Phase behavior and crystal structure of 3-(1-naphthyloxy)- and 3-(4-indolyloxy)-propane-1,2-diol, synthetic precursors of chiral drugs propranolol and pindolol

Article abstract of DOI:10.1016/j.molstruc.2013.04.018

Valuable precursors of popular chiral drugs propranolol and pindolol, 3-(1-naphthyloxy)-propane-1,2-diol 3 and 3-(4-indolyloxy)-propane-1,2-diol 4 were investigated by IR spectroscopy, DSC, and X-ray diffraction methods. Both compounds, crystallizing from enantiopure feed material, form "guaifenesin-like" crystal packing in which the classic H-bonded bilayers, framed in both sides by hydrophobic fragments of the molecules, acts as the basic crystal-forming motif. Diol 4 prone to spontaneous resolution and conserves its packing pattern crystallizing from racemate. Under the same conditions, diol 3 forms weakly stable solid racemic compound. Some reasons for such a behavior are identified and discussed.

Full text of DOI:10.1016/j.molstruc.2013.04.018

Accepted Manuscript
Phase behavior and crystal structure of 3-(1-naphthyloxy)- and 3-(4-indoly‐
loxy)-propane-1,2-diol, synthetic precursors of chiral drugs propranolol and
pindolol
Alexander A. Bredikhin, Aidar T. Gubaidullin, Zemfira A. Bredikhina, Robert
R. Fayzullin, Aida I. Samigullina, Dmitry V. Zakharychev
PII:
S0022-2860(13)00303-7
DOI:
http://dx.doi.org/10.1016/j.molstruc.2013.04.018
MOLSTR 19673
Reference:
To appear in:
Journal of Molecular Structure
Received Date:
Revised Date:
Accepted Date:
20 February 2013
29 March 2013
1 April 2013
Please cite this article as: A.A. Bredikhin, A.T. Gubaidullin, Z.A. Bredikhina, R.R. Fayzullin, A.I. Samigullina,
D.V. Zakharychev, Phase behavior and crystal structure of 3-(1-naphthyloxy)- and 3-(4-indolyloxy)-propane-1,2-
diol, synthetic precursors of chiral drugs propranolol and pindolol, Journal of Molecular Structure (2013), doi: http://
dx.doi.org/10.1016/j.molstruc.2013.04.018
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Phase behavior and crystal structure of 3-(1-naphthyloxy)- and
3-(4-indolyloxy)-propane-1,2-diol, synthetic precursors of chiral drugs
propranolol and pindolol
Alexander A. Bredikhin, Aidar T. Gubaidullin, Zemfira A. Bredikhina,
Robert R. Fayzullin, Aida I. Samigullina and Dmitry V. Zakharychev
A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
Arbuzov St., 8, Kazan 420088, Russian Federation
Abstract: Valuable precursors of popular chiral drugs propranolol and pindolol, 3-(1-
naphthyloxy)-propane-1,2-diol 3 and 3-(4-indolyloxy)-propane-1,2-diol 4 were investigated
by IR spectroscopy, DSC, and X-ray diffraction methods. Both compounds, crystallizing
from enantiopure feed material, form "guaifenesin-like” crystal packing in which the classic
H-bonded bilayers, framed in both sides by hydrophobic fragments of the molecules, acts as
the basic crystal-forming motif. Diol 4 prone to spontaneous resolution and conserves its
packing pattern crystallizing from racemate. Under the same conditions, diol 3 forms
weakly stable solid racemic compound. Some reasons for such a behavior are identified and
discussed.
Keywords: Propranolol; Pindolol; Thermochemical data; Single crystal X-ray analysis;
Chirality driven crystallization; Crystal packing.
1. Introduction
Non-specific β-blockers propranolol 1 [1a] and pindolol 2 [1b] are among the top in its
class, pindolol, except adrenergic activity, shows the properties of serotonin 5HT1A-
receptor antagonist.
H
N
OH
OH
H
H
O
N
O
N
Propranolol, 1
Pindolol, 2
H
N
OH
OH
4
3
O
OH
O
OH
Scheme 1.
Both propranolol and pindolol have pronounced stereoselectivity of biological activity
[2-4], and for this reason there is a need to obtain these substances in the single enantiomer
form. The study of the phase diagrams of these compounds showed that propranolol forms
a racemic compound in the crystalline phase. Moreover, propranolol belongs to the type of
"anticonglomerates", i.e. substances for which the dome of the phase diagram "temperature
of fusion (Tf) - enantiomeric composition (x)" with a maximum at x = 0.5 occupies almost
the entire phase diagram [5,6]. As for the pindolol, according to thermochemical data in the

