Case study on the effects of molecular structure on the mode of polymorphic transition inducing preferential enrichment

Article abstract of DOI:10.1002/ejoc.200800228

A series of (±)-N-{2-[4-(2-hydroxy-3-ethoxypropoxy)phenylcarbamoyl] ethyl}-N-methylpyrrolidinium p-halobenzenesulfonates [(±)-1a-c] were found to cause an unusual symmetry-breaking enantiomeric resolution phenomenon called preferential enrichment, whereas the N-methylpiperidinium analogues (±)-N-{2-[4-(2-hydroxy-3-ethoxypropoxy)phenylcarbamoyl] ethyl}-N-methylpiperidinium p-halobenzenesulfonates [(±)-2a-c] failed to show this phenomenon. By X-ray crystallographic and ATR-FTIR spectroscopic studies, (±)-1a-c were found to undergo the desired solvent-assisted solid-to-solid polymorphic transition of the first-formed and metastable γ-form into the stable δ-form, which could induce preferential enrichment. In contrast, (±)-2a-c were subject to the undesired solvent-mediated polymorphic transition of the γ-form into the α₂-form, and similarly, (±)-1d and (±)-2d bearing a p-toluenesulfonate ion also showed the undesired solvent-mediated polymorphic transition of the γ-form into the β-form; in these cases, preferential enrichment was not observed. Accordingly, the structure of the cyclic ammonium group as well as the basicity of the p-substituted benzenesulfonate ion largely affected the mode of the polymorphic transition. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800228

FULL PAPER
DOI: 10.1002/ejoc.200800228
Case Study on the Effects of Molecular Structure on the Mode of Polymorphic
Transition Inducing Preferential Enrichment
Masahiro Horiguchi,[a] Shinsuke Yabunaka,[a] Sekai Iwama,[a] Eiji Shimano,[a] Zsolt Lepp,[a]
Hiroki Takahashi,[a] Hirohito Tsue,[a] and Rui Tamura*[a]
Keywords: Chiral resolution / Polymorphism / Symmetry breaking / Chirality
A series of (Ϯ)-N-{2-[4-(2-hydroxy-3-ethoxypropoxy)phenyl-
carbamoyl]ethyl}-N-methylpyrrolidinium p-halobenzene-
preferential enrichment. In contrast, (Ϯ)-2a–c were subject to
the undesired solvent-mediated polymorphic transition of the
γ-form into the α2-form, and similarly, (Ϯ)-1d and (Ϯ)-2d
bearing a p-toluenesulfonate ion also showed the undesired
solvent-mediated polymorphic transition of the γ-form into
the β-form; in these cases, preferential enrichment was not
observed. Accordingly, the structure of the cyclic ammonium
group as well as the basicity of the p-substituted benzenesul-
fonate ion largely affected the mode of the polymorphic tran-
sition.
sulfonates [(Ϯ)-1a–c] were found to cause an unusual sym-
metry-breaking enantiomeric resolution phenomenon called
preferential enrichment, whereas the N-methylpiperidinium
analogues (Ϯ)-N-{2-[4-(2-hydroxy-3-ethoxypropoxy)phenyl-
carbamoyl]ethyl}-N-methylpiperidinium p-halobenzenesul-
fonates [(Ϯ)-2a–c] failed to show this phenomenon. By X-ray
crystallographic and ATR-FTIR spectroscopic studies, (Ϯ)-
1a–c were found to undergo the desired solvent-assisted so-
lid-to-solid polymorphic transition of the first-formed and
metastable γ-form into the stable δ-form, which could induce
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
Preferential enrichment is a symmetry-breaking dynamic
enantiomeric resolution phenomenon that occurs during
crystallization from the supersaturated solution of certain
kinds of racemic mixed crystals (or solid solutions) com-
posed of two enantiomers in the absence of any external
chiral element.[1,2] We have been studying the relationship
between the molecular structure and the occurrence of pref-
erential enrichment. The molecular structure required for
the occurrence of preferential enrichment is represented in
Figure 1. Structural requirements for showing preferential en-
richment.
Figure 1: (i) the amide, hydroxy, and terminal alkoxy groups zation from the supersaturated solution: (i) A solvent-as-
in the long-chain cation are indispensable to form hydrogen sisted solid-to-solid transformation of an initially formed
bonds, (ii) the terminal alkoxy group is limited to a meth- metastable polymorphic form into a thermodynamically
oxy, ethoxy, or phenoxy group, and (iii) the onium sulfonate stable one. (ii) Concomitant partial crystal disintegration
structure is advantageous for inducing polymorphism; the inside the transformed crystal lattice, which releases the ex-
p-substituted benzenesulfonate ion with low basicity is ap- cess enantiomer existing in the initial crystal into solu-
propriate for the occurrence of smooth polymorphic transi- tion.[1–4,6,7] Thus far, three modes of solvent-assisted solid-
tion as shown below.[1–5]
to-solid polymorphic transition inducing preferential en-
The mechanism of preferential enrichment was found to richment were found to occur, depending on the selection
include the following two key-processes during crystalli- of the terminal R substituent in the long-chain cation and
the para X substituent on the benzenesulfonate ion. For ex-
ample, in the cases of R = Me and Et, the transition a (or b)
[a] Graduate School of Human and Environmental Studies, Kyoto
from a γ-form to a δ-form (or an ε-form) occurs to induce
University,
preferential enrichment (Figure 2), whereas in the case of R
= Pr, the polymorphic transition does not occur, because
the steric hindrance fails to induce preferential enrich-
ment.[3,8] Furthermore, in the cases of R = Ph and p-
Kyoto 606-8501, Japan
Fax: +81-75-753-7915
E-mal: tamura-r@mbox.kudpc.kyoto-u.ac.jp
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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Effects of Molecular Structures on the Mode of Polymorphic Transition
Figure 2. Supramolecular structures characteristic of (a) γ-form, (b) δ-form, (c) ε-form, and (d) α1-form crystals.
