Absolute configuration and crystal packing chirality for three conglomerate-forming ortho-halogen substituted phenyl glycerol ethers

Article abstract of DOI:10.1016/j.molstruc.2010.04.045

Three conglomerate-forming ortho-Hal (Hal = Cl, Br, I) substituted phenyl glycerol ethers 1-3 were investigated by single-crystal X-ray analysis, and the absolute configuration for all substances was established. The molecular structures and crystal packi

Full text of DOI:10.1016/j.molstruc.2010.04.045

Journal of Molecular Structure 975 (2010) 323–329
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Absolute configuration and crystal packing chirality for three conglomerate-forming
ortho-halogen substituted phenyl glycerol ethers
*
Alexander A. Bredikhin , Aidar T. Gubaidullin, Zemfira A. Bredikhina
A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, 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:
Three conglomerate-forming ortho-Hal (Hal = Cl, Br, I) substituted phenyl glycerol ethers 1–3 were inves-
tigated by single-crystal X-ray analysis, and the absolute configuration for all substances was established.
The molecular structures and crystal packing details for halogen derivatives were compared with the
same characteristics for ortho-OCH3 and ortho-CH3 analogues. Two different types of crystal packing were
evaluated for these very much alike compounds. The interplay of the supramolecular crystal organization
chirality sense and the single molecule absolute configuration was demonstrated. Some stabilizing and
destabilizing interactions involving the ortho-substituents were revealed. The resolution of rac-2 by
entrainment procedure was successfully realized.
Received 4 March 2010
Received in revised form 28 April 2010
Accepted 29 April 2010
Available online 6 May 2010
Keywords:
Spontaneous resolution
Conglomerates
Molecular structure
Crystal packing
Ó 2010 Elsevier B.V. All rights reserved.
Supramolecular pattern chirality
Chirality transfer
1. Introduction
ortho-halogen substituted phenyl glycerol ethers, 3-(2-R-phen-
oxy)-propane-1,2-diols 1 (R = Cl), 2 (R = Br), and 3 (R = I).
The chirality phenomenon, origin and transformation of chiral
matter, and homochiral imperative of molecular evolution are
evergreen and multifold features in natural science [1]. Among
all others related problems spontaneous resolution of chiral sub-
stances [2] is of special interest in so far as it has close relation
to the origin of life [3] and to modern problem of economically
effective nonracemic compounds production [4]. Spontaneous res-
olution is intimately associated with the racemic conglomerate for-
mation. Supplementary interest to the conglomerate-forming
substances has its origin in a recently discovered by Dutch investi-
gators method in which grinding-induced attrition is used to trans-
form racemic conglomerates virtually quantitatively into a single
enantiomer [5].
In spite of the topic popularity, for nowadays the nature of
spontaneous resolution, the reasons why a chiral organic substance
falls on this or that side of the borderline dividing racemic com-
pound from racemic conglomerates remain very obscure [2]. One
way to gain a better understanding of the phenomenon consist of
systematic investigation of the crystal structure of conglomerate-
forming substances and their comparison with similar systems.
In this connection in the present paper we want to establish the
crystal structure as well as the absolute configuration for three
OH
O
R
OH
R = Cl (1); Br (2); I (3); OCH3 (4); CH3 (5).
For all this compounds the ability to spontaneous resolution
was established earlier by spectroscopy [6] and thermal analysis
[7]. We want to demonstrate how the chirality sense of the pri-
mary elements (absolute configuration of the molecules) has an
influence on the supramolecular solid state pattern chirality as a
whole. We shall correlate crystal organization characteristics for
compounds 1–3 with the like ones for chemically similar chiral
drugs guaifenesin 4 and mephenesin 5. Both latter compounds
prone to spontaneous resolution as it was established earlier [8].
The last purpose of our paper arises from the fact that nonracemic
ortho-halogen substituted phenyl glycerol ethers could be used as
the precursors for single enantiomer highly biologically potent
benzodioxanes [9]. In the original paper the single enantiomers
of phenyl glycerol ethers were synthesized from the enantiopure
precursors. However, for the conglomerate-forming substances
the possibility exists to apply a very effective direct racemate res-
olution approach [4]. It will be tested with rac-2.
