Chiral para-alkyl phenyl ethers of glycerol: Synthesis and testing of chirality driven crystallization, liquid crystal, and gelating properties

Article abstract of DOI:10.1016/j.tetasy.2013.05.017

A series of enantiopure and racemic p-alkylphenyl glycerol ethers 1a-k were synthesized. A new, sensitive, and pictorial method of comparison of the IR spectra of solid enantiopure and racemic samples was developed to obtain preliminary information on the crystallization types of these compounds. In order to detect the subtle differences in the organization of the chiral solid phase, a new easily implemented approach, based on a chromatographic measuring of the relative abundance of the enantiomers in a single solution in equilibrium with a solid sample of arbitrary (0 < ee < 1) composition, is reported. One new conglomerate compound (Alk = n-Pr) and one borderline case (Alk = n-Bu) are disclosed. Higher members of the series of 1 (starting with an n-Bu derivative) are turned into liquid crystals upon melting; no significant differences between racemic and non-racemic samples were found. Only enantiopure methyl-, n-butyl, n-pentyl, n-hexyl, and n-heptyl substituted 1 were able to form supramolecular gels in hydrocarbon solvents; all racemic ethers 1 did not show such ability.

Full text of DOI:10.1016/j.tetasy.2013.05.017

Tetrahedron: Asymmetry xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral para-alkyl phenyl ethers of glycerol: synthesis and testing of
chirality driven crystallization, liquid crystal, and gelating properties
⇑
Alexander A. Bredikhin , Dmitry V. Zakharychev, Robert R. Fayzullin, Olga A. Antonovich,
Alexander V. Pashagin, Zemfira A. Bredikhina
A.E. Arbuzov Institute of Organic and Physical Chemistry of Kazan Scientific Center of Russian Academy of Sciences, Arbuzov St., 8, Kazan 420088, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of enantiopure and racemic p-alkylphenyl glycerol ethers 1a–k were synthesized. A new, sensi-
tive, and pictorial method of comparison of the IR spectra of solid enantiopure and racemic samples was
developed to obtain preliminary information on the crystallization types of these compounds. In order to
detect the subtle differences in the organization of the chiral solid phase, a new easily implemented
approach, based on a chromatographic measuring of the relative abundance of the enantiomers in a sin-
gle solution in equilibrium with a solid sample of arbitrary (0 < ee < 1) composition, is reported. One new
conglomerate compound (Alk = n-Pr) and one borderline case (Alk = n-Bu) are disclosed. Higher members
of the series of 1 (starting with an n-Bu derivative) are turned into liquid crystals upon melting; no sig-
nificant differences between racemic and non-racemic samples were found. Only enantiopure methyl-, n-
butyl, n-pentyl, n-hexyl, and n-heptyl substituted 1 were able to form supramolecular gels in hydrocar-
bon solvents; all racemic ethers 1 did not show such ability.
Received 8 April 2013
Accepted 24 May 2013
Available online xxxx
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
meric composition of the parent substance is well-known for chiral
compounds.4,5 This relationship is due to differences in the nature
The behavior of chiral molecules in the formation of ordered
systems is stereoselective. Thus, during the process of nucleation
and crystal growth of the racemic material, both enantiomers
may be involved in a number of successive chiral discrimination
acts; this leads to the formation of different types of crystalline
racemate.1 In most cases, a molecular racemic compound arises,
that is, a heterochiral crystal lattice is formed from the identical,
and balanced in terms of enantiomeric composition, unit cells.
Racemic conglomerates consisting of enantiopure crystals are less
common, but nonetheless are often formed. Together, these two
cases cover more than 90% of the actual chiral crystals. In rare
cases, the crystalline phase is either a solid solution or an exotic
anomalous racemate.1,2
In all cases, information on the nature of the crystallization of
the target products has tremendous value to organic-practitioners.
If successful, one can take advantage of stereoselective crystalliza-
tion to obtain the enantiopure product, in addition to establishing a
multi-step strategy for its synthesis on a solid theoretical basis.2
So called ‘soft matters’, such as liquid crystals and gels formed
by polymeric and low molecular weight gelators (LMWG), are
the subject of constant interest in organic chemistry.3 The relation-
ship between the properties of such ‘soft matter’ and the enantio-
of self-assembly of chiral molecules, and to an extent the nature of
their crystallization.6,7 Consequently, information about the type of
chiral crystalline phase is essential during the search for new, and
the modification of known ‘soft matters’.
A noteworthy example of chiral discrimination involves the
simplest chiral organogelator p-tolyloxypropane-1,2-diol 1a. We
have shown that a high gelling ability is inherent in (R)- and (S)-
1a, while rac-1a does not form any supramolecular gels.8 Herein
we continued the search of LMWG among other para-substituted
phenyl glycerol ethers, rac-, and scal-3-(4-alkylphenoxy)-pro-
pane-1,2-diols 1a–k (Scheme 1).
Previously Tschierske et al. have reported that the members of
the racemic diol family 1 exhibit properties of thermotropic liquid
crystals (LC).9 On the other hand, we have shown that diols rac-1a
and scal-1a not only form metastable phases during the melt crys-
tallization, but also show pronounced chiral discrimination in this
process.7 Investigation into the effect of the chirality on the mani-
festation of liquid crystal properties within the 1b–k family is also
another aim herein.
Variously substituted phenyl glycerol ethers have been investi-
gated in our previous studies, and it was shown that these com-
pounds are characterized by a high frequency of conglomerate
formation.2 An important goal herein is to demonstrate new tech-
niques, which use standard conditions in a synthetic laboratory
equipment, to obtain valuable information about the subject.
⇑
Corresponding author. Tel.: +7 843 2319167; fax: +7 843 2731872.
E-mail address: baa@iopc.ru (A.A. Bredikhin).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.05.017
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A. A. Bredikhin et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
purity to ee P99% by simple recrystallization (fourth column) for
K2CO3
R
OH
+
R
O
all of the diols except for tert-butyl derivative 1e. In this case, it
is impossible to increase the starting ee value by subsequent crys-
tallizations; this could mean that the composition of the eutectics
for this substance is characterized by eeeu >91%.
3a-k
2a-k
Br
R
AD-mix-β
2a-k
Cl
O
OH
Valuable information on the nature of the crystallization of a
chiral substance can be obtained from a comparison of its racemic
and enantiomerically enriched (scalemic) sample melting points,
1a-k
(S)-
HO
H
the value
D
Tfr;s ¼ Trf ꢁ Tsf , shown in Table 1. The positive
D
Tfr;s values
OH
OH
3a-k
for 1a–c, e, and g–j indicate the formation of racemic compounds
by these substances in the solid phase. A value of
R
O
OH
D
Tfr;s P 30ꢂC
NaOH
rac-1a-k
points to high racemic compound stability in the case of 1e. This
information, in conjunction with the above data on the composi-
tion of the eutectics, is sufficient to conclude that the chiral sub-
stance 1e could be attributed to a type of ‘anticonglomerates’.
OH
R = CH3 a, C2H5 b, i-C3H7 c, n-C3H7 d, tert-C4H9 e, n-C4H9 f,
n-C5H11 g, n-C6H13 h, n-C7H15 i, n-C8H17 j, n-C9H19 k.
D
Tfr;s quantities are negative
Scheme 1. Synthesis and designation of the studied compounds.
For compounds 1d, 1f, and 1k the
and significant in absolute values: ꢁ14, ꢁ16, and ꢁ43 °C in the or-
der listed. Such melting points indicate that these compounds may
exhibit the property of spontaneous resolution during crystalliza-
tion. However other considerations should be taken into account
for definitive conclusions; for example, one could compare the
vibration spectra of these compounds in the solid phase.
2. Results and discussion
2.1. Chemistry
Herein non-racemic samples of scal-3-(4-alkylphenoxy)-pro-
pane-1,2-diols 1a–k were obtained from allyloxyalkyl benzenes
2a–k through Sharpless asymmetric dihydroxylations (SAD).10 Ear-
lier Wang et al., using methyl, methoxy, chloro, and cyanosubsti-
tuted allyloxybenzenes as examples, demonstrated that
dihydroxylation of ortho-substituted allyl ethers took place with
low enantioselectivity (products ee 28–63%), whereas the results
for para-substituted derivatives are satisfactory (ee 89–95%).11 In
the same paper, it was also found that the use of AD-mix-b as a re-
agent gave products with an (S)-configuration at the C2 carbon
atom. Our results are consistent with these conclusions. Ethers
2a-k, precursors of the target compounds, were obtained with
moderate yields (ꢀ60–70%) from the corresponding phenols 3a–
k and allyl bromide under the action of a base (K2CO3). To obtain
racemic diols rac-1a–k, we used the interaction of rac-3-chloropro-
pane-1,2-diol with the corresponding phenolates. Our approach to
the target compounds is outlined in Scheme 1. Some experimental
characteristics of the diols investigated are shown in Table 1.