FC6H4, the transition c from a γ-form to an α1-form methylpiperidinium group and a p-halobenzenesulfonate
successfully occurs to induce preferential enrichment (Fig- ion failed to display the phenomenon. Neither (Ϯ)-1d nor
ure 2).[4,5]
(Ϯ)-2d with a more basic p-toluenesulfonate ion exhibited
To clarify the hitherto unknown relationship between the preferential enrichment. Here we report these experimental
structure of the terminal ammonium group and the occur- results and discuss each mode of polymorphic transition
rence of preferential enrichment, we prepared a series of occurring during crystallization on the basis of X-ray crys-
new compounds (Ϯ)-1 and (Ϯ)-2, and their preferential en- tal structures, powder X-ray diffraction patterns, and in situ
richment experiments were performed (Figure 3 and ATR-FTIR spectra.
Table 1). As a result, (Ϯ)-1a–c bearing an N-methylpyrrol-
idinium group and a p-halobenzenesulfonate ion showed
Table 1. Preferential enrichment and the mode of polymorphic
transition for (Ϯ)-1 and (Ϯ)-2.
preferential enrichment, whereas (Ϯ)-2a–c having an N-
Compound
Solubility in
Preferentialen- Mode of polymorphic
EtOH [mgmL–1
]
richment
transition
(Ϯ)-1a
(Ϯ)-1b
(Ϯ)-1c
(Ϯ)-1d
(Ϯ)-2a
(Ϯ)-2b
(Ϯ)-2c
(Ϯ)-2d
207.5
55.1
45.0
13.3
141.0
49.6
44.4
67.0
yes[a]
yes[a]
yes[a]
no[b]
no[b]
no[b]
no[b]
no[b]
γ to δ
γ to δ
γ to δ
γ to β
γ to α2
γ to α2
γ to α2
γ to β
[a] Preferential enrichment occurred. [b] Preferential enrichment
did not occur.
Figure 3. Compounds studied in this paper.
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Results and Discussion
Preferential Enrichment of (؎)-1 and (؎)-2
The racemates of a series of cyclic N-methylammonium
sulfonates [(Ϯ)-1 and (Ϯ)-2] were prepared and recrys-
tallized from EtOH under the standard experimental condi-
tions for preferential enrichment. Consequently, (Ϯ)-1a and
(Ϯ)-1b successfully exhibited preferential enrichment by
crystallization from their three- and sevenfold supersatu-
rated solutions, respectively (Figures 4 and 5). Although
(Ϯ)-1c also exhibited preferential enrichment, 15-fold su-
persaturation and three or four weeks were required and
the reached ee value was at most 65% (Figure 6). In con-
trast, the N-methylpiperidinium analogues (Ϯ)-2a–(Ϯ)-2c
and the p-toluenesulfonate analogues (Ϯ)-1d and (Ϯ)-2d
failed to show preferential enrichment.
Figure 6. Preferential enrichment of (Ϯ)-1c. Conditions: [a] EtOH
(0.7 mL), –20 °C, 30 d; [b] EtOH (0.7 mL), –20 °C, 21 d; [c] EtOH
(0.5 mL), –20 °C, 21 d; [d] EtOH (0.4 mL), –20 °C, 21 d; [e] removal
of the solvent by evaporation.
Crystal Structure
To clarify the relationship between the crystal structure
and the occurrence of preferential enrichment, single crys-
tals suitable for X-ray crystallographic analyses were pre-
pared from the twofold supersaturated EtOH solutions at
20 °C for the stable forms of (Ϯ)-1c, (Ϯ)-1d, and (Ϯ)-2a
(Table 2; Figures 7, 9, and 10).
The crystal structure of (Ϯ)-1c was a δ-form that has
very often been observed for compounds showing preferen-
tial enrichment (Figure 7).[1–3] It is characterized by a cen-
trosymmetric cyclic dimer of type A, which is formed by
hydrogen bonding between the two hydroxy groups and the
two terminal ethoxy groups in a pair of R and S enantio-
mers (O···O distance 2.921 Å). Another centrosymmetric
cyclic dimer of type B is formed by (i) additional hydrogen
bonds between the two sulfonate ions and the two nearest
amide NHs (O···N distance 2.894 Å) and (ii) the electro-
static interactions between other oxygen atoms of the same
sulfonate ions and the ammonium nitrogen atoms in the
two neighboring long-chain cations (O–···N+ distance
3.867 Å). Thus, the alternate alignment of the type A and
type B cyclic dimers forms a heterochiral 1D chain.
Furthermore, each 1D chain interacts with two adjacent 1D
chains through other weak electrostatic interactions be-
tween the third oxygen atoms of the same sulfonate ions
and the ammonium nitrogen atoms (O–···N+ distance
4.370 Å) in the adjacent 1D chains to form a weak hetero-
chiral 2D sheet structure. Similarly, the crystal structures of
the stable forms of (Ϯ)-1a and (Ϯ)-1b were most likely to be
a δ-form, because they showed an X-ray powder diffraction
pattern (Figure 8) and an ATR-FTIR spectrum (Fig-
ure 11b) that were similar to those of (Ϯ)-1c.
Figure 4. Preferential enrichment of (Ϯ)-1a. Conditions: [a] EtOH
(0.8 mL), –20 °C, 7 d; [b] EtOH (0.7 mL), –20 °C, 7 d; [c] EtOH
(0.6 mL), –20 °C, 7 d; [d] EtOH (0.5 mL), –20 °C, 7 d; [e] removal
of the solvent by evaporation.
The crystal structure of the β-form of (Ϯ)-1d is charac-
terized by a heterochiral 1D chain consisting of two types
of centrosymmetric cyclic dimers (type B and type C); type
C is formed by the hydrogen bonds between (i) the two
hydroxy groups and the two sulfonate ions (O···O distance
Figure 5. Preferential enrichment of (Ϯ)-1b. Conditions: [a] EtOH
(1.3 mL), –20 °C, 7 d; [b] EtOH (1.2 mL), –20 °C, 7 d; [c] EtOH
(1.0 mL), –20 °C, 7 d; [d] EtOH (0.9 mL), –20 °C, 7 d; [e] removal
of the solvent by evaporation.
