during
HPLC analysis on a chiral stationary phase.
Scheme 1. Optically pure atropisomers 1a–1e, which were evaluated for
enantiospecific photoreactions and racemization at elevated pressure.
chiral transfer at high temperatures (about 708C), the use of
CHCl3 as a solvent was ruled out and MeCN was chosen as
the solvent of choice. The photoreaction of compound 1a
was expected to yield three different photoproducts, com-
pounds 2a–4a. In MeCN, at 708C and 0.1 MPa, photoir-
Results and Discussion
Optically pure atropisomeric compounds 1a–1e were syn-
thesized according to literature procedures.[26–31] The optical
purity of these samples was verified by HPLC analysis on a
chiral stationary phase, the sign/magnitude of the optical ro-
tation, and by the sign of the Cotton effect. Photochemical
transformation under high pressures and the racemization
kinetics of optically pure isomers of compounds 1 were in-
vestigated in spectrophotometric-grade solvents at a given
temperature and pressure in a custom-built high-pressure
vessel.[24–25] This high-pressure vessel was fitted with three
optical windows that were made of sapphire or diamond,
with an effective aperture of 9 mm or 3 mm (i.d.), respec-
tively. Sapphire windows were used for the photoirradiation
and UV/Vis and fluorescence spectroscopy experiments,
whilst birefringence-free diamond windows were used for
circular dichroism (CD) spectroscopy. A quartz inner cell
with inner dimensions of 3 mm (W)ꢁ2 mm (D)ꢁ7 mm (H)
was connected to a short flexible Teflon tube to adjust the
volume change under pressure. This quartz cell was filled
with a solution of the sample at a known concentration. The
top end of the Teflon tube was stoppered and the whole cell
was placed inside the pressure vessel. The vessel was fixed
inside the sample chamber of the spectrometer at a set hy-
drostatic pressure and temperature. The samples were ir-
AHCTUNGTREGrNNUN adiation of compound 1a gave b-lactam 2a as the major
photoproduct (2a/3a/4a, 70:28:2). Photoirradiation of opti-
cally pure 2-pyridone 1b at 708C and 0.1 MPa gave bicyclic
b-lactam 2b as the major photoproduct. HPLC analysis of
the photoreaction mixture on a chiral stationary phase re-
vealed the ee values for the photoproducts. At 708C and
0.1 MPa, the ee values of photoproducts 2a and 2b were
16% and 4%, respectively (Table 1). On the other hand, the
photoirACTHNUTRGENUGrN adiation of compounds 1a and 1b at 20 MPa gave ee
values of 30% and 18% in the corresponding photoproducts
(2a and 2b, respectively). Further increasing the pressure to
100 MPa in the photoirradiation of compound 1b resulted
in an ee value of 27% in the photoproduct (2b, Table 1;
entry 3). The clear increase in ee value upon increasing the
pressure during these photochemical transformations was
quite striking (Table 1).
Upon inspection of the ee values in Table 1, it was clear
that a moderate increase in pressure from 0.1 MPa to
20 MPa had a significant effect on axial-to-point chiral
transfer during these photochemical transformations. It is
likely that, at elevated pressure, the rate of racemization of
optically pure atropisomers is slow, which is reflected in the
enhanced ee values in the photoproduct. To confirm this
conjecture, we investigated the effect of pressure on the
ACHTUNGTRENNUNG
A
raceACTHGNUTERNNUmG ization of optically pure atropisomeric a-oxoamide 1a
lished the temperature-dependent photoreaction of optically
pure atropisomers of a-oxoamide 1a, which underwent
enantiospecific Norrish–Yang cyclization,[28] and 2-pyridone
1b, which underwent enantiospecific 4p-ring closure[30]
(Scheme 1), we selected these systems to investigate the
effect of elevated pressure on photochemical transforma-
tions at high reaction temperatures (Scheme 1).