Listed in the third column of Table 1, the values of the enantio-
meric excess for non-racemic diols 1a–k refer to the primary reac-
tion products, which were studied immediately after the SAD
reaction had finished. As expected, the length and degree of
branching of the alkyl substituent did not affect the enantioselec-
tivity of the reaction. It is possible to increase the enantiomeric
2.2. IR spectroscopy
A comparison of the IR spectra of crystalline racemic and enan-
tiomeric samples is often used to determine the type of chiral crys-
tallization. In this case, the similarity of the IR spectra shows the
similarity of the crystal structure of the samples and may indicate
that the test substance crystallizes as a conglomerate. In contrast,
the IR spectra of a racemic compound are usually different to those
of their respective enantiomers.1a,13 The main difficulty associated
with this approach consists of establishing reliable criteria for the
similarities and differences of complex spectroscopic curves.
Modern instruments record the spectra in digital form. Typi-
cally, such a spectrum represents a two-dimensional digital array
(Ai,
pressed in wave numbers in increments of 1 cmꢁ1), and Ai corre-
sponds to the extinction at this wave number. If the value for
mi), where mi stands for the vibrational frequency (usually ex-
m
the two arrays changes with the same step, the standard Pearson
correlation coefficient r can be used for their quantitative compar-
ison. This coefficient, calculated for two arrays fARi g and fAiAg
(superscripts R and A denote racemic and scalemic samples), was
proposed by us as a quantitative complement to traditional visual
comparison of normalized spectra.14 Building on this approach, for
a more detailed and demonstrable comparison of the vibrational
Table 1
Yield and enantiomeric excess of asymmetric dihydroxylation products (S)-1a–k and some physicochemical characteristics of rac- and scal-1a–k
Tfr;s
Diol
Yield (%)
eea (%)
Mp (°C)
cpb (°C)
D
Before
After
rac (lit.)
scal
rac (lit.)
scal
1a
1b
1c
1d
1e
1f
1g
1h
1i
48
43
53
57
72
79
59
61
65
70
68
88.8
91.5
92.5
86.5
91.0
91.1
90.0
89.8
91.4
90.8
90.7
99.0
99.5
99.0
99.7
<91
99.9
99.6
99.1
99.7
99.7
99.2
74–75 (70)c
68
61–62
57
82
55
70
52
48
51.5
60
7–6
7–6
3–1
-14
32–30
-16
13
15
14.5
5
—
—
—
—
—
—
—
68 (66)c
58–60
68 (49.5)c
— (67.5)
—
c
85–87 (84–86)d
54 (53)c
—
75 (75)c
75
78
85
85
89
—
65 (57)c
80 (80.5)c
85 (87)c
86 (88)c
89 (91)c
90 (92.5)c
63 (60)c
66 (61)c
1j
1k
65 (58)c
69 (55.5)c
112
ꢁ43
a
b
c
Enantiomeric excess of diols (S)-1a–k before and after recrystallization.
Clearing point.
Ref. 9.
d
Ref. 12.
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A. A. Bredikhin et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
3
spectra herein, we decided to use a graphical representation of the
correlation between the two spectra, that is, visually display them
in the coordinates ARi versus AiA. Figure 1 illustrates the features of
this approach.
cient (r = 0.948) as well as the ‘spreading’ of the correlation trajec-
tory over the area cannot be attributed to racemic conglomerates.
The reason for the abnormally high difference between the melting
point of the racemate and scalemate for this compound, found in
Section 2.1, will be explained in Section 2.4.
Two compounds, n-propyl and n-butyl-substituted diols 1d and
1f fall out of the total number under the comparison of the IR spec-
tra. The high value of r = 0.998 and the compact nature of the cor-
relation trajectory allow us to assign with a considerable degree of
certainty the diol 1d to the family of conglomerate formative com-
pounds. The correlation coefficient for the diol 1f was also high
(r = 0.994). However, analysis of the correlation trajectory reveals
non-obvious differences in the spectra of rac- and scal-1f by visual
inspection (Fig. 3).
As can be seen from Figure 3, we can see at least three spectro-
scopic components at 535, 1055, and 2955 cmꢁ1, for which there
are small spectroscopic shifts in the transition from the racemic so-
lid phase to the enantiopure. The differences in the spectra are
minimal, but the pattern of the changes is difficult to attribute to
the influence of impurities in the material or matrix. These results
led us to doubt that in this case we were dealing with a conglom-
erate. At the same time, the similarity of the spectra in the region
of hydrogen bonds O–Hꢃ ꢃ ꢃO led us to conclude that the experimen-
tal spectra belong to the crystal structure, which has an almost
identical system of intra- and intermolecular hydrogen bonds.
In order to accurately determine the type of crystallization of
racemic compounds 1d and 1f, we have developed another simple
technique that enables fast and reliable determination of the eu-
tectic composition of the chiral matter on the basis of experimental
data on the solubility of the sample of an intermediate enantio-
meric composition. In addition to the diols 1d, f, we also investi-
The right hand side of Figure 1 shows the parts of the condi-
tional spectra, several peaks of which are simulated by a Gaussian
with
r
= 5 cmꢁ1. One of the spectroscopic curves (called a model
spectrum) is shown as a set of different colored segments; the sec-
ond (reference spectrum) is shown as a thin black line. Each pair of
peaks illustrates the most common real situation accompanied the
spectra comparison, such as the coincidence of the bands, the dif-
ference in frequency or intensity, and baseline drift. Left of the fig-
ure shows the trajectories arising from the correlation of a pair of
spectral lines in the coordinates of the transmittance intensity AiR
versus AAi . The color of the trajectory linking two correlated spec-
trum, which is a graphical representation of a particular situation,
matches the color of the model spectrum fragment. It can be seen
that the proposed procedure is very sensitive to the context and
can reliably detect even slight differences of spectra lines in fre-
quency and/or intensity. Secondly, the shape of the correlation tra-
jectory is informative and makes it easy to identify a particular
type of mismatch. Of course, the real spectra can differ by several
parameters simultaneously. However, the proposed procedure re-
tains its attractiveness in this case as well.
It is clear that the proposed procedure is applicable not only to
compare the spectra of chiral compounds, but also to identify sub-
tle and non-obvious differences between any of the digital spectra.
For pairwise comparison of the experimental arrays we wrote a
simple program ‘Trajectory’ that uses the open source mathemati-
cal package Sage. It allows a user to display the original spectra, the
correlation trajectories, as well as to select and analyze fragments
of the spectra in interactive mode.
gated diol 1b, which, as we now know, forms
a racemic
The experimental IR spectra recorded for the crystal samples
1a–k (pellets in KBr), and the correlation coefficients and correla-
tion trajectories for each pair of ‘racemate-scalemate’ are shown
in Figure 2. It can be seen that the new criterion can easily ascer-
tain the essential difference in the spectra of the racemate and
scalemate for substances 1a–c, e, and g–k, without going into a de-
tailed analysis of the spectroscopic differences. Thus, despite the
fact that the correlation coefficient between pairs of spectra for
1c, 1e, 1h, and 1j amounted to 0.95 or more, in all these cases
the appearance of the trajectory leaves no doubt with regard to
the essential differences between the crystal structures of racemic
and homochiral samples. For compound 1k, the correlation coeffi-
compound in the solid phase.