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Effects of Molecular Structures on the Mode of Polymorphic Transition
Figure 7. (a) Crystal structure of the δ-form of (Ϯ)-1c; carbon atoms are represented by white circles, whereas nonwhite circles represent
oxygen, nitrogen, sulfur, and iodine atoms; (b) schematic representation of the intermolecular interactions in the same δ-form crystal.
2.849 Å) and (ii) other oxygen atoms of the same sulfonate nate ions and the amide NHs (O···N distance 2.813 Å; Fig-
ions and the two nearest amide NHs (O···N distance: ure 10b). The crystal structures of the stable form of (Ϯ)-
2.835 Å) in a pair of R and S enantiomers (Figure 9). The 2b and (Ϯ)-2c were assumed to take an α2-polymorph by
1D chain interacts with two adjacent 1D chains through judging from comparison of X-ray powder diffraction pat-
the C–H···O interaction between the methyl group of the terns (Figure S2) and the ATR-FTIR spectra (Figure 11d)
p-toluenesulfonate ion and an amide C=O (C···O distance of (Ϯ)-2a–c.
3.474 Å). The crystal structure of the stable form of (Ϯ)-2d
was judged to be a β-form, because of the similarity in the
X-ray powder diffraction pattern (Figure S1) and the ATR-
Mechanism of Polymorphic Transition
FTIR spectrum (Figure 11c) between (Ϯ)-1d and (Ϯ)-2d.
To learn the mode of polymorphic transition, we moni-
The crystal structure of the α2-form of (Ϯ)-2a consists of tored the crystallization process by in situ ATR-FTIR spec-
two unique intermolecular interactions (Figure 10): one is troscopy.[3,8,9,10] The individual spectra measured in the su-
a centrosymmetric cyclic dimer of type D and the other is a persaturated EtOH solutions were compared with those in
2D sheet structure that is composed of only the symmetry- suspension after completion of crystallization and those in
related sulfonate ions. The type D cyclic dimer is formed by the solid state (Figures 11, S3, and S4). Consequently, the
hydrogen bonds between the two hydroxy groups and the spectra measured before and after crystallization were quite
two amide carbonyl groups in a pair of R and S enantio- different from each other. The spectra in the supersaturated
mers (O···O distance 2.927 Å). The sulfonate 2D sheet is solution indicated that all eight racemates took a similar γ-
formed by two types of hydrogen bonds between the two form supramolecular structure, which exhibited a character-
oxygen atoms of one sulfonate ion and the two meta hydro- istic S–O stretching vibration at around ν = 1190, 1220, and
˜
gen atoms in the neighboring sulfonate ions (O···C dis- 1240 cm–1 (Figures 11a, S3, and S4), as reported pre-
tances 3.051 Å and 3.259 Å; Figure 10c). Furthermore, the viously.[3,8,9] The γ-form molecular assembly of (Ϯ)-1a in
type D cyclic dimer is sandwiched by the two adjacent sul- solution was gradually transformed into the metastable γ-
fonate 2D sheets through (i) the electrostatic interactions form crystal and then the stable δ-form during crystalli-
between the sulfonate oxygen atoms and the ammonium ni- zation (Figure 11a).
trogen atoms (O–···N+ distance 4.404 Å) and (ii) the hydro-
gen bonds between other oxygen atoms of the same sulfo- the mechanism of preferential enrichment was the polymor-
We already showed that the most important process in
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Figure 9. (a) Crystal structure of the β-form of (Ϯ)-1d; carbon
atoms are represented by white circles, whereas nonwhite circles
represent oxygen, nitrogen, and sulfur atoms; (b) schematic repre-
sentation of the intermolecular interactions in the same β-form
crystal; methyl groups in the ammonium groups were omitted for
clarify.
the weakened heterochiral (r,s) dimer site in an area where
an even number of homochiral S (R) chains were sur-
rounded by two R (S) chains in the initial γ-form crystal,
as reported previously (Figure 13).[1–3]
Although another type of heterochiral cyclic dimer (type
C) was also seen in the β-form of (Ϯ)-1d (Figure 9), prefer-
ential enrichment did not occur. From the crystallographic
analysis, the β-form of (Ϯ)-1d does not contain the disor-
Figure 8. Powder XRD patterns of (a) (Ϯ)-1a, (b) (Ϯ)-1b, and (c)
(Ϯ)-1c.
phic transition of a metastable γ-form into the other stable dered hydroxy groups that were observed in the δ-form of
polymorphs such as the δ-, ε-, and α1-forms, followed by (Ϯ)-1c. Furthermore, the O···O distance (Ͼ8 Å) between
partial crystal disintegration inside the resulting crystals, the sulfonate oxygen atom and the hydroxy group (arrow c)
which releases the slightly excess enantiomer in the initial in the initially formed γ-form crystal was known to be too
crystals into solution.[1–3,6,8] Because the resulting partial long to induce solid-to-solid polymorphic transition for
crystal disintegration originates from the initial random ar- forming the cyclic dimer of type C (Figure 14).[3,8] From
rangement of homochiral 1D chains in the metastable γ- these facts, the γ-to-β polymorphic transition is most likely
form crystal, the crystals deposited immediately after the to occur in a solvent-mediated manner that cannot induce
polymorphic transition should have a disordered molecular preferential enrichment.
arrangement.[1–3] This is assured by the existence of disor-
In contrast, for (Ϯ)-2a–c, the polymorphic transition of
dered oxygen atoms [occupancy factors: 0.84 and 0.16 for the γ-form into the α2-form was accompanied by a change
¯
O2(S) and O8(r), respectively] in the δ-form of (Ϯ)-1c (Fig- in the space group from P1 to P21/n. Therefore, half mole-
ure 12). The distance between O1 and O8Ј(s) or O1Ј and cules of each enantiomer in the γ-form crystal need to turn
O8(r) in the disordered heterochiral type A dimer is 0.4 Å to the opposite direction in order to generate the screw sym-
longer than that between O1 and O2Ј(R) or O1Ј and O2(S). metry. Because such a drastic molecular motion cannot oc-
Thus, the partial crystal disintegration most likely occurs at cur in the solid state, a solvent-mediated polymorphic tran-
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Effects of Molecular Structures on the Mode of Polymorphic Transition
Figure 11. ATR-FTIR spectra (a) during crystallization from the
supersaturated EtOH solution of (Ϯ)-1a at the beginning (dotted
line,····) and the end (broken line, – – ) of crystallization, with the
spectrum in the solid state of the δ-form (solid line, –––); (b) in the
solid state of the δ-form of (Ϯ)-1a–c; (c) in the solid state of the β-
form of (Ϯ)-1d and (Ϯ)-2d; (d) in the solid state of the α2-form of
(Ϯ)-2a–c.