* Corresponding author. Tel.: +7 843 273 45 73; fax: +7 843 273 18 72.
E-mail address: baa@iopc.ru (A.A. Bredikhin).
0022-2860/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2010.04.045

324
A.A. Bredikhin et al. / Journal of Molecular Structure 975 (2010) 323–329
four-circle diffractometer at 294 K (graphite monochromator,
Cu K (1.54184 Å) for (1, 2) and Mo K radiation (0.71069 Å) for
(3), /2h scan method. The crystal data, data collection, and the
2. Experimental
2.1. General
a
x
a
refinement details are given in Table 1. The stability of the crystals
and experimental conditions was checked every 2 h using three
control reflections, while the orientation was monitored every
200 reflections by centering two standards. No significant decay
was observed. Corrections for Lorentz and polarization effects
and absorption correction were applied. The structure was solved
by direct method using SIR [10] program and refined by the full
matrix least-squares using SHELXL [11] programs. All non-hydro-
gen atoms were refined anisotropically. The hydrogen atoms were
inserted at calculated positions and refined as riding atoms except
the hydrogen atoms on hydroxyl groups which were located from
difference maps and refined using a riding model. The absolute
structure of the single crystals was determined on the basis of
the Flack [12] parameter. All calculations were performed on PC
using WinGX [13] suit of programs. Data collection and data reduc-
tion were performed on Alpha Station 200 computer using MoLEN
[14] program. Analysis of the intermolecular interactions was per-
formed using the program PLATON [15].
Optical rotations were measured on a Perkin–Elmer model 341
polarimeter (everywhere over the paper the value of specific rota-
tion is given in deg ml gꢀ1 dmꢀ1, and the concentration of solu-
tions, c, appears in g/100 ml). Melting points for general purposes
were determined using a Boëtius apparatus and are uncorrected.
2.2. Materials
The syntheses of the compounds 1–3 in racemic and enantio-
pure form are described in our preceding paper [7]. For all com-
pounds single-crystal X-ray diffraction experiments have been
performed at first with enantiopure samples in attempt to estab-
lish the absolute configuration for these compounds. The sample
of (S)-1, 99.8% ee, was crystallized from CH2Cl2 and was character-
ized by mp 90–91 °C, ½a D20
¼ ꢀ14:0 (c 1.0, hexane/EtOH 4:1). The
ꢁ
sample of (R)-2, 99.5% ee, was crystallized from CH2Cl2 and was
characterized by mp 101–102 °C, ½a D20
¼ þ13:8 (c 1.0, hexane/EtOH
ꢁ
4:1). The sample of (S)-3, 99.9% ee, was crystallized from CH2Cl2
and was characterized by mp 110–112 °C, ½a D20
¼ ꢀ16:3 (c 1.0, hex-
ꢁ
3. Discussion
ane/EtOH 4:1). Crystal information listed in Table 1 belongs to
these samples. Other set of X-ray diffraction experiments have
been performed with individual crystals picked up from the bulk
racemate samples of the compounds 1–3, mp 70–72 °C, 80–82 °C,
and 90–92 °C, respectively. For all three substances the space
groups and the unit cell parameters for accidentally hand-picked
single crystals were identical (within the limits of experimental er-
ror) with those for enantiopure samples.
3.1. Crystal structure
It comes as no surprise that three compounds having very close
chemical structure have very close crystal structures too. As the
data of Table 1 suggest, all the nonracemic compounds 1–3 crystal-
lize in the same P212121 space group, Z0 = 1, having close parame-
ters of crystal unit cell. A small and systematic b and c axes
elongations in going from 1 to 3 are completely consistent with
the Van der Waals radii increase for the halogen atoms. For all
three compounds studied racemic samples crystallize in the same
noncentrosymmetric space group P212121 having almost identical
parameters of crystal unit cell as for the enantiopure ones. This fact
2.3. X-ray crystal structure analysis
The X-ray diffraction data for the crystals of 1–3 (see Sec-
tion 2.2) were collected on a Enraf–Nonius CAD-4 automatic
Table 1
Crystallographic data for (S)-ortho-Cl (1), (R)-ortho-Br (2), and (S)-ortho-I (3) substituted phenyl glycerol ethers.