2.3. Solubility test
One indication of the crystallization of a chiral compound as a
conglomerate is the ‘Meyerhoffer’s double solubility rule’,15 which
follows from simple thermodynamic considerations. Let us con-
sider a ternary heterogeneous system ‘stereoisomers + achiral sol-
vent’, in which the dissolution is not accompanied by dissociation
or association of stereoisomers, in terms of the thermodynamic
activity of its components. As the ‘origin’ for such a system, it nat-
urally accepts a crystalline phase of a pure enantiomer, the activity
Figure 1. Two conditional spectra ARi and AiA and their correlation in the axes ARi versus AAi . The reference spectrum (right panel) is shown as a black line, the bands in the
model spectrum and the corresponding bands’ correlation images (left panel) are shown as the colored fragments. Illustrated are the following cases: (a, black) peaks are
identical, the correlation trajectory lies on the diagonal tg
a
= 1; (b, red) intensities are identical, a small (1 cmꢁ1) shift in frequency, the trajectory is a narrow loop around the
diagonal; (c, green) significant (5 cmꢁ1) shift in frequency, wide loop; (d, magenta) peaks vary in height (2 times), straight line, deviating from the diagonal the stronger, the
more differences; (e, dark yellow) peaks are completely separated (or the corresponding peak is absent in one of the spectra), the trajectory degenerates into a horizontal and/
or vertical lines; (f, blue) peaks have an identical integral extinction but differ two times in extinction at the maximum, the trajectory is curved; (g, cyan) peaks are observed
on the background of a baseline shift of one of the spectra, a trajectory that is parallel to the diagonal.
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A. A. Bredikhin et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
Figure 2. IR spectra of racemic and enantiopure samples 1a–k and graphical representation of the correlations between them.
of which is by definition equal to unity. In an equilibrium state be-
tween the solid phase and solution (i.e., for a saturated solution)
the activity of the components in the solution and in the solid
phase is equal. Thus, the activity of an individual stereoisomer in
its saturated solution is also equal to unity. For a conglomerate
(assuming no mutual solubility of enantiomers in solid state) solid
phase is represented by a mechanical mixture of enantiopure crys-
tals of two enantiomers. Therefore, in this case the activities of
each of the enantiomers in a saturated solution are equal to unity.
However, since the solvent is achiral, activity coefficients of enan-
tiomers are the same, the concentrations of both enantiomers are
also equal. If the solubility of the enantiomers is not too large,
we can neglect the dependence of the activity coefficient on the
concentration and believe that each of these concentrations is
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A. A. Bredikhin et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
5
Figure 3. Typical loop-type fragments of the correlation trajectory (black lines) and the corresponding regions of the experimental IR spectra of racemic (red curves) and
enantiopure (blue curves) crystalline samples of diol 1f in the KBr matrix.
Table 2
equal to the concentration of a saturated solution of the individual
stereoisomers. Accordingly, the total concentration of a substance
in a saturated solution of a conglomerate should be twice as high
as in the saturated solution of an enantiopure substance.
The results of chromatographic determination of the concentration of individual
enantiomers [R]eu and [S]eu in solutions in equilibrium with a mixture of the crystals
of the racemate and scalemate, and the eutectic compositions xeu of the correspond-
ing systems, which are found on this basis, as well as the concentration of saturated
ꢀ
ꢁ
ꢀ
ꢁ
cyclohexane solutions of enantiopure CAsat and racemic
and f
C
samples of diols 1b, d,
Rc
sat
For a racemic compound, the activities of the enantiomers in
the solid phase are not equal to unity. If formed, the racemic com-
pound must be thermodynamically preferred over the conglomer-
ate, and therefore begin to crystallize from solution prior to the
(potential) racemic conglomerate, provided that at the beginning
of the crystallization, the concentration of each of the enantiomers
would be lower than for a saturated solution of the conglomerate.
This means that the activity of the enantiomers for a saturated
solution of the racemic compound, and therefore for its crystal
phase, should be less than unity, and the ratio of its solubility to
the solubility of the individual enantiomers is less than two.
It is clear that the activity of an enantiopure substance, which
forms an individual phase in the solid sample, is unity even though
the (excess) enantiomer is mixed with the phase of the racemic
compound. Its activity in a solution in equilibrium with this mix-
ture should also be equal to unity. Consequently, the equilibrium
concentration of the excess isomer [to be specific, let it be (R)-iso-
mer] corresponds to its solubility in enantiopure form:
Line
Parameter
Compound
1d
1b
1f
1
2
3
4
[S]eu
0.12 (0.01)
0.96 (0.04)
0.888 (0.001)
0.68 (0.02)
0.98 (0.04)
0.98 (0.04)
0.501 (0.001)
1.97 (0.07)
0.92 (0.03)
1.01 (0.03)
0.521 (0.005)
1.93 (0.06)
[R]eu
xeu (m.f.)a
Rc
b
C
sat
Rc
5
6
7
0.69 (0.03)
1.00 (0.05)
0.90 (0.01)
1.94 (0.07)
1.00 (0.12)
0.51 (0.02)
1.91 (0.06)
1.00 (0.05)
0.53 (0.03)
C
sat
CAsat
xeu (m.f.)c
The concentrations are presented as areas of the corresponding chromatographic
peak, normalized to the average peak area of a saturated solution of the enantiopure
substances. Statistical confidence intervals (
are indicated in parentheses.
a = 0.95) of the corresponding values
a
Calculated by the formula (3).
Calculated by the formula (4).
Calculated by the formula (5).
b
c
½Rꢄeu ¼ CAsat
ð1Þ
shown in line 3. The statistical characteristics (including confidence
intervals computed using standard statistical procedures) show the
high accuracy of this parameter, and consequently, the high resolu-
tion of the proposed test. Our experience has shown that the eutec-
tic composition can be accurately determined in one measurement,
and that the procedure does not require us to determine the abso-
lute values of concentration and thus conduct preliminary
calibrations.
Table 2 shows that for 1d, a value of xeu = 0.5 was determined
with an accuracy of ꢀ0.2%, which allows us to attribute this diol
to the family of conglomerate formatting compounds. At the same
time, the composition of the eutectics for 1f (xeu = 0.521) is statis-
tically significantly different from the value of 0.5, indicating the
formation of a racemic compound by this system. Even more tell-
ing is the same test for compound 1b (xeu = 0.89), for which the for-
mation of a racemic compound follows immediately from other
above cited data.
It should also be noted that the same results of a single mea-
surement of the relative composition of the equilibrium solution
in prescribed conditions, along with eutectic composition, provide
additional information about the system. According to equation
(1), the peak area of the predominant stereoisomer (Table 2, line
2) corresponds to the solubility of enantiopure substance. The
product of the same areas of the peaks corresponds to the solubil-
ity product, the scope of which extends to the racemic composi-
tion. Combining equations (1) and (2), the solubility of the
racemate can be easily calculated from the equation:
while the composition of the solution corresponds to the composi-
tion of the eutectics and is unambiguously determined by the solu-
bility ratio of its components through the solubility product (Psol):
Psol ¼ ½Rꢄeu ꢃ ½Sꢄeu ¼ const
ð2Þ
The expressions (1) and (2) were obtained on an empirical basis and
tested on experimental data in the work of Klussmann et al.16
Generally speaking, the composition of the eutectics for a chiral
substance explicitly identifies the type of its crystallization. Based
on this we propose a simple and effective test. For its use we re-
quire a solid sample containing simultaneously both enantiomers
in unequal amounts (i.e., integral enantiomeric purity of this sam-
ple 1 > ee > 0). In practice, such a sample is easy to prepare by mix-
ing approximately equal amounts of the racemate and
enantioenriched substance. The amount of the solid sample and
solvent are selected so that both enantiomers must be left in the
solid in equilibrium with a saturated solution. The relative equilib-
rium concentration of the enantiomers in this saturated solution
can be easily determined by chiral chromatography. The composi-
tion of the eutectics could be calculated on the basis of these data
by the formula:
½Rꢄeu
xeuðmole fraction; m:f:Þ ¼
ð3Þ
½Rꢄeu þ ½Sꢄeu
The results of the chromatographic analysis of saturated solutions
in equilibrium with the two-component solid phases for com-
pounds 1b, d, and f are shown in lines 1–2 of Table 2. The eutectic
compositions of these compounds, calculated by formula (3), are
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
Rc
sat
C
¼ 2 ꢃ ½Rꢄeu ꢃ ½Sꢄeu
ð4Þ
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6
A. A. Bredikhin et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
The calculated values using this formula are shown in line 4 of Ta-
ble 2. For the sake of comparison, the chromatographic data directly
obtained for the solutions of enantiopure and racemic samples in
equilibrium with the corresponding solid phases are shown in lines
5 and 6.
It is natural that the data for the equilibrium solutions of race-
mic and enantiopure samples (Table 2, lines 5–6) can also be used
for the eutectic composition estimate according to the formula:
1
xeuðm:f:Þ ¼
ð5Þ
ꢀ
ꢁ
2
Rc
sat
C
1 þ
2ꢃCAsat
The results of the calculation (line 7) were in good agreement with
the values determined by formula (3) (line 3), although the latter
were much more accurate.