Figure 12. (a) Type A cyclic dimer structure of (Ϯ)-1c with orienta-
tional disorder at the position of the hydroxy group on an asym-
metric carbon atom and (b) its schematic representation.
sition, which cannot induce preferential enrichment, should
occur. The reason why the N-methylpiperidinium analogues
showed such an undesired polymorphic transition can be
explained in terms of the steric hindrance of a larger piper-
idinium ring than a pyrrolidinium ring to prevent the γ-to-
δ transition a (Figure 14).
Figure 10. (a) Crystal structure of the α2-form of (Ϯ)-2a; carbon
atoms are represented by white circles, whereas nonwhite circles
represent oxygen, nitrogen, sulfur, and chlorine atoms; (b) sche-
matic representation of the intermolecular interactions in the same
α2-form crystal; (c) 2D sheet structure formed by the sulfonate ions
in the ab plane.
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of preferential enrichment, and it may be possible to find
another mode of polymorphic transition inducing preferen-
tial enrichment for the compounds that failed to show pref-
erential enrichment in this paper.
Experimental Section
Generals: Differential scanning calorimetry (DSC) was performed
at a scanning rate of 5 °Cmin–1. The in situ FTIR spectra in solu-
tion or suspension and the solid-state FTIR spectra were recorded
by using the attenuated total reflection (ATR) method on ReactIR
4000. 1H NMR spectra were recorded at 500 MHz, and 13C NMR
spectra were recorded at 126 MHz at 25 °C. HPLC analyses were
performed by using a chiral stationary phase column (Daicel Chi-
ralcel OD-H, 0.46ϫ25 cm), a mixture of hexane, ethanol, trifluoro-
acetic acid, and diethylamine (800:200:5:1) as the mobile phase at
a flow rate of 0.3 mLmin–1 at 30.0 °C, and a UV/Vis spectrometer
(254 nm) as the detector. Powder X-ray diffraction patterns were
recorded at a continuous scanning rate of 1°2θmin–1 by using Cu-
Kα radiation (40 kV, 40 mA) with the intensity of diffracted X-rays
being collected at intervals of 0.01°2θ. A Ni filter was used for the
removal of Cu-Kβ radiation.
Preparation of Racemic 1a–d and 2a–d: (Ϯ)-1-Bromo-2-[4-(2-hy-
droxy-3-ethoxypropoxy)phenylcarbamoyl]ethane (3) was prepared
according to the published procedure (Scheme 1).[11]
Figure 13. Polymorphic transition of the metastable γ-form into the
stable δ-form, which is essential for the occurrence of preferential
enrichment. This is a case in which an even number (four in this
case) of homochiral S chains are surrounded by two R chains in
the γ-form crystal, which results in partial crystal disintegration
after polymorphic transition.
Scheme 1. Synthesis of amines 4 and 5.
(؎)-N-{2-[4-(2-Hydroxy-3-ethoxypropoxy)phenylcarbamoyl]ethyl}-
pyrrolidine (4): To a mixture of 3 (8.00 g, 23 mmol) and water
(80 mL) was added pyrrolidine (5 mL) dropwise over 10 min at 0 °C
with stirring. The reaction mixture was warmed to room tempera-
ture and stirred vigorously for 48 h. The resulting mixture was ex-
tracted with CH2Cl2 (3ϫ30 mL), and the combined organic phase
was dried with anhydrous MgSO4, filtered, and evaporated, fol-
lowed by recrystallization from EtOH to give pure 4 as a colorless
solid (6.83 g, 20 mmol, 87 % yield). M.p. 132.1 °C (DSC). IR
Conclusions
The effect of the structure of the cyclic ammonium group
and the basicity of p-substituted benzenesulfonate ion on
the mode of the polymorphic transition was investigated.
Consequently, in order to induce the transition from the
metastable γ-form into the δ-form through solvent-assisted
solid-to-solid polymorphic transition, which is necessary to
induce preferential enrichment, the steric size of the cyclic
ammonium group must be small; otherwise, the solvent-me-
diated polymorphic transition occurs, which cannot induce
preferential enrichment. Furthermore, the basicity of the
sulfonate ion was found to be crucial for the occurrence of
preferential enrichment: (Ϯ)-1d and (Ϯ)-2d, having the
more basic p-toluenesulfonate ion rather than the p-halo-
benzenesulfonate ion, showed the solvent-mediated poly-
morphic transition of the γ-form into the β-form, so that
preferential enrichment did not occur. This can be ex-
plained in terms of the high basicity of the p-toluenesul-
fonate ion. However, thus far we have found three different
(KBr): ν = 3467, 2882, 2649, 1676, 1606, 1513, 1246, 1120,
˜
1
1057 cm–1. H NMR (500 MHz,CDCl3): δ = 1.22 (t, J = 7.0 Hz, 3
H), 1.85–1.89 (m, 4 H), 2.51 (dd, J = 5.1, 6.4 Hz, 2 H), 2.64–2.67
(m, 5 H), 2.83 (dd, J = 5.1, 6.4 Hz, 2 H), 3.53–3.59 (m, 3 H), 3.62
(dd, J = 4.5, 9.8 Hz, 1 H), 3.97–4.03 (m, 2 H), 4.15 (m, 1 H), 6.86
(ddd, J = 1.8, 3.8, 10.2 Hz, 2 H), 7.40 (ddd, J = 1.8, 3.8, 10.2 Hz,
2 H), 11.04 (s, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 15.1,
23.7, 24.6, 51.4, 53.1, 66.9, 69.1, 69.4, 71.3, 114.9, 121.1, 132.5,
154.8, 170.6 ppm. C18H28N2O4·0.4H2O (343.63): C 62.91, H 8.45,
N 8.15; found C 63.11, H 8.71, N 8.02.