The photoreactions of optically pure compounds 1a and
1b were investigated in MeCN at 708C under different pres-
sures, that is, 0.1–100 MPa (Table 1). Photoirradiation of
compound 1a in CHCl3 gave compound 2a as the exclusive
photoproduct. Because we had planned to evaluate axial
and 2-pyridone 1b at elevated temperature. In addition, to
determine whether the effect of pressure on inhibition/sup-
pression of the racemization of atropisomeric compounds
was a general phenomenon, we also evaluated the rates of
racemization for optically pure atropisomeric acrylanilides
1c–1e.
For a qualitative discussion of the effect of pressure on
racemization, it is important to calculate the activation
volume (DV°rac) for the racemization processes (Eqs. 1 and
2),[32] that is, the difference between the partial molar
volume of the transition state and the sum of the partial vol-
umes of the reactant(s) at a given temperature and pressure.
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Enantiospecific Photochemical Transformations at High Pressures
FULL PAPER
The value of activation volume is obtained at equilibrium,
when the internal force of the substrate equalizes the ap-
plied pressure. Because the rate constant depends on both
temperature and pressure, at any given temperature (T in
Kelvin), the effect of pressure (P in MPa) on the racemiza-
tion rate constant (krac) is given by Equations (1) to (5),[24–25]
where t1/2 is the half-life of racemization, R is the gas con-
stant (8.314 cm3 MPaKꢁ1 molꢁ1), C is a constant, [P]0 is the
initial concentration of the P isomer, x=[P0ꢁ([P],[M])],
([P],[M]) represents the concentration of the racemate at
time t, kB is the Boltzmann constant, and h is Planck’s con-
stant.
z
ð1Þ
ð2Þ
DVrac ¼ ꢁRTð@ ln krac=@PÞT
z
ðln kracÞT ¼ ꢁðDVrac=RTÞP þ C
ln½½Pꢂ0=ð½Pꢂ0ꢁxÞꢂ ¼ ln½ð½Pꢂþ½MꢂÞ=ð½Pꢂꢁ½MꢂÞꢂ ¼ krac
t1=2 ¼ ln 2=krac
t
ð3Þ
ð4Þ
z
z
ð5Þ
ðln krac=TÞ ¼ DSrac=R ꢁ DHrac=RT þ lnðkB=hÞ
A point to note is that, enantiomerization is a microscopic
phenomenon, whereas racemization is a macroscopic phe-
nomenon; thus, it is important to appreciate the relationship
between these processes, that is, krac =2ꢁkenant, where kenant is
the rate constant of enantiomerization.[9]
Racemization studies of optically pure isomers of com-
pounds 1a–1e were performed by using CD spectroscopy in
spectrophotometric-grade solvents at a given temperature
and pressure in the custom-built high-pressure vessel.[24–25]
To correlate the effects of pressure, temperature, and
volume on the racemization process, two sets of experiments
were performed (Figure 1, Figure 2, and Figure 3). In the
first set of experiments (Table 2, Figure 2), the pressure was
kept constant at 0.1 MPa and the temperature was varied to
determine the racemization rate constant (krac), the activa-
tion free energy of racemization (DG°rac),[33] the activation
enthalpy (DH°rac), and the activation entropy (DS°rac). In
the second set of experiments (Table 2, Figure 1, Figure 2,
and Figure 4), the temperature was kept constant and the
pressure was varied to determine the activation volume
(DV°rac), the racemization rate constant (krac), and the acti-
vation energy for racemization (DG°rac).[33]
Figure 1. Racemization of optically pure acrylanilide (+)-1c, as moni-
tored by CD spectroscopy at 0.1, 10, and 20 MPa in methylcyclohexane
(MCH) at 343 K.
The racemization of optically pure non-biaryl atropiso-
meric compounds was monitored by CD spectroscopy at ele-
vated temperatures at different pressures (Table 2 and
Table 3). To study the influence of solvent on the racemiza-
tion process, racemization studies were carried out in vari-
ous solvents. At pressures as high as 50 MPa, some of the
solutions became cloudy. This result indicates that, under
high pressures, the compounds precipitated/crystallized,
thereby making the solution cloudy. This precipitation/crys-
tallization presumably depended on the solubility of the
given compound and any physical interactions between the
solute and the solvent. Apart from the solvents listed in
Table 3, other solvents were not suitable for high-pressure
measurements, owing to microcrystallization/cloudiness of
the sample at these pressures. To enhance the racemization
rate, we performed our studies at elevated temperatures and
pressures in the range 0.1–20 MPa. CD measurements on
the pressurized samples (10 MPa and 20 MPa) were record-
ed at 343 K (Table 3).