Thus, our proposed approach, with minimal experimental ef-
fort, provides a way of reliable identification of the main types of
crystallization of chiral substances and simultaneously allows us
to receive almost the same amount of information on the solubility
of racemic and enantiopure phase as does the direct determination
of these quantities. At the same time, this procedure does not re-
quire a sample with high enantiomeric purity, and also allows
measurements at room temperature without special temperature
control.
Figure 4. Gel formed by (S)-1g in hexane (a) and crystals of rac-1g, obtained under
the same conditions (b).
2.4. Liquid crystalline properties
both configurations indicate a high tendency to supramolecular
gelation, rac-1a is completely devoid of gelation properties.8 The
ortho- and meta-tolyl glycerol ethers revealed no low molecular
weight gelator (LMWG) abilities either in racemic or enantiopure
form.7 In order to identify general regularities that govern gelation
in the series of aromatic ethers of glycerol, we examined this abil-
ity for para-alkylsubstituted diols 1b–k. We found that the non-
racemic diols scal-1f–i exhibited an ability to gel formation in a
hydrocarbon medium (here after the results for n-hexane are gi-
ven), to form stable opaque supramolecular gels, in which the frac-
tion of gelator amounts to 0.8–1.6 wt %. A typical gel formed by (S)-
1g (1 wt % in hexane) is shown in Figure 4a. At the same time, none
of the investigated racemic diols showed an ability to form a supra-
molecular gel in organic solvents. Under the same conditions, most
of the racemic derivatives formed thin plate-like crystals (similar
to that shown for the racemate in Fig. 4b). It should be noted that
non-racemic diols scal-1b–d, j–k also crystallized within the same
concentration range, but formed the needle crystals of an elon-
gated shape.
The relationship between the gelation and crystallization pecu-
liarities for LMWG of similar structures was studied earlier.17 Usu-
ally this fact is associated with different crystallization types of the
corresponding samples. This was the case for all of the investigated
racemic and enantiopure diols 1, with the exception of compounds
1d, f. However, based on the nature of the crystals, the non-race-
mic diols form close to each other resulting in crystal packing. An-
other reason for the different gelation ability of compounds with a
similar structure is their solubility.18 Apparently, this is the reason
for the different results obtained for non-racemic diols 1. Both fac-
tors, the crystal structure and the solubility, will be investigated in
subsequent studies.
We next studied the behavior of diols 1a–k upon heating. Com-
pounds 1a–e when heated at melting point immediately formed a
clear isotropic liquid phase. The melting of the high-order mem-
bers of the series, compounds 1f–k, went through two steps: after
the complete disappearance of the solid phase, a turbid anisotropic
liquid phase was formed, which upon further heating became
transparent. Such a behavior is typical of compounds forming a
thermotropic liquid crystalline phase, which with a temperature
increase becomes an isotropic liquid.
In addition to the melting point (mp), the temperatures of this
last transition (clearing point, cp) are also given in Table 1. The
melting and clearing points for compounds rac-1d, f–k were de-
fined by Tschierske et al.9 In general, our findings are consistent
with the literature, with some differences noted in Table 1. As
can be seen from Table 1, no significant differences between the
values of cp for the racemic and enantiomeric samples of the same
compound were observed. At first glance, the nonyl substituted
diol seems to be an exception. In this case the sample of scal-1k
melts to form an isotropic phase, so that its clearing point is miss-
ing. However in this case, the hypothetical transition temperature
of the metastable LC phase to isotropic liquid (by analogy with
other members of the series cpscal ꢀ cprac ꢀ 90 °C) is reached before
the melting of the crystals (mpscal = 112 °C). Apparently, it is this
factor, which explains the large value
D
Tfr;s, which was discussed
in Sections 2.1 and 2.2. If for all the other diols the investigated
thermoinitiated phase transition, designated as the ‘melting point’,
describes homogeneous processes (notably transition ‘crystal-iso-
tropic liquid’ for 1a–e, or ‘crystal-LC mesophase’ for 1f–j), then
for the last member the transition temperature ‘crystal-LC meso-
phase’ for rac-1k is compared with a transition temperature ‘crys-
tal-isotropic liquid’ for scal-1k. Thermodynamics imposes no
obvious limitations on the relationship of such temperatures.
3. Conclusion
2.5. Gelation abilities
A series of enantiomeric and racemic p-alkylphenyl terminal
glycerol ethers, 3-(p-alkylphenoxy)-propane-1,2-diols 1a–k were
synthesized by the SAD method from allyl phenyl ethers and the
reaction of the corresponding phenols with racemic 3-chloropro-
pane-1,2-diol. In order to obtain preliminary information on the
Recently, we found that the para-tolyl glycerol ether 1a is the
simplest known chiral organogelator with pronounced chirality
driven properties. While the non-racemic samples of scal-1a of
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A. A. Bredikhin et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
7
types of chirality that drove the crystallization, a new pictorial
method of the comparison of the IR spectra of solid enantiopure
and racemic samples was developed. This method consists of the
construction and analysis of the correlation trajectories between
the pairs of spectra. Testing this approach for the entire set of diols
synthesized allowed the identification of eight new cases of the
formation of racemic compounds, and allowed us to detect a new
case of spontaneous resolution (n-propyl derivative 1d) and a bor-
derline case of n-butyl derivative 1f.
In order to detect the subtle differences in the organization of
the solid phase of a chiral substance another new method was of-
fered, based on measuring the relative abundance of the enantio-
mers in the solution in equilibrium with a solid sample of
arbitrary intermediate (0 < ee < 1) composition. Using only the
chromatogram of this solution (if the separation of the peaks of
enantiomers is achieved) allowed us to accurately determine the
composition of the eutectic and as a result, reliably characterize
the type of crystallization of the substance. A value of xeu = 0.5 indi-
cated crystallization of the product in the form of a conglomerate,
whereas an xeu value different from 0.5 indicated the formation of a
racemic compound.
Higher members of the series of diols 1 (starting with n-butyl
derivative 1f) were turned into liquid crystals upon melting. No
significant differences in the behavior of racemic and non-racemic
samples were found in these cases. On the contrary, the ability of
para-alkylphenyloxypropanediols to form supramolecular gels in
hydrocarbon solvents inherits the expressed chirality driven char-
acter. The properties of the low molecular weight organogelator
are common to enantiopure samples of methyl-, n-butyl, n-pentyl,
n-hexyl, and n-heptylsubstituted diols 1a, f–i. All of the studied
compounds in racemic, and diols 1b–e, j–k in enantiopure form
do not show such ability. Apparently, for racemic samples the rea-
son for this lies with the qualitative features of the crystal packing,
and for enantiomeric samples—with the solubility (which is in turn
related to the energy of the crystal lattice).
(99%), 4-hexylphenol (P98%), AD-mix-alpha, and AD-mix-beta
were from Aldrich.
4.2.1. General procedure for the synthesis of aryl allyl ethers
2a–k
Aryl allyl ethers were prepared according to the published
method.19 A stirred suspension of the appropriate phenol 3a–k
(6 mmol), allyl bromide (0.8 g, 6.6 mmol), and ground water-free
K2CO3 (0.91 g, 6.6 mmol) in anhydrous acetone (10 mL) was re-
fluxed for approximately 12–14 h; the progress of the reaction
was monitored by TLC analysis (for product Rf ꢀ 0.7; eluent: hex-
ane/EtOAc = 9:1). The reaction mixture was diluted with water
(30 mL) and extracted with Et2O (3 ꢅ 40 mL). The collected organic
phases were washed with 1 M NaOH (15 mL) and dried over
MgSO4. The solvent was removed under reduced pressure to afford
ether 2a–k as fluid oil. The crude product was purified by column
chromatography (silica gel, eluent: hexane/EtOAc = 9:1–8:2).
4.2.1.1. 1-(Allyloxy)-4-methylbenzene 2a. Yield: 64%, bp 82–
83 °C (8 Torr), n2D3 ¼ 1:5162; [lit.20 bp 100–100.5 °C (9 Torr),
n2D5 ¼ 1:5157]. 1H NMR d 2.30 (s, 3H, CH3), 4.53 (ddd, J = 1.5,
5.3 Hz; 2H, OCH2), 5.29 (ddt, J = 1.5, 1.5, 10.5 Hz; 1H, CH2), 5.42
(ddt, J = 1.5, 1.5, 17.3 Hz; 1H, CH2), 6.07 (ddt, J = 5.3, 10.5,
17.3 Hz; 1H, CH), 6.82–6.85 (m, 2H, Ar), 7.07–7.11 (m, 2H, Ar). EI
mass-spectrum [m/z (I)]: 148(79), 133(32), 107(73), 91(19),
77(92), 65(16), 51(24), 41(100).