(؎)-N-{2-[4-(2-Hydroxy-3-ethoxypropoxy)phenylcarbamoyl]ethyl}-
N-methylpyrrolidinium p-Chlorobenzenesulfonate [(؎)-1a]: A mix-
modes of polymorphic transition that allow the occurrence ture of 4 (2.00 g, 5.9 mmol) and methyl p-chlorobenzenesulfonate
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Effects of Molecular Structures on the Mode of Polymorphic Transition
Figure 14. The mode of solvent-assisted solid-to-solid polymorphic transition of (a) a γ-form polymorph into (b) a δ-form polymorph.
The arrows a and b indicate the sites of the formation of new electrostatic interactions or new hydrogen bonds, and the broken arrow c
indicates the site of virtual rearrangement of hydrogen bonds necessary to form the β-form polymorph by a solvent-assisted solid-to-
solid transition.
(1.35 g, 6.5 mmol) in acetone (20 mL) was heated under reflux for
24 h. The mixture was evaporated, and the resulting solid was
washed with Et2O. After drying in vacuo, (Ϯ)-1a (2.90 g, 5.3 mmol,
90 % yield) was obtained as a colorless powder. M.p. 90.1 °C
(13C-14N coupling)], 65.8 [t, J = 3.1 Hz (13C-14N coupling)], 67.9,
70.3, 70.9, 72.7, 115.9, 123.0, 125.3, 128.9, 132.5, 132.7, 145.8,
157.4, 168.6 ppm. C25H35BrN2O7S (587.52): calcd. C 51.11, H 6.00,
N 4.77; found C 51.00, H 5.87, N 4.69.
(DSC). IR (KBr): ν = 3424, 3083, 2871, 1679, 1557, 1514, 1219,
˜
(؎)-N-{2-[4-(2-Hydroxy-3-ethoxypropoxy)phenylcarbamoyl]ethyl}-
N-methylpyrrolidinium p-Iodobenzenesulfonate [(؎)-1c]: M.p.
1100, 844 cm–1. 1H NMR (500 MHz, CD3OD): δ = 1.18 (t, J =
7.0 Hz, 3 H), 2.23 (m, 4 H), 2.95 (t, J = 7.3 Hz, 2 H), 3.09 (s, 3 H),
3.52–3.59 (m, 8 H), 3.75 (t, J = 7.3 Hz, 2 H), 3.94 (dd, J = 5.6,
9.4 Hz, 1 H), 4.00–4.05 (m, 2 H), 6.90 (d, J = 9.0 Hz, 2 H), 7.41
(d, J = 9.0 Hz, 2 H), 7.44 (d, J = 9.0 Hz, 2 H), 7.78 (d, J = 9.0 Hz,
2 H) ppm. 13C NMR (126 MHz, CD3OD): δ = 15.4, 22.7, 31.8,
49.2 (overlapped with the solvent peak), 61.3 [t, J = 3.1 Hz (13C-
14N coupling)], 65.8 [t, J = 3.1 Hz (13C-14N coupling)], 67.9, 70.3,
71.0, 72.8, 115.9, 123.0, 128.7, 129.5, 132.7, 137.1, 145.4, 157.4,
168.6 ppm. C25H35ClN2O7S (543.07): calcd. C 55.29, H 6.50, N
5.16; found C 55.36, H 6.40, N 5.15.
102.2 °C (DSC). IR (KBr): ν = 3431, 3087, 2869, 1678, 1611, 1513,
˜
1
1246, 1111, 843 cm–1. H NMR (500 MHz, CD3OD): δ = 1.18 (t,
J = 7.0 Hz, 3 H), 2.23 (br., 4 H), 2.95 (t, J = 7.3 Hz, 2 H), 3.09 (s,
3 H), 3.52–3.59 (m, 8 H), 3.75 (t, J = 7.3 Hz, 2 H), 3.94 (dd, J =
5.6, 9.4 Hz, 1 H), 4.00–4.06 (m, 2 H), 6.91 (d, J = 9.1 Hz, 2 H),
7.44 (d, J = 9.1 Hz, 2 H), 7.57 (d, J = 8.7 Hz, 2 H), 7.71 (d, J =
8.7 Hz, 2 H) ppm. 13C NMR (126 MHz, CD3OD): δ = 15.4, 22.7,
31.8, 49.2 (overlapped with the solvent peak), 61.2 [t, J = 3.1 Hz
(13C-14N coupling)], 65.8 [t, J = 3.1 Hz (13C-14N coupling)], 67.9,
70.3, 71.0, 72.8, 97.1, 115.9, 123.0, 128.8, 132.7, 138.6, 146.4, 157.4,
168.6 ppm. C25H35IN2O7S (634.52): calcd. C 47.32, H 5.56, N 4.41;
found C 47.38, H 5.46, N 4.39.
(Ϯ)-1b, (Ϯ)-1c, and (Ϯ)-1d were prepared in an analogous way to
the synthesis of (Ϯ)-1a.
(؎)-N-{2-[4-(2-Hydroxy-3-ethoxypropoxy)phenylcarbamoyl]ethyl}-
N-methylpyrrolidinium p-Bromobenzenesulfonate [(؎)-1b]: M.p.