The racemization rate constant (krac) and activation free
[33]
energy of racemization (DG°
)
rac
were determined from
the change in the intensity of the CD spectra in a given sol-
vent at a particular temperature under constant pressure
(Figure 1, Figure 2, Figure 3, Figure 4, and Table 2). For ex-
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4329

Y. Inoue, J. Sivaguru et al.
[a]
Table 2. Racemization rate constant (krac
)
and half-life of racemization
(t1/2) for optically pure atropisomers 1a–1e at different temperatures and
a pressure of 0.1 MPa.
[c]
Entry
Compound
Solvent[b]
EtOH
T [K]
krac [sꢁ1
]
t1/2 [h][c]
1
1a
333
341
346
333
341
348
323
333
343
323
333
343
343
348
353
363
338
343
348
333
343
358
333
343
353
338
343
348
1.7ꢁ10ꢁ5
3.7ꢁ10ꢁ5
7.1ꢁ10ꢁ5
2.4ꢁ10ꢁ5
5.7ꢁ10ꢁ5
1.5ꢁ10ꢁ4
3.5ꢁ10ꢁ4
1.0ꢁ10ꢁ3
1.5ꢁ10ꢁ3
9.0ꢁ10ꢁ5
3.1ꢁ10ꢁ4
9.1ꢁ10ꢁ4
3.5ꢁ10ꢁ5
5.6ꢁ10ꢁ5
9.8ꢁ10ꢁ5
2.6ꢁ10ꢁ4
1.2ꢁ10ꢁ5
2.1ꢁ10ꢁ5
3.1ꢁ10ꢁ5
1.9ꢁ10ꢁ5
4.5ꢁ10ꢁ5
3.1ꢁ10ꢁ4
3.7ꢁ10ꢁ5
8.1ꢁ10ꢁ5
2.1ꢁ10ꢁ4
4.3ꢁ10ꢁ5
8.3ꢁ10ꢁ5
1.4ꢁ10ꢁ4
12
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
5.2
2.7
8.0
3.4
1.3
0.55
0.2
0.13
2.1
0.63
0.21
5.5
3.4
2.0
0.75
16
MeCN
EtOH
MeCN
MCH
1b
1c
MeCN
MCH
MCH
MeCN
9.4
6.2
10
1d
1e
4.3
0.63
5.2
2.4
0.90
4.5
2.3
1.4
Figure 2. Racemization of optically pure compound (ꢁ)-1b, as monitored
by CD spectroscopy at 0.1 MPa in MeCN.
At 343 K and 0.1 MPa in MeCN, krac =9.1ꢁ10ꢁ4 sꢁ1 and
t1/2 =0.21 h, that is, 13 min (Table 2, entry 12). On increasing
the pressure to a moderate 12 MPa at 343 K, krac =6.8ꢁ
10ꢁ5 sꢁ1 and t1/2 =2.9 h (Table 3, entry 2). Thus, the half-life
increased 14 times with a small increase in the pressure
from 0.1 MPa to 12 MPa. In the case of compound 1b, there
was a noticeable change in the t1/2 value upon changing the
solvent from MeCN to EtOH (t1/2 =0.13 h, that is, 7.7 min in
EtOH; t1/2 =0.21 h, that is, 13 min in MeCN;
[a] Analysis of the racemization kinetics was performed inside a custom-
built high-pressure cell with diamond windows and monitored by CD
spectroscopy. All of these values carry an error of 10%. [b] [1a]=9.39ꢁ
10ꢁ5 m in EtOH and 1.16ꢁ10ꢁ4 m in MeCN; [1b]=7.36ꢁ10ꢁ5 m in EtOH
and 9.03ꢁ10ꢁ5 m in MeCN; [1c]=8.13ꢁ10ꢁ5 m in MCH and 1.2ꢁ10ꢁ5 m in
MeCN; [1d]=1.86ꢁ10ꢁ5 m in MCH; [1e]=2.27ꢁ10ꢁ4 m in MCH and
1.63ꢁ10ꢁ5 m in MeCN. [c] krac and t1/2 were obtained from Equations (3)
and (4), respectively. DG° values are provided in the Supporting Infor-
rac
mation.