4.2.1.2. 1-(Allyloxy)-4-ethylbenzene 2b. Yield: 68%, bp 91 °C
(8 Torr),
n2D3 ¼ 1:5164;
[lit.20
bp
96–96.8 °C
(9 Torr),
n2D5 ¼ 1:5124]. 1H NMR d 1.19 (t, J = 7.5 Hz; 3H, CH3), 2.57 (q,
J = 7.5 Hz, 2H, CH2), 4.48 (ddd, J = 1.5, 5.1 Hz; 2H, OCH2), 5.24
(ddt, J = 1.5, 1.5, 10.6 Hz; 1H, CH2), 5.42 (ddt, J = 1.5, 1.5, 17.3 Hz;
1H, CH2), 6.07 (ddt, J = 5.3, J = 10.5, 17.3 Hz; 1H, CH), 6.80–6.84
(m, 2H, Ar), 7.06–7.10 (m, 2H, Ar). EI mass-spectrum [m/z (I)]:
162(53), 147(44), 133(27), 121(31), 107(33), 93(48), 91(60),
65(19), 51(16), 41(100).
4. Experimental
4.1. General
4.2.1.3. 1-(Allyloxy)-4-isopropylbenzene 2c. Yield: 70%, bp 105–
106 °C (8 Torr), n2D3 ¼ 1:5053; [lit.21 bp 93–94 °C (6 Torr); lit.22
n2D5 ¼ 1:5074]. 1H NMR d 1.25 (d, J = 6.9 Hz; 6H, CH3), 2.89 (septet,
J = 6.9 Hz; 1H, CH), 4.56 (ddd, J = 1.5, 5.3 Hz; 2H, OCH2), 5.31 (ddt,
J = 1.5, 1.5, 10.5 Hz; 1H, CH2), 5.43 (ddt, J = 1.5, 1.5, 17.2 Hz; 1H,
CH2), 6.07 (ddt, J = 5.3, 10.5, 17.2 Hz; 1H, CH), 6.86–6.90 (m, 2H,
Ar), 7.13–7.17 (m, 2H, Ar). EI mass-spectrum [m/z (I)]: 176(35),
161(100), 133(13), 121(16), 105(21), 91(65), 77(20), 55(9), 41(79).
The NMR spectra were recorded on a Bruker Avance-400
(399.9 MHz for 1H; 100.5 MHz for 13C) spectrometer in CDCl3 with
TMS or the signals of the solvent as the internal standard (the sig-
nals of the aromatic protons in 1H NMR spectra for all diols 1a–k
and aryl allyl ethers 2a–k are present as a typical AA0BB0 system).
The IR spectra of the polycrystalline samples of rac- and (S)-diols
1a–k in KBr pellets were recorded on a Bruker Tensor 27 spectrom-
eter. Optical rotations were measured on a Perkin–Elmer model
341 polarimeter (concentration c is given as g/100 mL). Mass-spec-
tra EI were recorded on a mass-spectrometer DFS Thermo Electron
Corporation (70 eV). Melting points and clearing points (cp) of li-
quid crystal-isotropic melt transmissions for general purposes
were determined using a Boëtius apparatus and are uncorrected.
HPLC analyses were performed on a Shimadzu LC-20AD system
controller and UV monitor 275 nm was used as a detector. The col-
umns used, from Daicel, Inc., were Chiralcel OD-H (0.46 ꢅ 25 cm),
Chiralpak AD (0.46 ꢅ 25 cm), Chiralcel OJ (0.46 ꢅ 25 cm).
4.2.1.4. 1-(Allyloxy)-4-propylbenzene 2d. Yield: 67%, bp 116 °C
(8 Torr), n2D3 ¼ 1:5052. 1H NMR d 0.96 (t, J = 7.4 Hz; 3H, CH3), 2.57
(sextet, J = 7.4 Hz; 2H, CH2), 2.55 (t, J = 7.4 Hz; 2H, CH2), 4.54
(ddd, J = 1.5, 5.3 Hz; 2H OCH2), 5.30 (ddt, J = 1.5, 1.5, 10.5 Hz; 1H,
CH2), 5.44 (ddt, J 1.5, 1.5, 17.3 Hz; 1H, CH2), 6.07 (ddt, J = 5.3,
10.5, 17.3 Hz; 1H, CH), 6.85–6.88 (m, 2H, Ar), 7.09–7.28 (m, 2H,
Ar). EI mass-spectrum [m/z (I)]: 176(31), 147(88), 119(11),
107(45), 93(21), 91(28), 65(24), 51(10), 41(100).
4.2.1.5. 1-(Allyloxy)-4-tert-butylbenzene 2e. Yield: 55%, bp
114 °C (8 Torr), n2D3 ¼ 1:5050; [lit.21 bp 115–116 °C (8 Torr); lit.23
n2D4 ¼ 1:5058]. 1H NMR d 1.33 (s, 9H, CH3), 4.55 (ddd, J = 1.6,
5.3 Hz; 2H, OCH2), 5.29 (ddt, J = 1.6, 1.6, 10.5 Hz; 1H, CH2), 5.43
(ddt, J = 1.6, 1.6, 17.3 Hz; 1H, CH2), 6.07 (ddt, J = 5.3, 10.5,
17.3 Hz; 1H, CH), 6.86–6.90 (m, 2H, Ar), 7.30–7.35 (m, 2H, Ar). EI
mass-spectrum [m/z (I)]: 190(17), 175(100), 147(6), 135(11),
105(23), 91(28), 77(15), 65(10), 55(9), 41(59).
4.2. Synthesis
Racemic 3-chloropropane-1,2-diol (99+%) was purchased from
Acros Organics; 4-ethylphenol (97%), 4-isopropylphenol (98%), 4-
n-butylphenol (98%), 4-n-pentylphenol (98%), 4-n-heptylphenol
(98 + %), 4-n-octylphenol (99%), 4-n-nonylphenol (98+%), and allyl
bromide (99%) were purchased from Alfa Aesar; 4-propylphenol
4.2.1.6. 1-(Allyloxy)-4-n-butylbenzene 2f. Yield: 63%, bp 126–
127 °C (8 Torr), n2D3 ¼ 1:5063. 1H NMR d 0.94 (t, J = 7.3 Hz; 3H,
Please cite this article in press as: Bredikhin, A. A.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.05.017

8
A. A. Bredikhin et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
CH3), 1.33–1.39 (m, 2H, CH2CH3), 1.55–1.60 (m, 2H, CH2CH2CH2),
2.56 (t, J = 7.7 Hz; 2H, CH2), 4.53 (ddd, J = 1.5, 5.3 Hz; 2H, OCH2),
5.28 (ddt, J = 1.5, 1.5, 10.5 Hz; 1H, CH2), 5.42 (ddt, J = 1.5, 1.5,
17.3 Hz; 1H, CH2), 6.07 (ddt, J = 5.3, 10.5, 17.3 Hz; 1H, CH), 6.84–
6.86 (m, 2H, Ar), 7.09–7.11 (v, 2H, Ar). EI mass-spectrum [m/z (I)]:
190(31), 147(100), 133(8), 107(43), 91(25), 77(18), 65(17), 41(99).
MgSO4. The solvent was removed under reduced pressure to obtain
a solid residue or oil, which was crystallized in hexane at ꢁ10 °C.
The crude diols were purified by recrystallization from hexane/
EtOAc = 5:1 to give pure products as a white crystalline material
with 65–71% yield. The melting and cleaning points for diols rac-
1a–k are given in Table 1. NMR spectra were identical with those
cited below for corresponding (S)-1a–k.
