Homochiral crystal generation: Via sequential dehydration and Viedma ripening

Article abstract of DOI:10.1039/c6ce00119j

1,2-Bis(N-benzoyl-N-methylamino)benzene (2) forms centrosymmetric hydrate crystals (2·xH₂O) and non-centrosymmetric anhydrous crystals. Dehydration of this hydrate (30 min at 140 °C) resulted in the formation of chiral crystals (i.e. a physical racemate of the conglomerate crystals) as verified using solid-state circular dichroism and powder X-ray diffraction. Subsequent attrition-enhanced deracemization, also known as Viedma ripening, was used to obtain homochiral crystals of 2 within 5 h.

Full text of DOI:10.1039/c6ce00119j

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Homochiral Crystal Generation via Sequential Dehydration and
Viedma Ripening
a
a
a
b
a
Reajean Sivakumar , Mohammad S. Askari , Simon Woo , Carolin Madwar , Xavier Ottenwaelder ,
Received 00th January 20xx,
Accepted 00th January 20xx
b
a
D. Scott Bohle* , Louis A. Cuccia*
DOI: 10.1039/x0xx00000x
www.rsc.org/
1
,2-bis(N-benzoyl-N-methylamino)benzene
(2)
forms obtain homochiral populations of conglomerate-forming
5
,7–9
centrosymmetric hydrate crystals (2•xH
2
O) but non- crystals from an initial racemic state.
The remarkably
conglomerate crystal
30 min at 140 °C) resulted in the formation of chiral crystals (i.e. a mixture in saturated solution. Both chiral and achiral
centrosymmetric anhydrous crystals. Dehydration of this hydrate simple process involves grinding
a
(
physical racemate of the conglomerate crystals) as verified using molecules that crystallize as conglomerates, in non-
solid-state circular dichroism and powder X-ray diffraction. centrosymmetric space groups, can undergo Viedma ripening,
1
0,11
Subsequent attrition-enhanced deracemization, also known as albeit the former require racemizing conditions in solution.
Viedma ripening, was used to obtain homochiral crystals of 2 The initial broken mirror symmetry is a result of conglomerate
within 5 h.
crystallization, where the chirality of the system resides
intimately and sometimes solely in the solid state.
Conglomerate crystallization is often referred to as
spontaneous resolution even though the chiral crystals are not
The outstanding mystery of the origin of homochirality in
nature has been thoroughly investigated due to the essential
role it plays in chemistry, biochemistry and biology. The
mechanism to generate homochiral populations can be
generally separated into two steps: (i) the formation of an
initial chiral imbalance (i.e. mirror symmetry breaking) and (ii)
its subsequent amplification to homochirality. The initial
imbalance may be caused by statistical fluctuations, the parity
violation energy difference (PVED), the influence of circularly
polarized light or selective adsorption on chiral mineral
4
physically separated. In the extreme case of an achiral
conglomerate-forming molecule under optimal Ostwald
ripening conditions, one can envisage the formation of one
1
2–14
homochiral crystal.
Chiral or achiral molecules that form conglomerates must
crystallize in one of the 65 non-centrosymmetric Sohncke
1
5,16
space groups.
Our group is particularly interested in the
latter case, where it was estimated in 2005 that 8-10% of chiral
1
1
7–19
surfaces. In conglomerate crystal systems, this initial
crystal structures are formed from achiral molecules.
more recent survey of the Cambridge Structural Database (CSD
.36; 2015) estimates that 5 ± 2% of chiral crystal structures
A
imbalance can be amplified through, for example, the eutectic
2
model, Kondepudi’s model and more recently, Viedma
3,4
5
5
2
0
ripening.
are formed from achiral molecules (see ESI†). Out of the 127
97 structures (chiral and achiral molecules) in a Sohncke
space group, the majority crystallize in the P2 (31%) and
P2 (44%) space groups. Out of these structures in the P2
and P2 space groups, 9% and 14% are formed from
Generating chirality in the absence of chiral reagents (i.e.
spontaneous absolute asymmetric induction) is an attractive
route to obtain chiral materials and has clear implications with
3
1
1
2
1
2
1
1
6
regards to the origins of biological homochirality. Mirror
1 1 1
2 2
symmetry breaking and chiral amplification can be achieved by
effectively utilizing the unique nature of conglomerate crystals.
More specifically, attrition-enchanced deracemization, or
Viedma ripening, has proven to be an effective method to
achiral molecules, respectively (see ESI†). These statistics
represent a maximum frequency since a common early
crystallographic error was to miss assign space groups to lower
2
1
symmetry. Marsh has noted that these errors have dropped
2
significantly but still arise with alarming regularity.