solid phase, it forms a continuous non-ideal solid solution with a very pronounced
maximum at x = 0.5 [5]. In both cases, the features of the phase behavior of 1 and 2 make it
very difficult (not to say - make it impossible) to achieve high enantiomeric purity of their
solid samples by recrystallization. Consequently, the high enantiomeric purity of the final
products should be provided at the stage of nonracemic precursor’s preparation. The aim of
this work is to study the phase behavior and crystal structure of the glycerol ethers 3 and 4.
Compound 3, 3-(1-naphthyloxy)-propane-1,2-diol, has previously been used as a synthetic
precursor of non-racemic propranolol [7,8]. For compound 4, 3-(4-indolyloxy)-propane-
1,2-diol, the references [9,10] contain description of synthetic reactions that can lead to the
non-racemic pindolol. The structures of compounds 1-4 are shown in Scheme 1.
2. Experimental
2.1. Instrumentation
1
13
The NMR spectra (399.9 МHz for H and 100.5 MHz for C) were recorded on a Bruker
Avance-400 spectrometer with TMS as the internal standard. The IR spectra of the
polycrystalline samples of rac- and scal-compounds under investigations in KBr pellets
were recorded on a Bruker IFS-66v Fourier-transform spectrometer. Optical rotations were
measured on a Perkin-Elmer model 341 polarimeter (concentration c is given as g/100 ml).
Melting points for general purposes were determined using a Boëtius apparatus and are
uncorrected. Enantiomeric purity was checked by HPLC analysis performed on a Shimadzu
LC-20AD system controller. All thermal measurements were performed on a Perkin-Elmer
Diamond DSC model in aluminum pans using a heating rate of 10 K min-1. The mass of the
samples amounted to approximately 1.0 mg was measured by a Sartorius CPAQ-2P
microbalance, the measurement resolution is 1 μg. Both temperature scale and heat flux
were calibrated against the data for indium and naphthalene.
2.2. Materials
Racemic epichlorohydrin, 3-chloropropane-1,2-diol, 1-naphthol and 4-hydroxyindole were
commercially available. Nonracemic 3-chloro-1,2-propanediols were prepared through
Jacobsen kinetic hydrolytic resolution of rac-epichlorohydrin [11]. Racemic and (S)-diols 3
were synthesized by analogy with the published procedure [12] from 1-naphthol (10 mmol)
and rac- or (S)-3-chloropropane-1,2-diol (1.3 g, 12 mmol), respectively:
rac-3-(1-Naphthyloxy)-propane-1,2-diol, rac-3. Yield: 1.7 g (78 %), mp 98-100 oC
(hexane) {lit. [8]: mp 99-101 oC}.

o
(S)-3-(1-Naphthyloxy)-propane-1,2-diol, (S)-3. Yield: 1.6 g (73 %), mp 111-113 C
20
20
(hexane); [α]D = + 7.5 (c 1.0, MeOH) or [α]D = -8.5 (c 0.4, MTBE) {cf. lit. [8]: mp
o
25
111-113 C; [α]D = + 7.5 (c 1.0, MeOH)}; 99.6 % ee [chiral HPLC analysis; Daicel
Chiralpack AD-RH (0.46 x 15 cm) column, column temperature 40 оС; eluent:
water/isopropanol = 3:1; flow rate: 0.8 ml/min; UV detector 275 nm; tR = 16.1 min (minor),
tR= 25.8 min (major)]. 1Н NMR (CDCl3), δ: 2.00 (broad s, 2H, ОН), 3.88 (dd, J = 11.6, 5.3
Hz; 1Н, CH2O), 3.97 (dd, J = 11.6, 3.2 Hz; 1Н, CH2O), 4.26-4.33 (m, 3Н, CH2O, CH), 6.87
(d, J = 7.5 Hz; 1H, C2ArH), 7.39 (dd, J = 7.9, 8.2 Hz; 1H, C3ArH), 7.47-7.53 (m, 3Н,
C4,6,7ArH), 7.83 (d, J = 8.0 Hz; 1H, C5ArH), 8.24 (d, J = 8.0 Hz; 1H, C8ArH). 13C NMR δ:
63.8 (СН2ОН), 69.3 (ОСН2), 70.6 (СН); 105.1, 120.8, 121.5, 125.3, 125.5, 125.6, 126.4,
127.5, 134.5, 154.0 (naphthyl).
rac-3-(4-Indolyloxy)-propane-1,2-diol, rac-4 was prepared by analogy with the
published method [13]. To a stirred suspension of 1.3 g (9.4 mmol) K2CO3 in 5 ml CH3CN
a solution of 250 mg (1.9 mmol) 4-hydroxyindole in 3 ml CH3CN was added dropwise
within 10 min and the resulting mixture was stirred and heated under reflux for 2 h. Then
0.243 g (2.2 mmol) of racemic 3-chloropropane-1,2-diol was added dropwise and the
mixture was further stirred and heated under reflux for 16 hours. The reaction mixture was
filtrated and concentrated under reduced pressure to give a brown oil. The crude product
was purified by column chromatography (silica gel, acetone-hexane, 1:3-1:1) and was
crystallized in Et2O. Yield 268 mg (69 %); mp 95-97 oC (Et2O-MeCN) (lit. [13]: mp 96-98
1
oC). H NMR (DMSO-d6) δ: 3.49-3.52 (m, 2H), 3.82-3.88 (m, 1H), 3.96 (dd, J = 9.9, 5.9
Hz; 1H, CH2O), 4.08 (dd, J = 9.6, 4.5 Hz; 1H, CH2O), 4.63 (br.s, 1H, OH), 4.91 (br.s, 1H,
OH), 6.43–6.48 (m, 2H), 6.95-6.98 (m, 2H), 7.19 (t, J = 2.7 Hz; 1H), 11.0 (br.s, 1H, NH).
13C NMR δ: 63.4 (СН2ОН), 69.9 (ОСН2), 70.6 (СН); 99.0, 100.4, 105.2, 118.9, 122.2,
123.8, 137.8, 152.6 (indolyl).
(R)-3-(4-Indolyloxy)-propane-1,2-diol, (R)-4 was prepared from 4-hydroxyindole
(250 mg, 1.9 mmol) and (R)-3-chloropropane-1,2-diol (0.243 g, 2.2 mmol), as described
о
above for rac-4. The yield was 318 mg (82 %); mp 122-123 С (Et2O-MeCN, 3:1 v/v);
20
[α]D = –5.2 (c 1.5, MeOH); 95 % ee [chiral HPLC analysis; Daicel Chiralpack AD-RH
о
(0.46 x 15 cm) column; column temperature 30 С; eluent: isopropanol/water =1:3; flow
rate: 0.4 ml/min; UV detector 275 nm; tR = 10.1 min (major), tR = 14.4 min (minor)] {lit.
o
20
1
[9] for (S)-4: mp 119-120 C; [α]D = +5.1 (c 1.47, MeOH)}. H and 13C NMR spectra
were identical with that cited above for rac-4.
(S)-3-(4-Indolyloxy)-propane-1,2-diol, (S)-4 was prepared from 250 mg (1.9 mmol) 4-
hydroxyindole and (S)-3-chloropropane-1,2-diol (0.243 g, 2.2 mmol), as described above