Table 2, entries 9 and 12, respectively). We had pre-
Table 3. Racemization rate constants (krac) and half-life (t1/2) of 1a–1e under elevated
pressure at 343 K.[a]
viously postulated that the presence of hydrogen
bonds and the polarity of the solvent affected the
racemization rates in axially chiral 2-pyridones.[26–31]
The activation enthalpy (DH°rac) and activation
entropy (DS°rac) were obtained from the Eyring
plots for compounds 1a–1e (Equation (5), Table 4,
and Figure 4, ). All of the investigated compounds
showed negative DS° values and positive DH°
Entry
Compound/solvent
10 MPa
20 MPa
krac [sꢁ1
]
t1/2 [h]
krac [sꢁ1
]
t1/2 [h]
1
2
3
4
5
1a/EtOH[b]
1b/MeCN
1c/MCH
1d/MCH
1e/MCH
2.4ꢁ10ꢁ5
6.8ꢁ10ꢁ5[d]
2.1ꢁ10ꢁ5
2.5ꢁ10ꢁ5
6.5ꢁ10ꢁ5
8.0
5.6ꢁ10ꢁ6[c]
–
34[c]
–
2.9[d]
9.0
7.3ꢁ10ꢁ6
5.1ꢁ10ꢁ6[c]
4.2ꢁ10ꢁ5
27
7.9
2.9
38[c]
4.6
rac
rac
values. Negative DS° values are consistent with
[a] Analysis of the racemization kinetics was performed inside a custom-built high-
pressure cell with diamond window and monitored by CD spectroscopy. All of these
values carry an error of 10%. CD spectra monitored at 260 nm for compound 1a,
rac
the fact that the racemization of non-biaryl atrop-
AHCTUNGTREGiNNUN somers is entropically unfavorable, owing to the re-
310 nm for compound 1b, and 250 nm for compounds 1c–1e. DG° values are pro-
rac
vided in the Supporting Information. [b] For compound 1a in EtOH at 5 MPa, krac
=
stricted bond rotation that most often involves
steric hindrance. A point to note is the magnitude
of DS° values: The contribution of the DS°
2.2ꢁ10ꢁ5 sꢁ1 and t1/2 =8.8 h. [c] Pressure was maintained at 25 MPa. [d] Pressure was
maintained at 12 MPa.
rac
rac
value in the case of compound 1b was lower than
ample, in the case of optically pure 1c at 343 K, a decrease
in the ellipticity (q) was observed in the CD spectra at a
pressure of 0.1 MPa, whilst the decrease in q was minimal at
an elevated pressure of 20 MPa. The most-striking contrast
in the rate of racemization was displayed by compound 1b.
that in compounds 1a, 1c–1e; presumably, this result is due
to steric hindrance, which leads to restricted rotation around
ꢁ
the N Caryl bond. In compounds 1a, 1c–1e, the rotation of
ꢁ
the N Caryl bond has to overcome the steric impediments
owing to an alkyl substituent (Figure 5, top). On the other
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Enantiospecific Photochemical Transformations at High Pressures
FULL PAPER
Figure 3. Racemization of optically pure compound 1a, as monitored by
CD spectroscopy at 5 and 25 MPa in EtOH. CD signals were monitored
as time-course/scan experiment at 260 nm.
hand, in the case of compound 1b, the rotation has to over-
come the steric hindrance of an OH substituent. This lesser
steric bulk in the case of compound 1b is reflected in the
magnitude of DS°rac, which is, in turn, reflected in the race-
mization rate (t1/2). Whilst an increase in the temperature
enhances the racemization rates of non-biaryl atropisomers,
an increase in the pressure has the opposite effect. A com-
parison of Table 2 and Table 3 shows that, at a given temper-
ature, the racemization rate is faster at normal pressure
(0.1 MPa) and slower at elevated pressure (5–20 MPa); this
influence of pressure on the racemization rate was reflected
Figure 4. Top: Eyring plots for the racemization of substrates 1a–1e at
0.1 MPa. Bottom: Plot of the pressure dependence of racemization to de-
termine the activation volumes for compounds 1a–1e at 343 K; the sol-
vent that was used for a given compound is noted in the inset.
lated to be responsible for the enhanced chemical reactivi-
ty.[34–36] In our system (Table 4), the activation volume was
positive for the racemization process; that is, the partial
molar volume in the transition state increased considerably
when compared to the partial molar volume of the optically
pure atropisomeric reactant(s).