2
Through the ‘manipulation’ of crystalline structures in the
solid-state, crystal chirogenesis can be achieved to obtain
homochiral populations. For example, crystals that incorporate
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solvent molecules or host-guest inclusion crystals can undergo was substituted for benzoyl chloride as a starting reagent (see
3,27,31
2
a crystal-to-crystal transition from centrosymmetric hydrates ESI†).
1 1
Compound 3 crystallizes in either the P4 2 2 or
3 1
or solvates to non-centrosymmetric anhydrous or non- P4 2 2 enantiomorphic space groups. The absolute structure
2
3,24
31
solvated crystals.
Along these lines, Soai et al. have of
3
was determined by single-crystal X-ray diffraction (ESI†).
has not been
chirality by the face-selective removal of crystal water from reported. Viedma ripening at 2400 rpm for ca. 24 hours
individual achiral cytosine monohydrate crystals via thermal yielded homochiral crystals of
elegantly demonstrated the generation of absolute crystal In this case, a solvated crystal structure of
3
3
1
3.
2
5,26
dehydration or reduced pressure conditions.
Compounds
1 and 2 can form either achiral or chiral
crystals depending on the solvent used during crystallization.
Scheme 1
Crystallization of compound
formation of achiral crystals of
1
from water results in the
•H O with space group P2 /c,
1
2
1
whereas crystallization in anhydrous methanol yields chiral
2
5,26
crystals of
crystallization of compound
acetate or aqueous ethanol results in the formation of achiral
crystals of •xH O with space group P2 /n. DSC measurements
of •H O and
endothermic peaks at ca. 96°C and 152°C, respectively. The
non-stoichiometric water occupancy in •xH O was
1
with space group P2 2 2 .
Similarly,
1
1 1
2
from water-saturated ethyl
2
2
1
1
2•xH O confirm the loss of water with broad
2
2
2
2
Herein, we address the bulk conversion from an achiral
crystalline sample into homochiral sample using two
compounds: cytosine, and 1,2-bis(N-benzoyl-N-
methylamino)benzene, (Scheme 1).
centrosymmetric hydrate crystals of •H O and
determined by TGA analysis (x = 0.67) and is in agreement with
the values estimated from single-crystal X-ray diffraction (x =
a
1
2
3,25–28
0.59 to 0.78 for an old and
respectively; see ESI†). Crystallization of
such as anhydrous ethyl acetate, absolute ethanol, benzene
and chloroform, yields chiral crystals of with space group
Upon crystallization of these achiral molecules, a
to that of Vlieg et al., where Viedma ripening of alanine and racemic mixture of enantiomorphic conglomerate crystals
phenylalanine was achieved by non-centrosymmetric salt should be obtained. However, the commercial sample of
formation, while the deracemization of glutamic acid was used in these experiments was found to be scalemic (6% ee
a
freshly picked crystal,
2
Specifically,
•xH O were
2
from dry solvents,
1
2
2
2
subjected to thermal dehydration. Viedma ripening was
subsequently used to obtain homochiral crystal populations of
2
2
3,28
7
,23
P2 2 2 .
1 1 1
1
and
2
(Figure 1).
Our approach is somewhat reminiscent
1
2
9,30
7
enabled via a metastable conglomerate.
[
CD(−)290 nm]). Similarly, slow crystallization of
2 (from
anhydrous ethyl acetate in the presence of a drying tube, see
ESI†) resulted in a unequal distribution of chiral crystals, as
2
3
observed by Azumaya et al.. In our hands, separate
crystallization dishes typically yielded crystals of only one
chirality of
observed in
2
. This non-stochastic mirror symmetry breaking
and can be attributed to crystallization in a
1
2
8
,9,32–35
cryptochiral environment.
Achiral crystals of •H O and
anhydrous chiral crystals through dehydration using a heating
mantle (i.e. 3 h at 90 °C for •H O and 30 min at 140 °C for
•xH O; Figure 1). Starting from finely ground material
1
2•xH O were converted to
2
2
1
2
2
2
reduced the time required for the crystals to transform from
the centrosymmetric to non-centrosymmetric space groups. A
visual indication of the transformation was possible for
1, as
1•H O crystals were initially transparent but became opaque
2
upon dehydration. The phase transition from centrosymmetric
to non-centrosymmetric space group was validated through X-
ray powder diffraction (XRPD, Figures 2 and 3). Experimental
XRPD data for all compounds was compared with XRPD
patterns simulated from single-crystal X-ray diffraction data,
Figure 1: Top - general scheme. Bottom - (a) achiral hydrated crystal of
b) chiral crystal and (c) indexed chiral single crystal of
2
2
•xH O,
(
2.
either from the CSD (for
was (for
•xH O and , Figure 3, see ESI† for experimental details).