о
for rac-4. The yield was 310 mg (80 %); mp 122 С (Et2O-MeCN, 3:1 v/v); [α]D20 = +5.2 (c
1.49, MeOH); 96 % ee {lit. [9]: mp 119-120 oC; [α]D20 = +5.1 (c 1.47, MeOH)}. 1H and 13C
NMR spectra were identical with that cited above for rac-4.
Using the slightly nonracemic sample we have examined entrainment effect for 3-(4-
indolyloxy)-propane-1,2-diol, 4. Nonracemic sample of 3-(4-indolyloxy)-propane-1,2-diol
(S)-4 (0.2 g, 15% ee) was dissolved in a mixture of Et2O (2.5 ml) and CH3CN (1.5 ml) at 40
oC. The solution was cooled to r.t. and seeded with finely-pulverized (S)-4 (1 mg, 96% ee).
o
After standing the mixture for 17 h at -18 C, precipitated (S)-4 was collected by filtration
(28 mg after drying; 89% ee). For monitoring the entrainment process during seed-induced
crystallization “chiral” HPLC analysis of mother liquor has been used. It was found that
after the removing of crystalline precipitate the mother liquor was enriched with (R)-4 (5%
ee). This solution was partly evaporated, then cooled and seeded with finely-pulverized (R)-
o
4 (1 mg, 95% ee). After standing overnight at -18 C, 26 mg of (R)-3-(4-indolyloxy)-
propane-1,2-diol (33% ee) was collected by filtration. Simultaneously the mother liquor
was enriched with (S)-4 (5% ee). Thus, the full cycle of resolution by entrainment has been
demonstrated. Unfortunately, scarcity of initial material had prevented a bulk experiment.
2.3. X-ray analysis
The X-ray diffraction data for the crystals of 3-aryloxysubstituted glycerol ethers (S)-3, rac-
3 were collected on a «Enraf-Nonius CAD-4» automatic diffractometer using graphite
monochromated CuKα (1.54184 Å) radiation at 296 K. Data collection, editing and
refinement parameters of the unit cell are carried out using program MolEN [14]. The X-
ray diffraction data for the crystal of (R)-4 was collected on a Bruker Smart Apex II CCD
diffractometer using graphite monochromated MoKα (0.71073 Å) radiation at 296 K. Data
collection: images were indexed and integrated using the APEX2 data reduction package
[15], the SADABS program [16] was used for absorption correction.
The crystal data, data collection, and the refinement parameters are given in Table 1.
The structures were solved by direct method using program SIR [17] for (S)-3, rac-3 and
using SHELXS [18] program for (R)-4, and refined by the full matrix least-squares using
SHELXL [19] programs. All non-hydrogen atoms were refined anisotropically.
The positions of the hydrogen atoms of amino and hydroxyl groups were determined
based on the electronic density distribution and were refined isotropically. The others
hydrogen atoms were inserted at calculated positions and refined as riding atoms. The
absolute structure of the single crystal of 3-aryloxysubstituted glycerol ether (S)-3 was
determined on the basis of the Flack [20] parameter.