(؎)-N-{2-[4-(2-Hydroxy-3-ethoxypropoxy)phenylcarbamoyl]ethyl}-
N-methylpyrrolidinium p-Toluenesulfonate [(؎)-1d]: M.p. 105.7 °C
100.4 °C (DSC). IR (KBr): ν = 3438, 3080, 2869, 1679, 1558, 1513,
(DSC). IR (KBr): ν = 3373, 3064, 2884, 1680, 1610, 1507, 1219,
˜
˜
1
1245, 1117, 844 cm–1. H NMR (500 MHz, CD3OD): δ = 1.18 (t,
1120, 837 cm–1. 1H NMR (500 MHz, CD3OD): δ = 1.19 (t, J =
7.0 Hz, 3 H), 2.22 (m, 4 H), 2.35 (s, 3 H), 2.94 (t, J = 7.3 Hz, 2 H),
3.07 (s, 3 H), 3.51–3.59 (m, 8 H), 3.73 (t, J = 7.3 Hz, 2 H), 3.94
J = 7.0 Hz, 3 H), 2.23 (m, 4 H), 2.95 (t, J = 7.3 Hz, 2 H), 3.08 (s,
3 H), 3.52–3.59 (m, 8 H), 3.74 (t, J = 7.3 Hz, 2 H), 3.94 (dd, J =
5.6, 9.4 Hz, 1 H), 4.00–4.05 (m, 2 H), 6.90 (d, J = 9.1 Hz, 2 H), (dd, J = 5.6, 9.4 Hz, 1 H), 4.00–4.05 (m, 2 H), 6.90 (d, J = 9.0 Hz,
7.44 (d, J = 9.1 Hz, 2 H), 7.57 (d, J = 8.7 Hz, 2 H), 7.71 (d, J = 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.44 (d, J = 9.0 Hz, 2 H), 7.70 (d,
8.7 Hz, 2 H) ppm. 13C NMR (126 MHz, CD3OD): δ = 15.4, 22.7,
31.8, 49.2 (overlapped with the solvent peak), 61.2 [t, J = 3.1 Hz
J = 8.0 Hz, 2 H) ppm. 13C NMR (126 MHz, CD3OD): δ = 15.4,
21.3, 22.6, 31.8, 49.2 (overlapped with the solvent peak), 61.2 [t, J
Eur. J. Org. Chem. 2008, 3496–3505
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3503

R. Tamura et al.
FULL PAPER
= 3.1 Hz (13C-14N coupling)], 65.8 [t, J = 3.1 Hz (13C-14N coup-
ling)], 67.9, 70.3, 70.9, 72.7, 115.8, 123.0, 127.0, 129.8, 132.8, 141.7,
143.7, 157.4, 168.6 ppm. C26H38N2O7S (522.65): calcd. C 59.75, H
7.33, N 5.36; found C 59.57, H 7.37, N 5.18.
48.3, 60.9, 62.6, 67.9, 70.3, 70.9, 72.8, 97.1, 115.9, 123.0, 128.8,
132.7, 138.6, 146.4, 157.4, 168.6 ppm. C26H37IN2O7S (648.55):
calcd. C 48.15, H 5.75, N 4.32; found C 48.23, H 5.60, N 4.33.
(؎)-N-{2-[4-(2-Hydroxy-3-ethoxypropoxy)phenylcarbamoyl]ethyl}-
N-methylpiperidinium p-Toluenesulfonate [(؎)-2d]: M.p. 120.6 °C
(؎)-N-{2-[4-(2-Hydroxy-3-ethoxypropoxy)phenylcarbamoyl]ethyl}-
piperidine (5): To a mixture of 3 (6.00 g, 17 mmol) and water
(60 mL) was added piperidine (5 mL) dropwise over 10 min at 0 °C
with stirring. The reaction mixture was warmed to room tempera-
ture and stirred vigorously for 48 h. The resulting mixture was ex-
tracted with CH2Cl2 (3ϫ30 mL), and the combined organic phase
was dried with anhydrous MgSO4, filtered, and evaporated, fol-
lowed by recrystallization from EtOH to give pure 5 as a colorless
(DSC). IR (KBr): ν = 3364, 3067, 2870, 1689, 1612, 1508, 1222,
˜
1120, 841 cm–1. 1H NMR (500 MHz, CD3OD): δ = 1.19 (t, J =
7.0 Hz, 3 H), 1.67 (m, 2 H), 1.90 (quint, J = 5.7 Hz, 4 H), 2.35 (s,
3 H), 2.91 (t, J = 7.3 Hz, 2 H), 3.07 (s, 3 H), 3.38 (t, J = 5.8 Hz, 4
H), 3.52–3.59 (m, 4 H), 3.72 (t, J = 7.3 Hz, 2 H), 3.94 (dd, J = 5.6,
9.4 Hz, 1 H), 4.00–4.06 (m, 2 H), 6.90 (d, J = 9.1 Hz, 2 H), 7.21
(d, J = 8.0 Hz, 2 H), 7.44 (d, J = 9.1 Hz, 2 H), 7.70 (d, J = 8.0 Hz,
2 H) ppm. 13C NMR (126 MHz, CD3OD): δ = 15.4, 21.0, 21.3,
22.0, 30.1, 48.3, 61.0, 62.6, 67.9, 70.3, 70.9, 72.7, 115.9, 123.0,
127.0, 129.8, 132.8, 141.7, 143.7, 157.4, 168.6 ppm. C27H40N2O7S
(536.68): calcd. C 60.42, H 7.51, N 5.22; found C 60.34, H 7.62, N
5.23.
solid (4.86 g, 14 mmol, 82% yield). M.p. 94.2 °C (DSC). IR (KBr):
1
ν = 3478, 2947, 2783, 1681, 1606, 1517, 1246, 1122, 1058 cm–1. H
˜
NMR (500 MHz, CDCl3): δ = 1.22 (t, J = 7.0 Hz, 3 H), 1.54 (br.,
2 H), 1.68 (quint, J = 5.5 Hz, 4 H), 2.49 (dd, J = 5.0, 6.9 Hz, 2 H),
2.53 (br., 4 H), 2.65 (dd, J = 5.0, 6.9 Hz, 2 H), 3.53–3.59 (m, 3 H),
3.62 (dd, J = 4.5, 9.8 Hz, 1 H), 3.97–4.03 (m, 2 H), 4.15 (quint, J
= 5.4 Hz, 1 H), 6.88 (ddd, J = 1.8, 3.8, 10.2 Hz, 2 H), 7.46 (ddd, J
= 1.8, 3.8, 10.2 Hz, 2 H), 11.20 (s, 1 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 15.1, 24.3, 26.3, 32.5, 53.6, 54.4, 67.0, 69.2, 69.5, 71.3,
115.0, 120.9, 132.7, 154.8, 170.6 ppm. C19H30N2O4·0.3H2O
(355.86): C 64.13, H 8.67, N 7.87; found C 64.10, H 8.56, N 7.66.