Compound formula
(1) C9H11ClO3
(2) C9 H11BrO3
(3) C9H11IO3
M (g/mol)
202.63
247.09
294.08
Temperature, K
Crystal class
Space group
Crystal size
Z
294(2)
Orthorhombic
Orthorhombic
Orthorhombic
P212121
P212121
P212121
0.24 ꢂ 0.20 ꢂ 0.15 mm3
0.42 ꢂ 0.35 ꢂ 0.18 mm3
0.32 ꢂ 0.24 ꢂ 0.16 mm3
4
4
4
Radiation type
Cell parameters
Cu K
a = 4.900(4),
a
, 1.54184
Mo Ka, 0.71069
a = 4.873(3),
a = 4.853(6),
b = 7.5860(10),
b = 7.669(6),
b = 7.838(6),
0
0
0
c = 25.89(2) ÅA
962.4(11)
c = 26.510(18) ÅA
991(1)
c = 27.210(17) ÅA
1035(1)
0
V, ÅA3
F(0 0 0)
424
1.399
33.12
496
1.657
54.62
568
1.887
30.68
q
l
calc, g/cm3
, cmꢀ1
Extinction coefficient
h, deg
Reflections measured
Independent reflections
[R(int) = 0.1767]
0.023(8)
9.68 6 h 6 74.34
897
896
1101
0.029(1)
6.68 6 h 6 74.07
1101
0.006(2)
2.70 6 h 6 24.65
2570
[R(int) = 0.0000]
1342
[R(int) = 0.1464]
Number of parameters/restraints
119/0
119/1
107/0
Reflections [I > 2
r(I)]
794
663
832
Flack parameter
0.00(4)
0.06(4)
0.03(9)
R1/wR2 [I > 2
r
(I)]
0.0482/0.1255
0.0590/0.1324
1.068
0.243/ꢀ0.221
0.0252/0.0499
0.0449/0.0551
0.947
0.110/ꢀ0.096
0.0521/0.1126
0.1012/0.1468
0.732
0.622/ꢀ0.956
R1/wR2 (all reflections)
Goodness-of-fit on F2
0
qmax
/
qmin (e ÅAꢀ3
)

A.A. Bredikhin et al. / Journal of Molecular Structure 975 (2010) 323–329
325
molecules 1–3 have almost planar shapes of all except terminal
(H2)C1O1H1 fragments.
C9
C4
C3
C1
H2
H1
Supramolecular pattern of crystal organization for compounds
1–3 has much in common. Let us use chlorosubstituted compound
(S)-1 to illustrate the type of intermolecular hydrogen bonds sys-
tem in the crystal. The well pronounced motif for the (S)-1 crystal
lattice involves the 1D columns formed by H-bonded molecules
along the 21 axes (0b) (Fig. 1, grey zones).
C5
R
O3
C2
O1
21H O2
Scheme 1. Partial numbering accepted for molecules 1–5.
is consistent with our earlier conclusion concerning the conglom-
erate nature of racemic 1–3 [6,7].
For every specific column on the Fig. 1 each upper right and
lower left molecules present for the intermolecular hydrogen bond
columnar system their terminal primary hydroxyls, whereas lower
right and upper left molecules present for the same purpose their
secondary hydroxyls. The hydroxyl groups taking no part in this
namely H-bond column take part in the neighbouring ones, where
former ‘‘right” molecules became ‘‘left” ones and vice versa. As a re-
sult of simultaneous participation of every molecule in the two dif-
ferent 1D column formation the 2D ‘‘palisade-like” supramolecular
bilayer pattern of H-bonded molecules arranged parallel to crystal-
lographic plane 0ab arises. All the registered details are typical of
hydrogen bonds organization in guaifenesin crystals as well.
The important feature of the ascertained hydrogen bond system
lies in its chirality: the succession ‘‘closest donor – closest accep-
tor” (ꢃ ꢃ ꢃO1–H1ꢃ ꢃ ꢃO20–H210ꢃ ꢃ ꢃO100–H100ꢃ ꢃ ꢃ) organized along 0b axis
in the crystals of (S)-1 and (S)-3 gives rise to right-handed P-helix.