All calculations were performed on PC using WinGX [21] suit of programs. Analysis of
the intermolecular interactions was performed using the program PLATON [22]. Mercury
program package [23] was used for figures preparation.
The X-ray phase studies for the rac-4 samples were performed on Bruker D8 Advance
diffractometer equipped with Vario attachment and Vantec linear PSD, using CuK
α1
radiation (40 kV, 40 mA) monochromated by the curved Johansson monochromator (λ =
1.5406 Å). Room-temperature data were collected in the reflection mode with a flat-plate
sample. The samples were loaded into a standard sample holder or on a glass plate, which
was kept spinning (15 rpm) throughout the data collection. Patterns were recorded in the 2Θ
range between 3 and 60°, in 0.008° steps, with a step time of 0.3-1.0 s. Five powder
patterns were collected and summed for sample.
Crystallographic data (excluding structure factors) for the structures (R)-4, (S)-3 and
rac-3 have been deposited in the Cambridge Crystallographic Data Centre as
supplementary publication nos. CCDC 924943 - 924945 respectively. 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).

Table 1. Crystallographic data for diols (S)-3, rac-3, and (R)-4.
Compound
Formula
(S)-3
C13H14O3
218.24
rac-3
C13H14O3
218.24
(R)-4
C11H13NO3
207.22
M (g/mol)
Temperature, K
Crystal class
Space group
296(2)
296(2)
296(2)
Orthorhombic
Orthorhombic
Orthorhombic
P212121
0.30 x 0.30 x 0.50
mm3
Pbca
0.04 x 0.40 x 0.45
mm3
P212121
0.13 x 0.17 x 0.55
mm3
Crystal size
Z, Z´
4, 1
8, 1
4, 1
Cell parameters
a = 5.011(1)Ǻ
b = 7.528(10)Ǻ
c = 29.549(3)Ǻ
1115(1)
a = 7.929(5)Ǻ
b = 8.597(5)Ǻ
c = 33.42(2)Ǻ
2278(2)
a = 4.9639(2)Ǻ
b = 7.3670(3)Ǻ
c = 28.093(1)Ǻ
1027.34(7)
440
3
V, Ǻ
F(000)
464
1.300
0.750
928
1.273
0.734
calc g/cm3
1.340
0.098
ρ
μ, cm-1
θ range, deg
Reflections measured
Independent reflections
2.99 ≤ θ ≤ 74.40
4995
5.29 ≤ θ ≤ 74.29
2308
2.86≤ θ ≤ 31.19
7561
2256
2307
3276
[R(int) = 0.0278]
[R(int) = 0.0169]
[R(int) = 0.0439]
Number of parameters /
restraints
154/0
154 / 0
148 / 0
2174
-0.2(1)
1194
-
2490
-
Reflections [I>2σ(I)]
Flack parameter
0.0284 / 0.0770
0.0296 / 0.0781
0.0549 / 0.1347
0.1301 / 0.1721
0.0439/ 0.0964
0.0624/ 0.1060
R1 / wR2 [I>2σ(I)]
R1 / wR2 (all reflections)
Goodness-of-fit on F2
1.027
0.126 / -0.110
0.959
0.206 / -0.204
1.047
0.152/ -0.144
-3
ρ
max/ρmin (eǺ )

3. Discussion
3.1. Synthesis
All the investigated samples were obtained by the uniform procedure by reacting a
corresponding phenol with 3-chloropropane-1,2-diol 5 in the presence of a base. Scalemic
chloropropanediols 5 of preassigned configuration were obtained by partial stereoselective
hydrolysis of racemic epichlorohydrin according to the procedure developed by Jacobsen et al.
[11]. The use of rac-5 leads to the racemates, and the use of (S)- and (R)-3-chloropropane-1,2-diol
5 gives, respectively, target diols (S)-3, (S)-4 and (R)-4:
HO
H
OH
Cl
aq. KOH
(1.4 eq.)
(S)-5
30 min
HO
H
EtOH, r.t.
3 h,
OH
O
(S)-3
OH
H
OH
H
N
OH
Cl
H
K CO (5 eq.)
2 3
N
2 h
(R)-5
H
OH
CH CN, r.t.
3
16 h,
O
OH
(R)-4
OH
Scheme 2. Synthetic approaches to the compound studied.
3.2. IR spectra comparison
For the initial evaluation of the racemic variant of our studied compounds, we compared the IR
spectra of the pairs of racemic and highly enantiomerically enriched crystalline samples of 3 and 4
in KBr pellets (Fig. 1).
Figure 1. Comparison of the IR spectra of the crystalline samples (in KBr pellets) for chiral
diols 3 (a) and 4 (b). Red curves belong to racemic samples; blue curves belong to
scalemic samples.