These differences in volume change can be understood
based on the structures of the compounds that are employed
and on the factors that influence the racemization process.
In the case of compounds 1a, 1c–1e, the hindered rotation
by an increase in the DG° value, as well as in t1/2 value
rac
(Figure 1).[33]
To understand the influence of pressure, it is important to
appreciate the influence of activation volume during a
chemical transformation (in this case, racemization). Analy-
sis of Equations (1) and (2) indicates that, at a constant tem-
perature, the processes that occur through a transition state
with negative differential activation volume will be acceler-
ated under elevated pressure, whereas transition state(s)
with a positive differential activation volume will be deceler-
ated. For example, in the case of cycloaddition and conden-
sation reactions that have shown rate acceleration under ele-
vated pressure, a decrease in the partial molar volume in
the transition state along the reaction coordinate was postu-
ꢁ
around the N Caryl bond is due to the steric bulk of the
ortho-tert-butyl substituent on the N-phenyl group
(Figure 5). On the other hand, in the case of compound 1b,
both steric hindrance (from the ortho-hydroxydiphenylmeth-
yl substituent) and H-bonding interactions (from the OH
ꢁ
group) influence the N Caryl bond rotation (Figure 5). Thus,
ꢁ
to rotate the N Caryl bond in compounds 1a, 1c–1e, the
molecule has to effectively “expand” to accommodate the
bulky ortho-tert-butyl substituent. A closer look at the acti-
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Y. Inoue, J. Sivaguru et al.
to form H bonds). At elevated pressure, the solvent shell
surrounding the atropisomeric compounds will be packed
closely, so as to “freeze” the molecular conformation. Be-
ꢁ
cause racemization involves rotation around the N Caryl
bond, owing to tight packing of the solvent molecules/sol-
vent cluster around the atropisomeric compounds at elevat-
ed pressure, bond rotation is likely hindered, thereby result-
ꢁ
ing in the observed slow racemization. In addition, the N
Caryl bond rotation has to be accompanied by a change in
the arrangement of the “solvent cluster” that surrounds the
molecule during the racemization process. This change is re-
flected in the DV°
values (Table 4). Changes in the
rac
volume, owing to “molecular confinement”, would be pro-
nounced in the case of compound 1b because H-bonding in-
teractions are expected to contribute to the structure and
stability of the solvent shell surrounding the atropisomeric
substrate. Because the activation volume was large (125–
650 cm3 molꢁ1) for the atropisomeric systems that were in-
vestigated herein (Table 4), a moderate increase in pressure
(5–20 MPa) was able to slow the racemization process very
effectively.
Because increasing the pressure in these systems clearly
ꢁ
increases the barrier for rotation around the N Caryl bond,
excitation of the chromophores results in increased stereo-
specificity during the photochemical transformations. Be-
cause the ee values of the photoproduct are easily ascer-
tained at various pressures, the influence of the relative rate
constant on the formation of the individual enantiomers was
expressed as a linear function of pressure, as in Equation (6)
Figure 5. Pressure effects on racemization: Role of the solvents and non-
bonding interactions.
where kS/kR =(100+%ee)/
A
in Kelvin, P is the pressure in MPa, R is the gas
constant (8.314 cm3 MPaKꢁ1 molꢁ1), and kS and kR
represent the rate of formation of individual enan-
tiomeric photoproducts. From this function, the dif-
ferential activation volume (DDV°S-R) was calculat-
ed at a given temperature (Figure 6). From the
linear plot of lnk versus P, it is clear that the hydro-
static pressure causes no alteration of the reaction
mechanism or of the activation volumes over the
employed pressure range.