General Procedure for the Preferential Enrichment Experiment of
(؎)-1a, (؎)-1b, and (؎)-1c (Figure 4): (؎)-1a (1.15 , 500.0 mg,
0.921 mmol) was dissolved in EtOH (0.8 mL) on heating. The re-
sulting threefold supersaturated solution was allowed to stand at
–20 °C, and the ee value of the mother liquor was measured occa-
sionally. The solution was left until the ee value reached equilib-
rium after the crystals were deposited. Consequently, it took 7 d
for the first recrystallization. The deposited crystals were separated
from the mother liquor by filtration. After evaporation of the sol-
vent, S-enriched 1a (50.2 mg, 75.0% ee) was obtained as a viscous
colorless oil. The slightly R-enriched deposited crystals (449.6 mg,
8.4% ee) were subsequently recrystallized from EtOH (0.7 mL) in
a similar manner, which led to the deposition of antipodal S-rich
crystals (390.3 mg, 2.4% ee) and the enrichment of the R enanti-
omer in the mother liquor, from which R-enriched 1a (59.2 mg,
79.5% ee) was obtained as a viscous oil. Similar crystallizations
were repeated four times in all.
(Ϯ)-2a, (Ϯ)-2b, (Ϯ)-2c, and (Ϯ)-2d were prepared in an analogous
way to the synthesis of (Ϯ)-1a.
(؎)-N-{2-[4-(2-Hydroxy-3-ethoxypropoxy)phenylcarbamoyl]ethyl}-
N-methylpiperidinium p-Chlorobenzenesulfonate [(؎)-2a]: M.p.
114.4 °C (DSC). IR (KBr): ν = 3428, 3081, 2870, 1672, 1613, 1513,
˜
1
1225, 1119, 841 cm–1. H NMR (500 MHz, CD3OD): δ = 1.19 (t,
J = 7.0 Hz, 3 H), 1.68 (m, 2 H), 1.91 (quint, J = 5.7 Hz, 4 H), 2.91
(t, J = 7.3 Hz, 2 H), 3.08 (s, 3 H), 3.40 (t, J = 5.8 Hz, 4 H), 3.52–
3.59 (m, 4 H), 3.74 (t, J = 7.3 Hz, 2 H), 3.93 (dd, J = 5.6, 9.4 Hz,
1 H), 4.00–4.06 (m, 2 H), 6.90 (d, J = 9.1 Hz, 2 H), 7.41 (d, J =
8.7 Hz, 2 H), 7.43 (d, J = 9.1 Hz, 2 H), 7.78 (d, J = 8.7 Hz, 2 H)
ppm. 13C NMR (126 MHz, CD3OD): δ = 15.4, 21.0, 22.0, 30.1,
48.3, 61.0, 62.6, 67.9, 70.3, 71.0, 72.8, 115.9, 123.0, 128.7, 129.4,
132.7, 137.1, 145.4, 157.4, 168.6 ppm. C26H37ClN2O7S (557.10):
calcd. C 56.05, H 6.69, N 5.03; found C 56.16, H 6.53, N 5.04.
An analogous procedure was use for (Ϯ)-1b (Figure 5) and (Ϯ)-1c
(Figure 6).
For reference, (S)-enriched 1a–c were synthesized from commer-
cially available (S)-epichlorohydrin. (S)-1a (90.9% ee): [α]2D0
=
(؎)-N-{2-[4-(2-Hydroxy-3-ethoxypropoxy)phenylcarbamoyl]ethyl}-
N-methylpiperidinium p-Bromobenzenesulfonate [(؎)-2b]: M.p.
+1.84(1) (c = 2.138, MeOH); (S)-1b (90.9% ee): [α]2D0 = +1.41(2) (c
= 2.137, MeOH); (S)-1c (93.6% ee): [α]2D0 = +1.97(2) (c = 2.136,
116.5 °C (DSC). IR (KBr): ν = 3428, 3078, 2868, 1672, 1609, 1507, MeOH).
˜
1222, 1116, 839 cm–1. H NMR (500 MHz, CD3OD): δ = 1.19 (t,
1
X-ray Crystallographic Analysis of the δ-Form of 1c, the β-Form of
J = 7.0 Hz, 3 H), 1.68 (m, 2 H), 1.92 (quint, J = 5.7 Hz, 4 H), 2.91
(t, J = 7.3 Hz, 2 H), 3.08 (s, 3 H), 3.40 (t, J = 5.8 Hz, 4 H), 3.52–
3.59 (m, 4 H), 3.74 (t, J = 7.3 Hz, 2 H), 3.93 (dd, J = 5.6, 9.4 Hz,
1 H), 4.00–4.05 (m, 2 H), 6.90 (d, J = 9.1 Hz, 2 H), 7.44 (d, J =
9.1 Hz, 2 H), 7.57 (d, J = 8.7 Hz, 2 H), 7.72 (d, J = 8.7 Hz, 2 H)
ppm. 13C NMR (126 MHz, CD3OD): δ = 15.4, 21.0, 22.0, 30.1,
48.3, 60.9, 62.6, 67.9, 70.2, 70.9, 72.7, 115.9, 123.0, 125.3, 128.9,
132.5, 132.7, 145.8, 157.4, 168.6 ppm. C26H37BrN2O7S (601.55):
calcd. C 51.91, H 6.20, N 4.66; found C 51.61, H 6.01, N 4.46.
1d, and the α2-Form of 2a: For the X-ray crystallographic analysis,
the single crystal was mounted in a sealed capillary. The data col-
lections were performed at 296 K with an Enraf–Nonius Kappa
CCD diffractometer with graphite monochromated Mo-Kα radia-
tion for the δ-form of (Ϯ)-1c, at 296 K with a Rigaku CCD dif-
fractometer with graphite monochromated Mo-Kα radiation for the
β-form of (Ϯ)-1d, and at 173 K with a Rigaku RAXIS RAPID
diffractometer with graphite monochromated Mo-Kα radiation for
the α2-form of (Ϯ)-2a. All of the crystallographic calculations were
performed by using the CrystalStructure software package of Ri-
gaku and Rigaku/MSC. The crystal structures were solved by direct
(؎)-N-{2-[4-(2-Hydroxy-3-ethoxypropoxy)phenylcarbamoyl]ethyl}-
N-methylpiperidinium p-Iodobenzenesulfonate [(؎)-2c]: M.p.