The IR spectra of the optically active (scalemic) and racemic forms should be identical for the
normal conglomerate (and in some extent for the solid solution) formative compounds. As a
quantitative measure of similarity of the spectra, we have used the standard Pearson correlation
coefficient r between two vectors {AiR} and {AiS}, were Ai represents extinction corresponding to
a given vibration frequency νi for real 2D arrays (Ai,νi) of digital spectra of the racemic (upper
index R) and highly enantioenriched scalemic (upper index S) samples. The value r(AR,AS)=1
corresponds to a perfect correlation of two vectors (identity of the spectra in our case). The
comparison procedure is described in more details in our preceding works [24]; the r values
obtained for the pairs of racemic and highly enantiomerically enriched samples of compounds 3
and 4 are 0.89 and 0.98 correspondingly. Based on these data, it is possible to assume that
naphthyloxydiol 3 crystallizes to form a racemic compound. At the same time there is a substantial
likelihood that indolyloxydiol 4 is a conglomerate forming compound.
3.3. Thermochemical data
The DSC measured melting points and enthalpies of fusion of rac-3, rac-4, (S)-3 and (R)-4 (96.9,
97.5, 110.8, and 121.5 °C; 32.2, 20.8, 39.0, and 34.7 kJ·mol-1 for the samples in the order listed)
have been used for the construction of the binary phase diagrams for chiral diols 3 and 4 (Figure 1).
The basic literature on the subject and formulas used for calculations has been described in detail in
our resent review [25].
Figure 2. Binary melting phase diagrams for chiral diols 3 (a) and 4 (b). Circles: experimental
points; blue lines: calculated Schröder-Van Laar curves branches; red line: calculated
Prigogine-Defay curve.
The W-shaped phase diagram form with an ill-defined middle cupola is indicative of a weakly
stable racemic compound formation from enantiomers of naphthyloxy derivative 3 in the solid state

(the calculated value of free energy for the process ΔG0 = -720 J·mol-1). The eutectic for 3 (Tfeu
=
96.0 °C) is composed of 0.62 mole fraction of a predominant enantiomer and of 0.38 mole fraction
of another one as determined by the cross point for different liquidus legs position. Hence, the
samples having initial ee value slightly higher than 0.24 could be extra enantioenriched during
recrystallization.
In the transition from the naphthyloxy to indolyloxy substituted diol 4 the phase diagram
transformed, acquiring V-shaped. The dome in the middle disappears, and the branches of the
liquidus line converge at x = 0.5. The intersection of the theoretical curves is characterized by the
value of 97.2 ° C on the temperature axis, which is almost identical to the experimental eutectic
melting point Tfeu = 97.5 °C. The calculated entropy of mixing of enantiomers in the liquid state is
equal to ΔSm = 5.23 J·K-1·mol-1, which is close to theoretical value of Rln2 for an ideal solution of
l
conglomerate. Thus, in accordance with the above described IR data, 3-(4-indolyloxy)-propane-
1,2-diol, a synthetic precursor of API pindolol, crystallizes to form a conglomerate. This fact
allows believing that racemic 4 can be resolved into individual enantiomers by direct methods
based on the stereoselective crystallization.
It is known that not every conglomerate formative racemic substance can be resolved by a
preferential crystallization approach [25,26]. Therefore, we realized an attempt of a two-step
experiment which has demonstrated the entrainment effect during the crystallization of slightly
enantioenriched diol 4 solutions. The experiment (see experimental part) showed that the enriched
in (+)-enantiomer solution after seeded crystallization become enriched in (-)-enantiomer, and then
seeded crystallization of (-)-enantiomer again enriches the mother liquor in (+)-enantiomer.
Unfortunately, there were only small quantities of rac-4 at our disposal. For this reason it was
impossible to carry out cyclic crystallization further. However, the very fact of the mother liquor
change of the sign of rotation of the polarization plane gives us hope for the success of resolution
by entrainment in preparative scale.

3.4. Single crystal X-ray investigations
The experimental details of the crystallographic experiments are listed in Table 1. No abnormal
structure parameters (bond lengths and bond angles) were found for all three substances studied.
Figure 3. Molecular structure and numbering scheme for the symmetry independent molecules
in scalemic [(R)-4 and (S)-3] and racemic [rac-3, (S)-enantiomer is shown for ease of
comparison] samples of the investigated aryloxypropanediols.
3.4.1. (R)-3-(4-Indolyloxy)-propane-1,2-diol,(R)-4
A single crystal suitable for X-ray analysis we were able to prepare only for enantiopure
indolyloxy substituted diol (R)-4. However, a comparison of the experimental powder diffraction
pattern for the rac-4 sample with the pattern, theoretically calculated from single crystal data for
(R)-4, shows the identity of the crystal structures of the racemic and scalemic samples (Fig. 4).
This special feature is inherent in conglomerate formative substances.
Figure 4. Calculated X-ray powder pattern of (R)-4 (red) and experimental X-ray powder
pattern of rac-4 (black) at 296 K.