Table 4. Activation enthalpy, entropy, and volume for the racemization of optically
pure compounds 1a–1e at 343 K.
Entry
Compound/
solvent
DS°[a] [Jmolꢁ1 Kꢁ1
]
DH°[a] [kJmolꢁ1
]
DV°[b] [cm3 molꢁ1
]
1
2
3
4
5
1a/EtOH
1b/MeCN
1c/MCH
1d/MCH
1e/MCH
ꢁ29.0
ꢁ2.55
ꢁ38.3
ꢁ9.23
ꢁ82.2
103
103
101
109
82.9
234
651
251
254
126
[a] Obtained from Equation (5) by using the values in Table 2. [b] Obtained from
Equation (2) by using the values in Table 3. All of these values carry an error of 10%.
z
ð6Þ
lnðkS=kRÞ ¼ ꢁðDDVSꢁR=RTÞP þ C
vation volume (DV°rac) for racemization (Table 4) indicated
A point that should be emphasized is with regards to the
difference between DV° and DDV°S-R. The activation
that DV° value was higher in the case of compound 1b
rac
rac
(about 650 cm3 molꢁ1) than in compounds 1a, 1c–1e (about
120–250 cm3 molꢁ1), in stark contrast to the activation entro-
py values (DS°rac) for compound 1b compared to com-
pounds 1a, 1c–1e. To appreciate this dichotomy, a key
factor that needs to be considered in the racemization pro-
volume (DV°rac) is the change in volume that is required for
racemization of the atropisomers, whereas the differential
activation volume (DDV°SꢁR) is a reflection of the difference
in the volume of the diastereomeric transition state during
the course of the phototransformation that leads to the pho-
toproduct. Hence, a direct comparison (both magnitude and
sign) of the two parameters should not be made.
This study has uncovered a very simple and effective way
to suppress racemization in non-biaryl atropisomeric com-
pounds. Because the activation volume during racemization
is large, a moderate increase of the pressure in the system
ACHTUNGTRENNUNGcess (especially at elevated pressure) is the solvent clusters
that surround atropisomeric molecules. At normal pressure,
the solvent shell that surrounds compounds 1a, 1c–1e is ex-
pected to be loose (van der Waals forces), whereas, with
compound 1b, the molecule interacts with the solvent/sol-
vent shell through H bonding (with solvent that has ability
4332
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Chem. Eur. J. 2013, 19, 4327 – 4334

Enantiospecific Photochemical Transformations at High Pressures
FULL PAPER
Figure 6. Left: Plot of the pressure dependence of the relative rate con-
stant at 343 K to determine the differential activation volume (DDV°)
during the photo-induced 4p-ring closure of compound 1b in MeCN.
Right: The absolute value of DDV° is provided because the sign will
depend on which enantiomer in the photoproduct is enhanced during the
photochemical transformation. kS and kR represent the rate of formation
of the individual enantiomeric photoproducts.
enables us to slow the racemization process and freeze the
axial chirality, even at higher temperatures. This simple
strategy of employing moderate pressures has enabled us to
manipulate stereospecific photochemical transformations in
solution, even at elevated temperatures. Thus, this strategy
could be very useful for overcoming the racemization of
atropisomeric photochromophores at a given temperature
and for employing them in effective stereospecific photo-
chemical transformations.
Figure 7. Custom designed high-pressure vessel for spectroscopic meas-
urements and for photochemical reactions.
short flexible Teflon tube for adjusting the volume change under pres-
sure, was filled with a solution of the sample. The top end of the quartz
cell was stoppered and the whole cell was placed inside the pressure
vessel. The vessel was fixed inside the sample chamber of the spectrome-
ter (Figure 7, bottom). The temperature inside the sample chamber was
maintained by a temperature-control unit and the sample was maintained
at a set hydrostatic pressure (0.1–100 MPa).