This phenomenon could be seen in the Fig. 1 for (S)-1; for the best
examination the same 1D column enlarged image is given in the
As it follows from Table 1, the Flack parameter for the samples
with negative sign of optical rotation in hexane/EtOH 4:1 is well
consistent with S-configuration of the C2 carbon atom (the situa-
tion of chloride 1 and iodide 3). On the same basic the positive sign
of optical rotation in the identical mixed solvent corresponds to R-
enantiomer (the case of bromide 2).
All the molecules in the 1–3 crystals have no unusual geometric
parameters and adopt very similar conformations. This conforma-
tion could be described by enumeration of torsion angles formed
by non-hydrogen atoms of the common structure fragment
C5C4O3C3C2C1O1 (see Scheme 1 for the accepted numbering).
The torsions for compounds 1–3 found in this work are listed in Ta-
ble 2 alongside with the same values earlier obtained for guaifen-
esin 4 and mephenesin 5 [8]. For the purpose of comparison all the
torsions are listed for R-enantiomers (the real torsions for S-enan-
tiomers have opposite signs). As it follows from the Table 2 the
Table 2
The principal torsion angles (see Scheme 1 for the numbering) for (R)-enantiomers of the compounds 1–3 (this work) and 4–5 (Ref. [8]).
Torsions
Compounds
1
2
3
4
5, Molecule B
5, Molecule A
C5C4O3C3
C4O3C3C2
O3C3C2C1
C3C2C1O1
O3C3C2O2
RC5C4O3
178.9(3)
175.5(3)
53.3(3)
52.0(3)
176.9(2)
0.3(4)
179.9(3)
174.9(3)
51.8(4)
52.9(4)
177.0(3)
1.6(5)
177.2(12)
175.1(10)
55.4(13)
55.0(13)
178.8(9)
3.4(17)
174.9(1)
177.7(1)
54.1(1)
51.2(1)
177.23(9)
–
ꢀ177.9(2)
ꢀ175.1(1)
65.3(2)
ꢀ179.8(2)
ꢀ175.1(2)
ꢀ59.6(2)
ꢀ60.5(2)
64.1(2)
60.6(2)
ꢀ172.6(1)
3.7(3)
0.5(3)
Fig. 1. 1D H-bonded columns (grey zones) jointed into 2D ‘‘palisade-like” supramolecular bilayer pattern in the (S)-1 crystals, intermolecular hydrogen bonds denoted by
dashed lines.

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A.A. Bredikhin et al. / Journal of Molecular Structure 975 (2010) 323–329
Fig. 2. 1D H-bonded columns (grey zone): (a) P-helix in the compound (S)-3 crystals, (b) M-helix in the compound (R)-2 crystals; intermolecular hydrogen bonds are denoted
by dashed lines.
Fig. 2a for (S)-3. Having an opposite as compared to (S)-1 and (S)-3
configuration, molecules in the (R)-2 crystalline sample adopt not
an equal but mirror conformation. This in turn causes that the
whole hydrogen bond pattern for (R)-2 is mirror image of the other
two. The same succession ‘‘closest donor–closest acceptor” in this
case forms left-handed M-helix (grey zone in the Fig. 2b). Thus,
in the case of conglomerate-forming ortho-halogen substituted
phenyl glycerol ethers we have an expressive example of chirality
transfer from the lowest level of single molecule to the level of
supramolecular organization of the crystal as a whole.
The supramolecular organization of the halogen derivatives 1–3
closely matched the one of guaifenesin 4; among other things the
M-helix character of the H-bonded columns was also recognized
for (R)-4 [8]. At the same time, for the very close to o-Hal substi-
tuted phenyl glycerol ethers o-Me derivative (mephenesin, 5),
retaining the conglomerate-forming nature, quite a different crys-
tal lattice is observed. Mephenesin crystallizes in P21 space group
with two symmetry independent molecules A and B having differ-
ent conformations (Table 2, Fig. 3) in the unit cell [8]. The main
supramolecular motifs for crystals 5 are 1D columns aligned
around 21 screw axes parallel with 0b axis (Fig. 3, grey zones).