Analysis of crystallographic data for scalemic diol 4 identifies a set of classic intermolecular
hydrogen bonds and C-H··· π interactions, which play an important role in the formation of the
crystal packing (Table 2).
Table 2. Parameters of the intermolecular H-bonds and H··· π interactions for compound
(R)-4 in crystals.
о
D–H, Å
Symmetry operation
D–H⋅⋅⋅A
H⋅⋅⋅A, Å
D⋅⋅⋅A, Å
∠ DHA,
0.87(2)
0.95(2)
0.89(3)
1.84(2)
1.76(2)
2.37(3)
2.687(2)
2.701(2)
3.256(2)
о
166(2)
179(2)
172(2)
2-x,-1/2+y,3/2-z
1+x,y,z
-1/2+x,3/2-y,2-z
O1-H1⋅⋅⋅O2
O2-H2⋅⋅⋅O1
N8-H8⋅⋅⋅N8
H···Cg, Å
2.54(3)
N···Cg
Symmetry operation
-1/2+x,3/2-y,2-z
∠ N-H···Cg,
147(2)
N8-H8→ Cg
3.323(2)
Сg = center of gravity of the fragment N8-C7-C6-C5-C9
System of intermolecular hydrogen bonds O-H⋅⋅⋅O generates primary supramolecular crystal-
forming motif for (R)-4, namely infinite homochiral bilayer, which projections are shown in Figure
5. In short, the bilayer is formed by a 1D spiral system of H-bonds located along 21 screw axes;
(R)-enantiomers form left-handed M-helix. Bilayer extends parallel to the plane a0b. Only glycerol
fragments of the molecules are involved in the formation of the bilayer, whereas aromatic
fragments are concentrated at the periphery.
Figure 5. The main supramolecular motif in the (R)-4 crystals: 2D bilayer formed by spiral
intermolecular H-bond sequences located along 21 screw axes. Hydrogen bonds are
depicted by blue dashed lines; view along 0b and 0a axes.
This supramolecular motif is common in the family of terminal aromatic glycerol ethers
(TAGE) [25]. An example of this structure was observed for the first time for conglomerate
formative chiral drug guaifenesin [27]. We named the motif as "guaifenesin-like" and described it

in detail in our preceding papers [28,29]. The crystal structure of (R)-4 is interesting because it
enlightens the way of combining the individual 2D bilayers in a three-dimensional network. The
main role in this effect belongs to N-H bonds. They are capable of forming infinite chains of
hydrogen bonds N-H⋅⋅⋅N (as illustrated in Fig. 6) as well as N-H ··· π contacts with the indole
fragments belonging to adjacent layers (π-stacking of edge-to-face type or T-shaped π-interaction;
see Tab. 2). Packing index in the (R)-4 crystals is 68.7%.
Figure 6. The N-H⋅⋅⋅N hydrogen bonds between neighboring bilayers in the (R)-4 crystals;
view along 0b axis.
3.4.2. (S)-3-(1-Naphthyloxy)-propane-1,2-diol, (S)-3
Enantiopure naphthyloxy diol 3 has many common structural features with indolyloxy diol 4.
Not surprisingly, that crystallizing in the same Sohncke space group P212121, (S)-3 molecules form
the same main supramolecular motif, as (R)-4 molecules do. Moreover, the unit cell parameters are
very close between these two compounds (Tab. 1). The only significant difference between them
consist with their chirality senses: (S)-enantiomers of diol 3 form a right-handed P-spiral 1D H-
bonded columns within the 2D bilayers. Close to each other are the parameters of the
intermolecular hydrogen bonds that provide the physical strength of the supramolecular bilayer (cf.
Tab. 3 and Tab. 2).
Table 3. Parameters of the intermolecular H-bonds and C-H··· π interactions for (S)-3 crystals.
о
D–H, Å
Symmetry operation
D–H⋅⋅⋅A
H⋅⋅⋅A, Å
D⋅⋅⋅A, Å
∠ DHA,
0.87(2)
0.89(2)
1.86(2)
1.83(2)
2.726(4)
2.725(4)
о
170(1)
176(2)
1-x,-1/2+y,1/2-z
1+x,y,z
O1-H1⋅⋅⋅O2
O2-H2⋅⋅⋅O1
Symmetry operation
1+x,y,z
H⋅⋅⋅Cg, Å
∠ C-H⋅⋅⋅Cg,
143
C⋅⋅⋅Cg
С3-Н32→ Cg
2.78
3.599(5)
Сg center of gravity of the fragment C4-C5-C10-C11-C12-C13

No other classical hydrogen bonds, except ones involved in the formation of supramolecular
primary motif, present in the (S)-3 crystals. During the formation of the crystal packing adjacent
layers are connected to each other by the dispersion interactions of hydrophobic periphery and
weak C-H⋅⋅⋅π contacts. That is, in contrast to the strong binding of bilayers for the indole
derivative 4, in crystals of naphthyl derivative 3 the bilayers are weakly related. Packing indices
for the compounds (S)-3 (68.5%) and (R)-4 (68.7%) are almost identical. Despite this, the indole
derivative 4 undergoes spontaneous resolution (that is, generates homochiral packing during
racemate crystallization), whereas naphthalene derivative 3 has not. It is possible that the lack of
directional interactions, which connect the primary fragments, determines the type of
crystallization for racemates of the compounds 3 and 4.
3.4.3. rac-3-(1-Naphthyloxy)-propane-1,2-diol, rac-3
The differences between the crystal structure of the racemic and scalemic naphthyloxy substituted
diols 3 could be detected already at the level of conformation of the crystal forming molecules (Fig.
3). In the crystals of most (but not all) of the studied terminal aromatic glycerol ethers, and in
particular, in the crystals of (R)-4 and (S)-3, four atoms form all-trans chain C4O3C3C2O2 within
the acyclic fragment. In the crystals of rac-3 five atoms form the all-trans chain C4O3C3C2C1O1.
As a result, all of non-hydrogen atoms, except for O2, lie almost in the same plane, which includes
(along with hydrogen atoms H6-H13 of the naphthyl fragment) 22 atoms. Atoms C1 (0.096Å), C2
(0.092Å) and C3 (0.095Å) deviate to the greatest extent from the calculated plane.
Analysis of crystallographic data for rac-3 identifies a set of classic intermolecular hydrogen
bonds of O-H···O type (Table 4), which differs from discussed above.
Table 4. Parameters of the intermolecular H-bonds for compound rac-3 in the crystal.
о
D–H, Å
Symmetry operation
D–H⋅⋅⋅A
H⋅⋅⋅A, Å
D⋅⋅⋅A, Å
∠ DHA,
1.03(4)
0.98(3)
1.72(4)
1.76(3)
2.729(3)
2.718(3)
167(3)
167(3)
1/2+x,y,1/2-z
1-x,-1/2+y,1/2-z
O1-H1⋅⋅⋅O2
O2-H2⋅⋅⋅O1
These H-bonds generate new packing, not previously encountered in the series of TAGEs. The
main supramolecular crystal forming motif for racemic naphthyloxy diol is a parallel to a0b plane
bilayer, occupying a limited (~ 16.5Å) space along 0c axis (Fig. 7a,b) and extending infinitely in
the 0a and 0b directions (Fig. 7c).
Bilayer fastening system of hydrogen bonds represents the infinite zigzag chains, oriented
along the 21 screw axes, parallel to the 0b direction. By virtue of symmetry (space group Pbca), it
creates conditions for a single bilayer division into zones (stripes, ribbons), formed by the