Conclusion
General procedure for the photoreactions of compounds 1a–1e under
pressure: Compound 1 was dissolved in dry MeCN (1a: 11.5 mm, 1b:
1.4 mm, 1c: 11.5 mm, 1d: 10 mm, 1e: 5.7 mm) and the solution was trans-
ferred into a custom-designed quartz cell (Figure 7, top-right). Then, this
cell was placed inside a high-pressure vessel that was equipped with a
sapphire window. Irradiation was performed by using an optical fiber
Our investigation provides a simple route for modulating
the rate of racemization in non-biaryl chromophores by
moderately increasing the pressure in the system. This strat-
egy may be extended to the asymmetric transformations of
other non-biaryl compounds at elevated temperatures with
minimal racemization. Owing to the slow rate of racemiza-
tion, the enantiospecific chiral transfer was effective at ele-
vated pressure during the photoreactions. In addition, be-
cause non-biaryl atropisomers are potential ligands for
asymmetric synthesis, either the slow racemization or frozen
chiral configuration that are obtained at moderate pressures
open up avenues to employ them in reactions that require
high temperatures.
that contained a light source from a Xenon lamp with a 300
band-pass filter (Asahi spectra, 302 Max power-supply unit).
N
Acknowledgements
The authors at NDSU thank the NSF for financial support (CHE-
1213880 and NSF CAREER CHE-0748525). J.S. and A.J.A thank NSF
for an NSF Graduate Student Fellowship to A.J.A. J.S. and E.K. thank
the NSF-ND EPSCoR for
a Doctoral Research Fellowship (EPS-
0814442) for E.K. This work was supported by the JSPS (23750129 to
G.F., 21245011 to Y.I.). The authors thank the Global Education and Re-
search Center for Bioenvironmental Chemistry (GCOE) program at
Osaka University for awarding a Visiting Professorship to J.S. and a Stu-
dent Fellowship to A.J.A.
Experimental Section
High-pressure spectroscopic measurements, apparatus, setup, and data
collection: All spectroscopic measurements under high pressure were
performed in a custom-built high-pressure vessel (Figure 7, left). This
vessel was fitted with three optical windows that were made of sapphire
or diamond, with an effective aperture of 9 mm or 3 mm (i.d.), respec-
tively. The apparatus was designed and manufactured by Teramecs Co.
(Kyoto, Japan). The materials for the windows were sapphire for UV/Vis
and fluorescence spectroscopy and birefringence-free diamond for CD
spectroscopy. A quartz inner cell (Figure 7, right) with an inner dimen-
sion of 3 mm (W)ꢁ2 mm (D)ꢁ7 mm (H), which was connected to a
[1] A. Miyashita, A. Yasuda, H. Takaya, K. Toriumi, T. Ito, T. Souchi,
R. Noyori, J. Am. Chem. Soc. 1980, 102, 7932–7934.
[2] D. P. Curran, H. Qi, S. J. Geib, N. C. DeMello, J. Am. Chem. Soc.
1994, 116, 3131–3132.
[3] D. P. Curran, G. R. Hale, S. J. Geib, A. Balog, Q. B. L. Cass, A. L. G.
Degani, M. Z. Hernandes, L. C. G. Freitas, Tetrahedron: Asymmetry,
1997, 38, 3955–3975.
[4] J. Clayden, Chem. Commun. 2004, 127–135.
Chem. Eur. J. 2013, 19, 4327 – 4334
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4333

Y. Inoue, J. Sivaguru et al.
[5] T. Adler, J. Bonjoch, J. Clayden, M. Font-Bardia, M. Pickworth, X.
Solans, D. Sole, L. Vallverdu, Org. Biomol. Chem. 2005, 3, 3173–
3183.
[6] J. Clayden, W. J. Moran, P. J. Edwards, S. R. LaPlante, Angew.
Chem. 2009, 121, 6516–6520; Angew. Chem. Int. Ed. 2009, 48, 6398–
6401.
[21] P. C. Michels, D. S. Clark, Appl. Environ. Microbiol. 1997, 63, 3985–
3991.
[22] I. B. Rietveld, M. Barrio, J.-L. Tamarit, B. Do, R. Cꢂolin, J. Phys.
Chem. B 2011, 115, 14698–14703.
[23] A. Sharma, J. H. Scott, G. D. Cody, M. L. Fogel, R. M. Hazen, R. J.