118.6 °C (DSC). IR (KBr): ν = 3421, 3080, 2866, 1671, 1610, 1507, methods and refined by using full-matrix least-squares. All non-
˜
1211, 1112, 833 cm–1. H NMR (500 MHz, CD3OD): δ = 1.19 (t,
J = 7.0 Hz, 3 H), 1.68 (m, 2 H), 1.91 (quint, J = 5.7 Hz, 4 H), 2.91
(t, J = 7.3 Hz, 2 H), 3.08 (s, 3 H), 3.39 (t, J = 5.8 Hz, 4 H), 3.52–
3.59 (m, 4 H), 3.74 (t, J = 7.3 Hz, 2 H), 3.94 (dd, J = 5.6, 9.4 Hz,
hydrogen atoms were refined anisotropically. The summary of the
fundamental crystal data and experimental parameters for the
structure determination is given in Table 2. CCDC-679608 [for (Ϯ)-
1c], -679609 [for (Ϯ)-1d], and -679610 [ for(Ϯ)-2a] contain the sup-
1
1 H), 4.00–4.06 (m, 2 H), 6.90 (d, J = 9.1 Hz, 2 H), 7.44 (d, J = plementary crystallographic data for this paper. These data can be
9.1 Hz, 2 H), 7.56 (d, J = 8.7 Hz, 2 H), 7.77 (d, J = 8.7 Hz, 2 H)
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
ppm. 13C NMR (126 MHz, CD3OD): δ = 15.4, 21.0, 22.0, 30.1,
3504
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 3496–3505

Effects of Molecular Structures on the Mode of Polymorphic Transition
Table 2. X-ray analytical data for (Ϯ)-1c, (Ϯ)-1d, and (Ϯ)-2a.
[1] R. Tamura, T. Ushio, “Preferential Enrichment: A Dynamic
Enantiomeric Resolution Phenomenon Caused by Polymor-
phic Transition During Crystallization” in Enantiomer Separa-
tion: Fundamentals and Practical Methods (Ed.: F. Toda),
Kluwer Academic Publishers, Dordrecht, 2004, pp. 135–163.
[2] R. Tamura, H. Takahashi, D. Fujimoto, T. Ushio, Top. Curr.
Chem. 2007, 269, 53–82.
[3] R. Tamura, D. Fujimoto, Z. Lepp, K. Misaki, H. Miura, H.
Takahashi, T. Ushio, T. Nakai, K. Hirotsu, J. Am. Chem. Soc.
2002, 124, 13139–13153.
[4] M. Horiguchi, S. Okuhara, E. Shimano, D. Fujimoto, H. Taka-
hashi, H. Tsue, R. Tamura, Cryst. Growth Des. 2007, 7, 1643–
1652.
[5] M. Horiguchi, S. Okuhara, E. Shimano, D. Fujimoto, H. Taka-
hashi, H. Tsue, R. Tamura, Cryst. Growth Des. 2008, 8, 540–
548.
[6] H. Miura, T. Ushio, K. Nagai, D. Fujimoto, Z. Lepp, H. Taka-
hashi, R. Tamura, Cryst. Growth Des. 2003, 3, 959–965.
[7] D. Fujimoto, R. Tamura, Z. Lepp, H. Takahashi, T. Ushio,
Cryst. Growth Des. 2003, 3, 973–979.
[8] D. Fujimoto, H. Takahashi, T. Ariga, R. Tamura, Chirality
2006, 18, 188–195.
[9] R. Tamura, M. Mizuta, S. Yabunaka, D. Fujimoto, T. Ariga,
S. Okuhara, N. Ikuma, H. Takahashi, H. Tsue, Chem. Eur. J.
2006, 12, 3515–3527.
Compounds
1c
1d
2a
Polymorphic form
δ
β
α2
Crystal system
Space group
a [Å]
b [Å]
c [Å]
triclinic
P1
triclinic
P1
monoclinic
P21/n
10.3214(5)
10.1843(6)
25.5920(15)
90
95.0494(18)
90
2679.7(3)
4
¯
¯
9.454(1)
10.4043(8)
14.658(2)
107.619(6)
96.572(6)
92.618(7)
1360.2(3)
2
9.1465(7)
13.705(2)
12.1298(12)
111.098(4)
98.574(6)
104.609(6)
1323.4(3)
2
α [°]
β [°]
γ [°]
V [Å3]
Z
R[a], Rw
0.0470, 0.0600 0.086, 0.142
0.0604, 0.0791
[b]
[a] R = Σ||Fo| – |Fc||/Σ|Fo| for IϾ3.0σ(I) data. [b] Rw = [Σ|cYsim(2θi) –
Iexp(2θi) – Yback(2θi)|]/Σ|Iexp(2θi)|.
Supporting Information (see footnote on the first page of this arti-
cle): Powder XRD patterns of the β-form crystal of (Ϯ)-1d and
(Ϯ)-2d; powder XRD patterns of the α2-form crystal of (Ϯ)-2a–c;
ATR-FTIR spectra of (Ϯ)-1b–d and (Ϯ)-2a–d; powder XRD pat-
terns of (Ϯ)-1c, (Ϯ)-1d, and (Ϯ)-2a obtained experimentally and
simulated from the X-ray crystallographic data.
[10] For polymorphic transition during crystallization of carboxylic
acids, see R. J. Davey, G. Dent, R. K. Mughal, S. Parveen,
Cryst. Growth Des. 2006, 6, 1788–1796.
Acknowledgments
[11] H. Takahashi, R. Tamura, T. Ushio, Y. Nakajima, K. Hirotsu,
Chirality 1998, 10, 705–710.
The present work was supported by the Grand-in-Aid for Scientific
Research from the Japan Society for the Promotion of Science (No.
15350023).
Received: February 29, 2008
Published Online: May 27, 2008
Eur. J. Org. Chem. 2008, 3496–3505
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3505