The central part of this column is formed by developed system of
intermolecular hydrogen bonds and is hydrophilic in nature. The
columns are linked with one another only through hydrophobic
and/or dispersion interactions of the vast periphery formed mainly
by o-tolyl fragments (Fig. 3).
of four molecules in the case of guaifenesin 4 and its halogen ana-
logues 1–3, and the R-molecules packing gives rise to right-handed
P-helix, whereas R-molecules of the compounds 2 and 4 form left-
handed H-bond M-helixes in their crystals.
Thus, for the conglomerate-forming aryl glycerol ethers the
crystal lattice types are divisible into two groups which could be
called as guaifenesin-like and mephenesin-like. The last one con-
tains two symmetry independent molecules (Z0 = 2) in the unit cell.
The reasons and consequences of the presence of multiple mole-
cules in the crystal asymmetric unit were hotly debated [16].
High-Z0 structures have been described as ‘‘snapshot pictures”
and also as ‘‘fossil relics” of early stages in crystallization. Such a
structures could be treated as inferior to the closely related Z0 = 1
ones for a number of reasons. Analyzing the factors that may lead
to the appearance of structures with Z0 > 1, Steed points on the
occurrence of a small number of strongly intermolecularly inter-
acting functionalities, especially if unevenly distributed over the
molecular surface and on the frustration between the require-
ments of close packing and satisfaction of intermolecular interac-
tions of strongly interacting functionalities [16b].
Because of no fragment other than ortho-substituent distin-
guishes one compound from another in the 1–5 series, we have fo-
cused our attention on the intermolecular interactions involving
these substituents. Let us analyze from this point of view the crys-
tal structure of the chlorine derivative 1. We have used the Mer-
cury program package [17] for short contacts search and
identification. No short contacts involving chlorine atom have been
revealed when the constrain of shorter or equal of the sum of Van
der Waals radii (subsequently referred to as SVDWR) distance be-
tween contacting atoms has been used. Under the constrain of
SVDWR + 0.1 Å the first contact comes to light between Cl atom
and H2 secondary alcohol group methyne atom of neighbouring
molecule (ꢀ1 + x, y, z), belonging to the same ‘‘palisade-like” supra-
molecular bilayer pattern (see above). In Fig. 5 these contacts are
denoted by blue dashed lines and are visualized by spacefill style
in the bottom part. If the constrain of SVDWR + 0.2 Å was used, an-
other type of C–Hꢃ ꢃ ꢃCl short contacts emerge, namely between
para-Car–H atoms H7 of a certain bilayer and Cl atoms of the neigh-
bouring one (ꢀ1/2 + x, 3/2 ꢀ y, 1 ꢀ z). In Fig. 5 these contacts are
denoted by red dashed lines and are visualized by spacefill style
in the middle. Only when constrain SVDWR + 0.3 Å was applied
the short contacts between chlorine atoms (ꢀ1/2 + x, 2 ꢀ y, 1 ꢀ z)
and (1/2 + x, 2 ꢀ y, 1 ꢀ z) belonging to neighbouring bilayers ap-
pear; in Fig. 5 these contacts are denoted by green dashed lines
and are visualized by spacefill style in the upper part. It is well
Both A (red1 in the Fig. 3) and B independent molecules take part
in the intermolecular hydrogen bonding. Within the marked frag-
ment in the Fig. 3 upper and lower stacks are formed by A molecules
(let us denote them using low indices up and lw), while the left and
right stacks are formed by B molecules (denoted by l and r indices by
analogy). Concerning the intermolecular hydrogen bond pattern, the
succession ‘‘closest donor – closest acceptor” is more intricate in the
case of mephenesin than in the cases of the above analyzed com-
pounds 1–4. Fig. 4 (enlarged marked zone of Fig. 3) illustrates this
pattern in more details.