enantiomers of common configuration. This is clearly seen in the projections along the 0b (Fig. 8a)
and 0c directions. Within the crystal lattice the primary bilayers are fastened together by the
dispersion and hydrophobic interactions of aromatic fragments, gathered in the periphery of the
bilayer. The presence of an inversion center in the center of the unit cell forces the neighboring
bilayers touch each other with the fragments containing molecules with the opposite configurations.
Thus, it turns out that the elongated in the 0b direction endless homochiral stripes are shifted by
half a period in the 0a and 0c directions (Fig. 8b).
Figure 7. The main supramolecular motif in the rac-3 crystals: 2D bilayer formed by zigzag
chains of intermolecular H-bond sequences located along 21 screw axes parallel to 0b direction.
Hydrogen bonds are depicted by blue dashed lines; view along 0a (a), 0b (b), and 0c (c) axes.
The low packing index (equal to 67%) points
on the loose nature of the rac-3 crystal packing.
Thus, compound 3 is an example of a violation of
Wallach rule [30,31], according to which the
density of racemic crystal is greater than the
density of homochiral crystal for the same
substance. However, a racemate of compound 3
crystallized from solution or melt to form a
racemic compound, not a racemic conglomerate.
We found no obvious crystallographic
conditioning factors for this phenomenon.
Apparently to explain the behavior of rac-3 the
need exists to turn to other arguments. First of all,
the formation of racemic crystals from a racemic
feed material is always encouraged by the kinetic
effects, well described in Brock et al. paper [31].
These effects may be negligible in the significant
differences in the energy of the homo- and
heterochiral crystal packing. But they can
determine the result of crystallization in
borderline cases, to which the crystallization of
compound 3 clearly belongs.

Figure 8. Segmentation of the 2D bilayer on to homochiral zones (a), and the mode of the bilayers
combination within the unit cell (b) of rac-3 crystal. View along 0b axis; (R)-enantiomers
are depicted in orange color, (S)-enantiomers are depicted in blue.
4. Conclusions
Synthetic precursors of valuable chiral drug substances propranolol 1 and pindolol 2, 3-(1-naph-
thyloxy)-propane-1,2-diol 3 and 3-(4-indolyloxy)-propane-1,2-diol 4, crystallizing from
enantiopure starting materials, form a very similar "guaifenesin-like” crystal packing. In both cases
the basic supramolecular motif appears to be 2D bilayer, formed by a sequence of 1D spiral
intermolecular hydrogen bonds located along 21 screw axes; in both cases (R)-enantiomers form
left-handed M-helixes and (S)-enantiomers form right-handed P-helixes. Only glycerol fragments
of the molecules are involved in the formation of the bilayer, whereas aromatic fragments are
concentrated at the periphery. In the case of indole derivative 4 primary 2D bilayers are combined
into 3D crystal structure mainly due to N-H···N hydrogen bonds between indole fragments of
adjacent bilayers. There are no classic hydrogen bonds and/or other directional interactions, which
connect the primary fragments in the 3D crystal structure of naphthalene derivative 3. These
differences are responsible for the different crystallization behavior of racemic samples of 4 and 3.
Under these conditions indolyloxy diol 4 forms the enantiopure crystalline phase, that is, acts as a
conglomerate formative compound. Naphthyloxy diol 3, being crystallized from the racemic feed
material, forms weakly stable racemic compound with rather loose crystal packing. The
predominant formation of the racemic compound, not racemic conglomerate, in the case of rac-3
may be due to kinetic effects, which always promotes a racemic compound formation during
crystallization from a racemic substrate.
Acknowledgment
The authors thank the Russian Fund of Basic Research for financial support (Grant number 13-
03-00174). The authors thank Drs. Alexander Pashagin and Rimma Eliseenkova for valuble
technical assistance.