Hemley, W. T. Huntress, Science 2002, 295, 1514–1516.
[24] Y. Inoue, E. Matsushima, T. Wada, J. Am. Chem. Soc. 1998, 120,
10687–10696.
[7] U. Berens, J. M. Brown, J. Long, R. Selke, Tetrahedron: Asymmetry
1996, 7, 285–292.
[25] M. Kaneda, A. Nakamura, S. Asaoka, H. Ikeda, T. Mori, T. Wada,
Y. Inoue, Org. Biomol. Chem. 2003, 1, 4435–4440.
[26] A. J.-L. Ayitou, J. Sivaguru, J. Am. Chem. Soc. 2009, 131, 5036–
5037.
[27] A. J.-L. Ayitou, J. Sivaguru, Chem. Commun. 2011, 47, 2568–2570.
[28] A. J.-L. Ayitou, J. L. Jesuraj, N. Barooah, A. Ugrinov, J. Sivaguru, J.
Am. Chem. Soc. 2009, 131, 11314–11315.
[29] J. L. Jesuraj, J. Sivaguru, Chem. Commun. 2010, 46, 4791–4793.
[30] E. Kumarasamy, J. L. Jesuraj, J. N. Omlid, A. Ugrinov, J. Sivaguru, J.
Am. Chem. Soc. 2011, 133, 17106–17109.
[31] E. Kumarasamy, J. Sivaguru, Chem. Commun., DOI: 10.1039/
C2CC37123E.
[32] G. A. Lawrance, D. R. Stranks, Inorg. Chem. 1977, 16, 929–935.
[33] See the Supporting Information.
[34] B. M. Trost, J. R. Parquette, A. L. Marquart, J. Am. Chem. Soc.
1995, 117, 3284–3285.
[35] K. Matsumoto, J. C. Kim, N. Hayashi, G. Jenner, Tetrahedron Lett.
2002, 43, 9167–9169.
[36] C. J. T. Kuster, H. W. Scheeren in High-Pressure Promoted Cycload-
ditions for Application in Combinatorial Chemistry (Eds.: R. van
Eldik, F. -G. Klꢃrner), Wiley-VCH, 2007, pp. 284–304.
[8] I. Agranat, S. Cohen, R. Isaksson, J. Sandstroem, M. R. Suissa, J.
Org. Chem. 1990, 55, 4943–4950.
[9] C. Wolf, Dynamic Stereochemistry of Chiral Compounds: Principles
and Applications, RSC Publishing, Cambridge, 2008.
[10] M. Shindo, K. Koga, K. Tomioka, J. Am. Chem. Soc. 1992, 114,
8732–8733.
[11] J. L. Gustafson, D. Lim, S. J. Miller, Science 2010, 328, 1251–1255.
[12] O. Trapp, Anal. Chem. 2006, 78, 189–198.
[13] F. Maier, O. Trapp, Angew. Chem. Int. Ed. 2012, 51, 2985–2988.
[14] O. Trapp, Chirality 2006, 18, 489–497.
[15] O. Trapp, L. Sahraoui, W. Hofstadt, W. Kçnen, Chirality 2010, 22,
284–291.
[16] O. Trapp, G. Schoetz, V. Schurig, Chirality 2001, 13, 403–414.
[17] H. O. Kalinowski, H. Kessler in Topics in Stereochemistry. Vol. 7
(Eds.: E. L. Eliel, N. L. Allinger), Wiley, New York, 1973, pp. 295–
383.
[18] M. C. K. Choi, S. S. Chan, K. Matsumoto, Tetrahedron Lett. 1997, 38,
6669–6672.
[19] R. M. Hazen, N. Boctor, J. A. Brandes, G. D. Cody, R. J. Hemley, A.
Sharma, H. S. Yoder Jr, J. Phys. Condens. Matter 2002, 14, 11489–
11494.
[20] H. W. Jannasch, C. O. Wirsen, C. D. Taylor, Science 1982, 216, 1315–
1317.
Received: October 13, 2012
Published online: January 30, 2013
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Chem. Eur. J. 2013, 19, 4327 – 4334