It is obvious from the Fig. 4 that the sequence O1Aup
—
H1Aup ꢃ ꢃ ꢃ O2Br—H21Br ꢃ ꢃ ꢃ O1B0 —H1B0 ꢃ ꢃ ꢃ O2A0lw—H21Al0w ꢃ ꢃ ꢃ O1Alw
—
—
r
r
H1Alw ꢃ ꢃ ꢃ O1Bl ꢀ H1Bl ꢃ ꢃ ꢃ O2B0—H21B0 ꢃ ꢃ ꢃ O2A0u0p—H21A00 ꢃ ꢃ ꢃ O1A0up
l
l
up
H1A0up ꢃ ꢃ ꢃ constitutes full P-helix pitch. Note, that in the case of
mephenesin eight molecules fall inside of one helix pitch instead
1
For interpretation of color in Figs. 1–6, the reader is referred to the web version of
this article.

A.A. Bredikhin et al. / Journal of Molecular Structure 975 (2010) 323–329
327
Fig. 3. 1D H-Bonded column (marked by bold style) surrounded by the same ones in the crystal of compound 5 (viewed along the 0b axis, A molecules denoted by red colour).
Fig. 4. The detailed view of the intermolecular hydrogen bond pattern in the (R)-5 crystal. Some of the hydrogen atoms taking no part in the hydrogen bonds are omitted for
clarity.
known that (moderately) short contacts of the C–Hꢃ ꢃ ꢃHal type are
stabilizing in nature and could be treated as the non-classical
hydrogen bonds [18]. Almost the same statement can also be made
about the halogenꢃ ꢃ ꢃhalogen interactions [19]. So, all the revealed
chlorine noncovalent contacts stabilize the compound 1 crystal
lattice.
The same is true for all other variable substituents (Br and I
atoms and oxygen atom of OCH3 group) in the guaifenesin-like
crystal lattice forming compounds 2–4. But the situation changes
if the CH3 group replaces for example chlorine atom within the
same, i.e. the compound 1, crystal lattice. To obtain this hypothetic
structure the Cl atom has been replaced by carbon atom of CH3

328
A.A. Bredikhin et al. / Journal of Molecular Structure 975 (2010) 323–329
Fig. 5. The main short contacts involving chlorine atom in the compound 1 crystal. See text for details.
group in the files for o-Cl substituted compound on the last stages
of refinement. The distance C–C(H3) was constrained to standard
value, the hydrogen atoms were inserted at calculated positions
of CH3 group and were refined using a riding model. Then the
structure was refined (10 cycles) and the cif-file of the hypothetic
‘‘guaifenesin-like mephenesin” was generated.
67.6%, and 66.7%. Hence, further displacements of the molecules
within the bilayer or of the bilayers themselves in attempt to relax
CH3 group contacts would result in complete destruction of the
crystal. In our opinion, therein lies the answer to the mephene-
sin-like lattice arising.
Two from the three above analyzed for Cl atom contacts are re-
tained for CH3 group in this hypothetic structure. These are
CH3ꢃ ꢃ ꢃH3C (ꢀ1/2 + x, 3/2 ꢀ y, ꢀz) and (1/2 + x, 3/2 ꢀ y, ꢀz) and
HOC–Hꢃ ꢃ ꢃH3C (1 + x, y, z) short contacts; both types are illustrated
in Fig. 6. Two substantial reasons must be taken into account dur-
ing the analysis of these contacts consequences. Firstly, both H
atom and CH3 group have much in common, they bear rather posi-
tive than negative charge, they are rather electrophilic than nucle-
ophilic. Secondly, the distances between two carbon atoms for the
CH3ꢃ ꢃ ꢃH3C contact (3.77 Å) and between H and C atoms for the
HOC–Hꢃ ꢃ ꢃH3C contact (2.99 Å) are sufficiently smaller than SVDWR
(4.0 Å and 3.2 Å correspondingly). Hence, the interactions in ques-
tion are strongly destabilizing in nature. The packing indices for
the real prototype structures 1–3 are already as low as 67.7%,
3.2. Resolution of 3-(2-bromophenoxy-)propane-1,2-diol, rac-2, by
entrainment procedure
Racemates resolution by entrainment [4] is a gratifying labor
since success allows one to obtain easily both enantiomers without
resorting to any enantiopure auxiliaries. But even in the case of
conglomerate-forming substances it is not always easy to use the
benefits of a spontaneous resolution. Coquerel and coworkers
[4,20] are of the opinion that almost half of conglomerate-forming
compounds would demonstrate poor entrainment characteristics.