4.2.1.7. 1-(Allyloxy)-4-n-pentylbenzene 2g. Yield: 67%, bp
135 °C (8 Torr), n2D3 ¼ 1:5047. 1H NMR d 0.91 (t, J = 7.3 Hz; 3H,
CH3), 1.31–1.39 (m, 4H, CH2(CH2)2CH3), 1.55–1.63 (m, 2H,
CH2CH2CH2), 2.56 (t, J = 7.7 Hz; 2H, CH2), 4.53 (ddd, J = 1.5,
5.3 Hz; 2H, OCH2), 5.28 (ddt, J = 1.5, 1.5, 10.5 Hz; 1H, CH2), 5.42
(ddt, J = 1.5, 1.5, 17.3 Hz; 1H, CH2), 6.07 (ddt, J = 5.3, 10.5,
17.3 Hz; 1H, CH), 6.84–6.86 (m, 2H, Ar), 7.05–7.13 (m, 2H, Ar). EI
mass-spectrum [m/z (I)]: 204(21), 147(100), 119(9), 107(34),
91(17), 77(11), 65(10), 41(99).
4.2.3. General procedure for the asymmetric dihydroxylation
process
Sharpless asymmetricdihydroxylation process (SAD) was carried
out according to the literature.11 A stirred solution of AD-mix (1.4 g)
in t-BuOH (5 mL) and water(5 mL) was cooled to 0 °C. To the suspen-
sion, aryl allyl ether 2a–k (1 mmol) was added and then the reaction
mixture was stirred intensively at 0 °C for 20 h. Next, Na2SO3 (1.5 g)
was added and stirred at room temperature for 30 min. The t-BuOH
layer was separated and the aqueous layer was extracted with EtOAc
(3 ꢅ 30 mL). The combined organic layers were washed with brine
(20 mL), dried over MgSO4, and concentrated under reduced pres-
sure to give the product as crystals or as an oil. If needed, the crude
product was purified by column chromatography (silica gel, eluent:
hexane/EtOAc = 8:2–4:6). Yields and enantiomeric excesses of the
prepared diols scal-1a–k are shown in Table 1. The use of AD-mix-
b gave (S)-enantiomers. For analytical purposes, the diols were puri-
fied by recrystallization from hexane/EtOAc = 5:1 to give pure prod-
ucts as white crystalline materials.
4.2.1.8. 1-(Allyloxy)-4-n-hexylbenzene 2h. Yield: 68%,
n2D3 ¼ 1:5030. 1H NMR d 0.94 (t, J = 6.8 Hz, 3H, CH3), 1.31–1.40
(m, 6H, CH2(CH2)3CH3), 1.59–1.67 (m, 2H, CH2CH2CH2), 2.59 (t,
J = 7.7 Hz; 2H, CH2), 4.56 (ddd, J = 1.5, 5.3 Hz; 2H, OCH2), 5.32
(ddt, J = 1.5, 1.5, 10.5 Hz; 1H, CH2), 5.45 (ddt, J = 1.5, 1.5, 17.3 Hz;
1H, CH2), 6.11 (ddt, J = 5.3, 10.5, 17.3 Hz; 1H, CH), 6.86–6.90 (m,
2H, Ar), 7.11–7.15 (m, 2H, Ar). EI mass-spectrum [m/z (I)]:
218(18), 147(100), 133(8), 107(34), 91(18), 77(12), 55(8), 41(79).
4.2.1.9. 1-(Allyloxy)-4-n-heptylbenzene 2i. Yield: 69%, nD23
¼
1:4958. 1H NMR d 0.90 (t, J = 7.3 Hz; 3H, CH3), 1.31–1.48 (m, 8H,
CH2(CH2)4CH3), 1.55–1.63 (m, 2H, CH2CH2CH2), 2.55 (t, J = 7.7 Hz;
2H, CH2), 4.53 (ddd, J = 1.5, 5.3 Hz; 2H, OCH2), 5.28 (ddt, J = 1.5,
1.5, 10.5 Hz; 1H, CH2), 5.42 (ddt, J = 1.5, 1.5, 17.3 Hz; 1H, CH2),
6.07 (ddt, J = 5.3, 10.5, 17.3 Hz; 1H, CH), 6.84–6.86 (m, 2H, Ar),
7.05–7.12 (m, 2H, Ar). EI mass-spectrum [m/z (I)]: 232(26),
147(100), 107(32), 91(15), 77(8), 55(10), 41(74).
4.2.3.1. (S)-3-(4-Methylphenoxy)-propane-1,2-diol (S)-1a. Mp
68 °C, ½a 2D0
¼ þ9:1 (c 0.8, EtOH), 99.0% ee [chiral HPLC analysis;
ꢄ
Daicel Chiralpak AD column; column temperature 22 °C; eluent:
2-propanol/hexane = 1:4; flow rate: 1 mL/min; tR = 7.4 min (min-
or), tR = 8.4 min (major)]; [lit.8 mp 67–69 °C, ½a D20
¼ þ9:0 (c 0.8,
ꢄ
EtOH), 96% ee; lit.25 for (R)-1a: ½a D20
¼ ꢁ9:2 (c 1.0, EtOH), 97% ee].
ꢄ
1H NMR d 2.14 (t, J = 5.9 Hz, 1H, OH), 2.28 (s, 3H, CH3), 2.70 (d,
J = 4.3 Hz, 1H, OH), 3.72–3.77 (m, 1H, CH2OH), 3.81–3.86 (m, 1H,
CH2OH), 3.99–4.05 (m, 2H, CH2O), 4.06–4.09 (m, 1H, CHOH), 6.81
(m, 2H, Ar), 7.08 (m, 2H, Ar). 13C NMR d 20.4, 63.7, 69.4, 70.4,
114.5, 130.0, 130.6, 153.3.
4.2.1.10. 1-(Allyloxy)-4-n-octylbenzene 2j. Yield: 67%, nD23
¼
1:4989. 1H NMR d 0.91 (t, J = 6.9 Hz; 3H, CH3), 1.30–1.40 (m, 10H,
CH2(CH2)5CH3), 1.55–1.63 (m, 2H, CH2CH2CH2), 2.56 (t, J = 7.8 Hz;
2H, CH2), 4.54 (ddd, J = 1.5, 5.3 Hz; 2H, OCH2), 5.30 (ddt, J = 1.5,
1.5, 10.5 Hz; 1H, CH2), 5.43 (ddt, J = 1.5, 1.5, 17.3 Hz; 1H, CH2),
6.09 (ddt, J = 5.3, 10.5, 17.3 Hz; 1H, CH), 6.84–6.87 (m, 2H, Ar),
7.08–7.12 (m, 2H, Ar). EI mass-spectrum [m/z (I)]: 246(24),
147(100), 133(9), 107(29), 91(11), 77(7), 55(7), 41(65).
4.2.3.2. (S)-3-(4-Ethylphenoxy)-propane-1,2-diol (S)-1b. Mp
61–62 °C, ½a 2D0
¼ þ6:7 (c 1.2, EtOH), 99.5% ee [chiral HPLC analysis;
ꢄ
Daicel Chiralcel OD-H column; column temperature 27 °C; eluent:
2-propanol/hexane = 3:17; flow rate: 1.0 mL/min; tR = 9.0 min
(minor), tR = 11.2 min (major)]. 1H NMR d 1.22 (t, J = 7.6 Hz; 3H,
CH3), 2.29 (br s, 2H, OH), 2.61 (q, J = 7.6 Hz; 2H, CH2), 3.76 (dd,
J = 5.4, 11.4 Hz; 1H, CH2OH), 3.85 (dd, J = 3.8, 11.4 Hz; 1H, CH2OH),
4.01–4.07 (m, 2H, CH2O), 4.09–4.14 (m, 1H, CHOH), 6.83–6.90 (m,
2H, Ar), 7.10–7.17 (m, 2H, Ar). 13C NMR d 15.8, 28.0, 63.7, 69.4,
70.44, 114.5, 128.8, 137.2, 156.5. Anal. Calcd for C11H16O3: C,
67.32; H, 8.22. Found: C, 67.24; H, 8.28.
4.2.1.11. 1-(Allyloxy)-4-n-nonylbenzene 2k. Yield: 61%, nD23
¼
1:4964. 1H NMR d 0.90 (t, J = 6.8 Hz; 3H, CH3), 1.30–1.38 (m, 12H,
CH2(CH2)6CH3), 1.54–1.61 (m, 2H, CH2CH2CH2), 2.55 (t, J = 7.7 Hz;
2H, CH2), 4.53 (ddd, J = 1.5, 5.3 Hz; 2H, OCH2), 5.28 (ddt, J = 1.5,
1.5, 10.5 Hz; 1H, CH2), 5.42 (ddt, J = 1.5, 1.5, 17.3 Hz; 1H, CH2),
6.07 (ddt, J = 5.3, 10.5, 17.3 Hz; 1H, CH), 6.84–6.86 (m, 2H, Ar),
7.05–7.12 (m, 2H, Ar). EI mass-spectrum [m/z (I)]: 260(15),
147(100), 133(8), 107(29), 91(12), 77(6), 55(7), 41(65).