•H O and •xH O yielded physical
2
1•H O and 1, Figure 2) or remeasured
Anhydrous
synthesized through generation of
followed by N-methylation from ortho-phenylenediamine and racemates, as confirmed by baseline solid-state circular
1
was commercially available, while
2
2
2
2
a
secondary anilide Finally, dehydration of
1
2
2
2
2
3
benzoyl chloride (see ESI†). 1,2-bis-(N-benzenesulfonyl-N- dichroism (CD) signals. Our attempts at face-selective
methylamino)benzene, (Scheme 1), was synthesized using a dehydration from individual achiral
•xH O were unsuccessful
similar procedure as that of
3
2
2
2
5
2, where benzenesulfonyl chloride (see ESI†).
2
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Figure 4: Left - Solid-state CD spectra of the chiral crystals of
1 in KBr: (b) After
dehydration, (a) and (c) following Viedma ripening. Viedma ripening was carried
out using 0.25 g sample suspended in 3 mL of saturated solution in anhydrous
methanol with 3 g of ceramic grinding media (0.8 mm) stirring at 2400 rpm for
ca. 65 hours. Right - CD calibration curve of
homochiral crystals ([CD( )290 nm]).
1 in KBr prepared from mixtures of
±
Figure 2: Transformation of
(b) XRPD of
1
•H
2
2
O (P2
generated from the CSD (CYTOSM), (c)
generated from the CSD (CYTSIN).
1 1 1 1 .
/c) to 1 (P2 2 2 ) (a) Experimental XRPD
for
1
•H
2
O
,
Experimental XRPD for
1
•H
O
1
and (d) XRPD of
1
Figure 5: Left - Solid-state CD spectra of the chiral crystals of
2 in KBr: (b)
immediately after dehydration, (a) and (c) following Viedma ripening. Viedma
ripening was carried out using 0.25 g sample suspended in 3 mL of saturated
solution in anhydrous ethyl acetate with 3 g of ceramic grinding media (0.8 mm)
stirring at 1500 rpm for ca. 5 hours. Right - CD calibration curve of
prepared from mixtures of homochiral crystals ([CD( )260 nm]).
2 in KBr
±
The absolute structure of
X-ray diffraction and solid-state CD carried out on the same
single crystal. Since only contains light atoms, the diffraction
data was acquired with a Cu Kα radiation source. The correct
2 was confirmed by single-crystal
2
enantiomer was validated by
of -0.03(10) and the conformation of
respective CD signal. The chirality of
two chiral axes (Ar-N). Crystals formed from (aS,aS)-
in a negative CD signal at 260 nm, whereas (aR,aR)-
a
low Flack parameter
2
was correlated with its
2
is due to the presence of
resulted
would
2
Figure 3: Transformation of
for •xH O, (b) XRPD of
Experimental XRPD for , (d) XRPD of
2
•xH
2
O (P2
generated from single crystal data, (c)
generated from single crystal data.
1 1 1 1
/n) to 2 (P2 2 2 ) (a) Experimental XRPD
2
2
2
•H
2
O
2
2
2
2
3,28
give a positive CD signal at 260 nm (see ESI†).
Viedma ripening was then carried out on the racemic
mixtures of or in an attempt to yield homochiral crystals
see ESI† for experimental details). In both cases, asymmetric amplification using dehydration coupled with
amplification to homochirality occurred. For
five attrition-enchanced deracemization, as exemplified here with
experiments yielded homochiral crystals with negative CD compounds and . We are currently probing the CSD for
signal and five yielded homochiral crystals with positive CD further examples of achiral molecules that form both solvated
signal at 290 nm (Figure 4). For , four experiments yielded achiral crystals as well as the corresponding non-solvated
To conclude, homochiral crystals can be produced through
1
2
7
(
1,
1
2
2
3
6,37
homochiral crystals with negative CD signal and one chiral crystals.
experiment yielded homochiral crystals with positive CD signal
at 260 nm (Figure 5).
Acknowledgements
We thank an anonymous referee of a previous manuscript for
suggesting the sequential dehydration/Viedma ripening
experiment with cytosine. We thank Prof. Tomislav Friščić and
his group (McGill University) for help in obtaining X-ray
powder diffraction data. We thank Petr Fiurasek (McGill
University) for help with the TGA measurements. NSERC is
thanked for financial support, and we also acknowledge our
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§
Spectral data, experimental procedure along with
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