Discovering new conglomerates in the family of aryl glycerol
ethers we decided to examine their abilities for preferential resolu-
tion. This task was all the more interesting since scal-3-(2-halogen-
phenoxy)-propane-1,2-diols, as it was mentioned in the
Fig. 6. The main short contacts involving CH3 groups of mephenesin molecules in the guaifenesin-like crystal lattice. See text for details.

A.A. Bredikhin et al. / Journal of Molecular Structure 975 (2010) 323–329
329
introduction section, were already used for the very potent bioac-
tive substances preparation. Thus R-2 was smoothly converted to
R-2-hydroxymethylbenzo-1,4-dioxane R-6 with good yield and
high enantiomeric excess [9]:
like, for these conglomerate-forming compounds were identified.
Supramolecular 1D motifs, H-bonded columns for both types, go
back to homochiral spirals, but the links between the absolute con-
figuration of the molecules and the chirality sense of their crystal
forming supramolecular ensembles are opposite. Whereas for guai-
fenesin-like lattice (R)-molecules give rise to left-handed helix, for
mephenesin-like lattice (R)-molecules give rise to right-handed he-
lix. Some proposals were made about the nature of intermolecular
interactions stabilizing and/or destabilizing of one or other type of
crystal packing.
OH
3 mol% Pd(OAc)2, 2.5 mol% L,
1.5 equiv K3PO4 in toluene
O
OH
O
OH
Br
O
(R)-2
(R
)-6; 72%, 99 ee
P(t-Bu)2
L =
5. Supplementary materials
Crystallographic data (excluding structure factors) for the struc-
tures reported in this paper have been deposited in the Cambridge
Crystallographic Data Centre as supplementary publication Nos.
CCDC 767,905 for 1, 767,907 for 2, and 767,906 for 3. Copies of
the data can be obtained free of charge upon application to the
CCDC (12 Union Road, Cambridge CB2 1EZ UK. Fax: (internat.)
+44 1223/336 033; E-mail: deposit @ccdc.cam.ac.uk).
In the original paper the compound R-2 was synthesized from
the enantiopure precursor. Using the racemic sample of the com-
pound 2 as an example we have examined entrainment effect for
this class of compounds.
Over the course of the resolution a supersaturated solution of
diol rac-2 (3.65 g), including a moderate excess of (R)-2 (0.55 g),
was prepared by heating the mixture in 40 ml of EtOH/H2O (4:6,
v/v) at 40 °C. The solution was cooled to 20 °C and a small amount
(15 mg) of finely pulverized seed crystals of (R)-2 was added. The
stirred solution was allowed to crystallize for about 75 min at
17 1 °C. For monitoring the entrainment process during seed-in-
duced crystallization of oversaturated slightly nonracemic solu-
tions we have used optical rotation of mother liquor aliquots
controlled by polarimetry. Precipitated (R)-2 was collected by fil-
tration. The weight of (R)-2 obtained after filtration (0.96 g after
drying; 91% ee) was more than the common weight of the initial
excess of the (R)-enantiomer and seed added. The extra portion
of rac-2 (0.95 g) was then dissolved in the mother liquor at 40 °C
in order that the overall quantity of 2 in the solution could be
recovered. The mixture was heated until the solid was completely
dissolved and then cooled to 20 °C. After the addition of (S)-2
(15 mg) as seed crystals to the solution, and stirring the mixture
for 80 min at 17 1 °C, (S)-2 (0.78 g after drying; 80% ee) was col-
lected by filtration. Further resolution was carried out at 17 1 °C
by adding amended amounts of rac-2 to the filtrate in a manner
similar to that described above. After second cycle, 0.55 g of (R)-2
(82% ee) and 0.45 g of (S)-2 (78% ee) were collected.
Acknowledgement
The authors thank the Russian Fund of Basic Research for finan-
cial support (Grant number 09-03-00308).
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