4.2.3.3. (S)-3-(4-Isopropylphenoxy)-propane-1,2-diol (S)-1c. Mp
57 °C, ½a 2D0
¼ þ6:7 (c 1.0, EtOH), 99.0% ee [chiral HPLC analysis;
ꢄ
4.2.2. General procedure for the synthesis of racemic 3-(4-alk-
ylphenoxy)-propane-1,2-diols 1a–k
Daicel Chiralcel OD-H column; column temperature 22 °C; eluent:
2-propanol/hexane = 1:9; flow rate: 1.0 mL/min; tR = 16.7 min
(minor), tR = 21.3 min (major)]. 1H NMR d 1.24 (d, J = 7.0 Hz; 6H,
CH3), 2.32 (br s, 2H, OH), 2.88 (septet, J = 7.0 Hz; 1H, CH), 3.76
(dd, J = 5.4, 11.4 Hz; 1H, CH2OH), 3.85 (dd, J = 3.8, 11.4 Hz; 1H,
CH2OH), 4.01–4.07 (m, 2H, CH2O), 4.09–4.14 (m, 1H, CHOH),
6.84–6.89 (m, 2H, Ar), 7.13–7.19 (m, 2H, Ar). 13C NMR d 24.2,
33.3, 63.7, 69.2, 70.4, 114.4, 127.4, 141.7, 156.5. Anal. Calcd for
Racemic diols 1a–k were synthesized in a manner similar to the
literature.24 To a stirred solution of phenol 3a–k (15 mmol) in
EtOH (9 mL) a solution of NaOH (0.72 g, 18 mmol) in water
(3 mL) was added. The resulting mixture was stirred and heated
at reflux for 2 h. After cooling to 50 °C, rac-3-chloropropane-1,2-
diol (1.95 g, 17.6 mmol) in 3 mL of EtOH was added slowly and
the reaction mixture was stirred and heated at reflux for a further
10–15 h; the termination time of the reaction was determined by
TLC analysis. After cooling, the reaction mixture was diluted with
water (70 mL) and extracted with Et2O (3 ꢅ 60 mL). The collected
organic layers were washed with 1 M NaOH (15 mL) and dried over
C12H18O3: C, 68.54; H, 8.63. Found: C, 68.43; H, 8.55.
4.2.3.4. (S)-3-(4-n-Propylphenoxy)-propane-1,2-diol (S)-1d. Mp
82 °C, ½a 2D0
ꢄ
¼ þ7:2 (c 1.0, EtOH), ½a D20
¼ þ7:3 (c 0.98, MeOH), 99.7%
ꢄ
ee [chiral HPLC analysis; Daicel Chiralcel OD-H column; column
Please cite this article in press as: Bredikhin, A. A.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.05.017

A. A. Bredikhin et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
9
temperature 27 °C; eluent: 2-propanol/hexane = 1:9; flow rate:
1.0 mL/min; tR = 15.9 min (minor), tR = 21.2 min (major)]. 1H NMR
d 0.94 (t, J = 7.5 Hz; 3H, CH3), 1.62 (sextet, J = 7.5 Hz; 2H, CH2),
1.99 (br s, 2H, OH), 2.54 (t, J = 7.5 Hz; 2H, CH2), 3.76 (dd, J = 5.4,
11.4 Hz; 1H, CH2OH), 3.85 (dd, J = 3.8, 11.4 Hz; 1H, CH2OH), 4.01–
4.07 (m, 2H, CH2O), 4.08–4.15 (m, 1H, CHOH), 6.81–6.87 (m, 2H,
Ar), 7.07–7.13 (m, 2H, Ar). 13C NMR d 13.7, 24.7, 37.1, 63.7, 69.3,
70.4, 114.4, 129.44, 135.64, 156.5. Anal. Calcd for C12H18O3: C,
68.54; H, 8.63. Found: C, 68.68; H, 8.45.
114.8, 129.8, 136.3, 156.9. Anal. Calcd for C15H24O3: C, 71.39; H,
9.59. Found: C, 71.42; H, 9.68.
4.2.3.9. (S)-3-(4-n-Heptylphenoxy)-propane-1,2-diol (S)-1i. Mp
51.5 °C, cp 85 °C, ½a D20
¼ þ6:5 (c 1.0, EtOH), 99.7% ee [chiral HPLC
ꢄ
analysis; Daicel Chiralcel OD-H column; column temperature
20 °C; eluent: 2-propanol/hexane = 1:4; flow rate: 1.0 mL/min;
tR = 7.6 min (minor), tR = 9.5 min (major)]. 1H NMR d 0.90 (t,
J = 6.9 Hz; 3H, CH3), 1.23–1.35 (m, 8H, CH2(CH2)4CH3), 1.59 (quin-
tet, J = 7.5 Hz; 2H, CH2CH2CH2), 1.85 (br s, 2H, OH), 2.56 (t,
J = 7.6 Hz; 2H, CH2), 3.77 (dd, J = 5.4, 11.4 Hz; 1H, CH2OH), 3.86
(dd, J = 3.9, 11.4 Hz; 1H, CH2OH), 4.01–4.08 (m, 2H, CH2O), 4.09–
4.15 (m, 1H, CHOH), 6.83–6.87 (m, 2H, Ar), 7.09–7.14 (m, 2H, Ar).
13C NMR d 14.1, 22.6, 29.1, 29.2, 31.7, 31.8, 35.0, 63.7, 69.4, 70.7,
114.2, 129.3, 135.9, 156.4. Anal. Calcd for C16H26O3: C, 72.14; H,
9.84. Found: C, 72.38; H, 9.90.
4.2.3.5. (S)-3-(4-tert-Butylphenoxy)-propane-1,2-diol (S)-
1e. The crude product (S)-1e was purified by column chromatog-
raphy. Mp 55 °C, ½a D20
ꢄ
¼ þ6:6 (c 1.0, EtOH), ½a D20
¼ þ6:2 (c 0.6,
ꢄ
MeOH), 91.0% ee. [For reliable ee determination the crude diol
was transformed into a diastereomeric mixture of cyclic sulfites
via reaction between scal-1e (1 equiv) and SOCl2 (1.5 equiv) in
CH2Cl2 at 0 °C. Chiral HPLC analysis of the reaction mixture: Daicel
Chiralcel OJ column; column temperature 22 °C; eluent 2-propa-
nol/hexane = 3:7, flow rate 1.0 mL/min; tR = 10.9 min (major),
tR = 17.4 min (major), tR = 27.7 min (minor), tR = 46.5 min (minor).]
4.2.3.10. (S)-3-(4-n-Octylphenoxy)-propane-1,2-diol (S)-1j. Mp
60 °C, cp 89 °C, ½a D20
¼ þ5:8 (c 1.0, EtOH), ee 99.7% [chiral HPLC
ꢄ
analysis; Daicel Chiralcel OD-H column; column temperature
20 °C; eluent: 2-propanol/hexane = 1:9; flow rate: 1.0 mL/min;
tR = 10.9 min (minor), tR = 14.8 min (major)]. 1H NMR d 0.91 (t,
J = 6.7 Hz; 3H, CH3), 1.24–1.38 (m, 10H, CH2(CH2)5CH3), 1.60 (quin-
tet, J = 7.5 Hz; 2H, CH2CH2CH2), 1.95 (br s, 2H, OH), 2.57 (t,
J = 7.6 Hz; 2H, CH2), 3.77 (dd, J = 5.4, 11.4 Hz; 1H, CH2OH), 3.86
(dd, J = 3.8, 11.4 Hz; 1H, CH2OH), 4.02–4.09 (m, 2H, CH2O), 4.09–
4.16 (m, 1H, CHOH), 6.83–6.88 (m, 2H, Ar), 7.09–7.15 (m, 2H, Ar).