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Table 1. Crystallographic data for diols (S)-3, rac-3, and (R)-4.
Compound
Formula
(S)-3
C13H14O3
218.24
rac-3
C13H14O3
218.24
(R)-4
C11H13NO3
207.22
M (g/mol)
Temperature, K
Crystal class
Space group
296(2)
296(2)
296(2)
Orthorhombic
Orthorhombic
Orthorhombic
P212121
0.30 x 0.30 x 0.50
mm3
Pbca
0.04 x 0.40 x 0.45
mm3
P212121
0.13 x 0.17 x 0.55
mm3
Crystal size
Z, Z´
4, 1
8, 1
4, 1
Cell parameters
a = 5.011(1)Ǻ
b = 7.528(10)Ǻ
c = 29.549(3)Ǻ
1115(1)
a = 7.929(5)Ǻ
b = 8.597(5)Ǻ
c = 33.42(2)Ǻ
2278(2)
a = 4.9639(2)Ǻ
b = 7.3670(3)Ǻ
c = 28.093(1)Ǻ
1027.34(7)
440
3
V, Ǻ
F(000)
464
1.300
0.750
928
1.273
0.734
calc g/cm3
1.340
0.098
ρ
μ, cm-1
θ range, deg
Reflections measured
Independent reflections
2.99 ≤ θ ≤ 74.40
4995
5.29 ≤ θ ≤ 74.29
2308
2.86≤ θ ≤ 31.19
7561
2256
2307
3276
[R(int) = 0.0278]
[R(int) = 0.0169]
[R(int) = 0.0439]
Number of parameters /
restraints
154/0
154 / 0
148 / 0
2174
-0.2(1)
1194
-
2490
-
Reflections [I>2σ(I)]
Flack parameter
0.0284 / 0.0770
0.0296 / 0.0781
0.0549 / 0.1347
0.1301 / 0.1721
0.0439/ 0.0964
0.0624/ 0.1060
R1 / wR2 [I>2σ(I)]
R1 / wR2 (all reflections)
Goodness-of-fit on F2
1.027
0.126 / -0.110
0.959
0.206 / -0.204
1.047
0.152/ -0.144
-3
ρ
max/ρmin (eǺ )
Table 2. Parameters of the intermolecular H-bonds and H··· π interactions for compound
(R)-4 in crystals.
о
D–H, Å
Symmetry operation
D–H⋅⋅⋅A
H⋅⋅⋅A, Å
D⋅⋅⋅A, Å
∠ DHA,
0.87(2)
0.95(2)
0.89(3)
1.84(2)
1.76(2)
2.37(3)
2.687(2)
2.701(2)
3.256(2)
о
166(2)
179(2)
172(2)
2-x,-1/2+y,3/2-z
1+x,y,z
-1/2+x,3/2-y,2-z
O1-H1⋅⋅⋅O2
O2-H2⋅⋅⋅O1
N8-H8⋅⋅⋅N8
H···Cg, Å
2.54(3)
N···Cg
Symmetry operation
-1/2+x,3/2-y,2-z
∠ N-H···Cg,
147(2)
N8-H8→ Cg
3.323(2)
Сg = center of gravity of the fragment N8-C7-C6-C5-C9

Table 3. Parameters of the intermolecular H-bonds and C-H··· π interactions for (S)-3 crystals.
о
D–H, Å
Symmetry operation
D–H⋅⋅⋅A
H⋅⋅⋅A, Å
D⋅⋅⋅A, Å
∠ DHA,
0.87(2)
0.89(2)
1.86(2)
1.83(2)
2.726(4)
2.725(4)
о
170(1)
176(2)
1-x,-1/2+y,1/2-z
1+x,y,z
O1-H1⋅⋅⋅O2
O2-H2⋅⋅⋅O1
Symmetry operation
1+x,y,z
H⋅⋅⋅Cg, Å
∠ C-H⋅⋅⋅Cg,
143
C⋅⋅⋅Cg
С3-Н32→ Cg
2.78
3.599(5)
Сg center of gravity of the fragment C4-C5-C10-C11-C12-C13
Table 4. Parameters of the intermolecular H-bonds for compound rac-3 in the crystal.
о
D–H, Å
Symmetry operation
D–H⋅⋅⋅A
H⋅⋅⋅A, Å
D⋅⋅⋅A, Å
∠ DHA,
1.03(4)
0.98(3)
1.72(4)
1.76(3)
2.729(3)
2.718(3)
167(3)
167(3)
1/2+x,y,1/2-z
1-x,-1/2+y,1/2-z
O1-H1⋅⋅⋅O2
O2-H2⋅⋅⋅O1

Highlights:
• Crystallization features of chiral drugs propranolol and pindolol precursors are investigated.
• 3-(4-Indolyloxy)-propane-1,2-diol is a conglomerate formative compound.
• Hydrogen N-H···N bonds are responsible for conglomerate stabilization.
• 3-(1-Naphthyloxy)-propane-1,2-diol forms weakly stable solid racemic compound.
• The predominant formation of the racemic compound may be due to kinetic effects.