13C NMR d 14.5, 23.0, 29.7, 29.9, 32.1, 32.3, 35.5, 64.2, 69.8, 70.8,
114.8, 129.8, 136.3, 156.9. Anal. Calcd for C17H28O3: C, 72.82; H,
10.06. Found: C, 72.71; H, 10.11.
{Lit.25
½
a 2D0
ꢄ
¼ þ7:5 (c 1.0, EtOH), >99% ee}. 1H NMR d 1.32 (s, 9H,
CH3), 2.18 (br s, 2H, OH), 3.76 (dd, J = 5.3, 11.4 Hz; 1H, CH2OH),
3.85 (dd, J = 3.7, 11.4 Hz; 1H, CH2OH), 4.02–4.08 (m, 2H, CH2O),
4.09–4.14 (m, 1H, CHOH), 6.85–6.89 (m, 2H, Ar), 7.30–7.34 (m,
2H, Ar). 13C NMR d 31.5, 34.1, 63.7, 69.3, 70.4, 114.1, 126.34,
144.1, 156.1. Anal. Calcd for C13H20O3: C, 69.61; H, 8.99. Found:
C, 69.43; H, 9.03.
4.2.3.6. (S)-3-(4-n-Butylphenoxy)-propane-1,2-diol (S)-1f. Mp
70 °C, cp 75 °C, ½a D20
¼ þ6:6 (c 1.0, EtOH), 99.9% ee [chiral HPLC
ꢄ
analysis; Daicel Chiralcel OD-H column; column temperature
27 °C; eluent: 2-propanol/hexane = 1:9; flow rate: 1.0 mL/min;
tR = 15.9 min (minor), tR = 19.3 min (major)]. 1H NMR d 0.93 (t,
J = 7.3 Hz; 3H, CH3), 1.35 (sextet, J = 7.3 Hz, 2H, CH2CH3), 1.53–
1.62 (m, 2H, CH2CH2CH2), 2.07 (br s, 2H, OH), 2.57 (t, J = 7.6 Hz;
2H, CH2), 3.76 (dd, J = 5.4, 11.4 Hz; 1H, CH2OH), 3.85 (dd, J = 3.8,
11.4 Hz; 1H, CH2OH), 4.01–4.08 (m, 2H, CH2O), 4.08–4.14 (m, 1H,
CHOH), 6.83–6.86 (m, 2H, Ar), 7.09–7.13 (m, 2H, Ar). 13C NMR d
13.9, 22.3, 33.8, 34.7, 63.7, 69.4, 70.4, 114.2, 129.4, 135.8, 156.4.
Anal. Calcd for C13H20O3: C, 69.61; H, 8.99. Found: C, 69.45; H, 8.96.
4.2.3.11.
(S)-3-(4-n-Nonylphenoxy)-propane-1,2-diol
(S)-
1k. Mp 112 °C, ½a 2D0
ꢄ
¼ þ5:3 (c 0.5, MeOH), 99.2% ee [chiral HPLC
analysis; Daicel Chiralcel OD-H column; column temperature
22 °C; eluent: 2-propanol/hexane = 1:4; flow rate: 1.0 mL/min;
tR = 5.8 min (minor), tR = 6.9 min (major)]. 1H NMR d 0.90 (t,
J = 6.9 Hz; 3H, CH3), 1.22–1.36 (m, 12H, CH2(CH2)6CH3), 1.59 (quin-
tet, J = 7.5 Hz; 2H, CH2CH2CH2), 2.03 (br s, 2H, OH), 2.56 (t,
J = 7.6 Hz; 2H, CH2), 3.77 (dd, J = 5.4, 11.4 Hz; 1H, CH2OH), 3.85
(dd, J = 3.9, 11.4 Hz; 1H, CH2OH), 4.01–4.08 (m, 2H, CH2O), 4.09–
4.14 (m, 1H, CHOH), 6.82–6.88 (m, 2H, Ar), 7.08–7.14 (m, 2H, Ar).
13C NMR d 14.1, 22.6, 29.2, 29.3, 29.5, 29.6, 31.7, 31.9, 35.0, 63.7,
69.4, 70.4, 114.4, 129.3, 135.9, 156.4. Anal. Calcd for C18H30O3: C,
73.43; H, 10.27. Found: C, 73.24; H, 10.38.
4.2.3.7. (S)-3-(4-n-Pentylphenoxy)-propane-1,2-diol (S)-1g. Mp
52 °C, cp 78 °C, ½a D20
¼ þ7:6 (c 1.0, EtOH), 99.6% ee [chiral HPLC
ꢄ
analysis; Daicel Chiralcel OD-H column; column temperature
20 °C; eluent: 2-propanol/hexane = 1:9; flow rate: 1.0 mL/min;
tR = 13.2 min (minor), tR = 18.9 min (major)]. 1H NMR d 0.91 (t,
J = 6.9 Hz; 3H, CH3), 1.27–1.39 (m, 4H, CH2(CH2)2CH3), 1.55–1.63
(quintet, J = 7.5 Hz; 2H, CH2CH2CH2), 2.22 (br s, 2H, OH), 2.56 (t,
J = 7.6 Hz; 2H, CH2), 3.76 (dd, J = 5.4, 11.4 Hz; 1H, CH2OH), 3.85
(dd, J = 3.8, 11.4 Hz; 1H, CH2OH), 4.01–4.08 (m, 2H, CH2O), 4.08–
4.14 (m, 1H, CHOH), 6.83–6.87 (m, 2H, Ar), 7.09–7.13 (m, 2H, Ar).
13C NMR d 14.0, 22.5, 31.3, 31.4, 35.0, 63.7, 69.4, 70.4, 114.2,
129.4, 135.9, 156.4. Anal. Calcd for C14H22O3: C, 70.56; H, 9.30.
Found: C, 70.44; H, 9.21.
4.3. Determination of the solubility
The solubility of compounds 1c, d, and f was determined by
chromatographic measurements of the concentration of the satu-
rated solution of these compounds in analytical grade cyclohexane.
Racemic and enantiopure samples (approximately 10 mg), as well
as their mixture in a 1:1 ratio were placed in glass vials (5 mL) fit-
ted with a stirrer bar after which the solvent (4 mL) was added. The
vessel was sealed with a ground-glass stopper; the contents were
continuously stirred overnight at 20 1 °C. The vessel was allowed
to stand for 2–3 h without stirring for sedimentation of excessive
solid phase, and then the liquid phase was sampled with a syringe.
The solution was forced over a Teflon filter (MillexÒ-LH) with a
4.2.3.8. (S)-3-(4-n-Hexylphenoxy)-propane-1,2-diol (S)-1h. Mp
48 °C, cp 85 °C ½a 2D0
¼ þ6:4 (c 1.0, EtOH), 99.1% ee [chiral HPLC
ꢄ
analysis; Daicel Chiralcel OD-H column; column temperature
20 °C; eluent: 2-propanol/hexane = 1:9; flow rate: 1.0 mL/min;
tR = 12.2 min (minor), tR = 17.5 min (major)]. 1H NMR d 0.91 (t,
J = 6.8 Hz; 3H, CH3), 1.28–1.40 (m, 6H, CH2(CH2)3CH3), 1.60 (quin-
tet, J = 7.5 Hz; 2H, CH2CH2CH2), 2.52 (s, 2H, OH), 2.57 (t,
J = 7.6 Hz; 2H, CH2), 3.77 (dd, J = 5.5, 11.4 Hz; 1H, CH2OH), 3.85
(dd, J = 3.7, 11.4 Hz; 1H, CH2OH), 4.01–4.08 (m, 2H, CH2O), 4.09–
4.15 (m, 1H, CHOH), 6.83–6.88 (m, 2H, Ar), 7.09–7.14 (m, 2H, Ar).
13C NMR d 14.5, 23.0, 29.4, 32.1, 32.2, 35.5, 64.2, 69.8, 70.9,
pore diameter of 0.45 lm from one syringe to another. The condi-
tions of the chromatographic measurements were identical to
those described in Sections 4.1 and 4.2. The areas of the chromato-
graphic peaks were used directly as a numerical characteristic of
the equilibrium content of each of the stereoisomers in the liquid
phase. For each system, there were at least two independent exper-
iments; the chromatographic determination of the concentration
within each run was repeated 2–3 times. The results for each sys-
Please cite this article in press as: Bredikhin, A. A.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.05.017

10
A. A. Bredikhin et al. / Tetrahedron: Asymmetry xxx (2013) xxx–xxx
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tem were combined and subjected to standard statistical analysis
to assess the confidence interval of the parameters (n = 5–6,
a
= 0.95).
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was dissolved. The resulting solution was cooled in air to room
temperature, and then left for 30 min at this temperature. The state
of the materials was evaluated by the ‘stable-to-inversion of a vial’
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Please cite this article in press as: Bredikhin, A. A.; et al. Tetrahedron: Asymmetry (2013), http://dx.doi.org/10.1016/j.tetasy.2013.05.017