Mapping the structural boundaries of quasiracemate fractional crystallization using 2-substituted diarylamides

Article abstract of DOI:10.1039/c7cc01638g

Video-assisted hot stage polarized light microscopy of 55 quasienantiomeric pairs, constructed from 22 chiral diarylamides that systematically differ in topology, reveals the structural boundaries of molecular shape to supramolecular assembly.

Full text of DOI:10.1039/c7cc01638g

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Mapping the structural boundaries
of quasiracemate fractional crystallization
Cite this:DOI: 10.1039/c7cc01638g
using 2-substituted diarylamides†
Received 2nd March 2017,
Accepted 31st March 2017
Ian C. Tinsley, Jacqueline M. Spaniol and Kraig A. Wheeler
*
DOI: 10.1039/c7cc01638g
rsc.li/chemcomm
Video-assisted hot stage polarized light microscopy of 55 quasie- nature of this structural feature. To date, virtual screening
nantiomeric pairs, constructed from 22 chiral diarylamides that based on molecular shape similarity has been widely used in
systematically differ in topology, reveals the structural boundaries drug discovery;12 however, surprisingly, no practically useful set
of molecular shape to supramolecular assembly.
of parameters or experiments for probing supramolecular
synthesis via topological features exist.
The manner in which molecules recognize each other holds critical
Here we report the systematic investigation of the relationship
importance to nearly every area of science.1–3 This significance between molecular shape and molecular recognition. We find
stems from the key underpinning of molecular assembly to our that an understanding can be effectively achieved by mapping
most basic understanding of chemical processes. Whether these the shape space of quasiracemate fractional crystallization using
interactions relate to small-molecule catalytic transformations or structurally simple chiral diarylamides precursors (Scheme 1).
complex physiological processes, the structural features respon- Quasiracemates – pairs of chemically distinct molecules of
sible for molecular association play into the well-known adage opposite handedness [e.g., (R)-X and (S)-X0 (ref. 13)] – without
that form follows function where material property arises from the exception, cocrystallize with component alignment that mimic
collective structural features of the molecular components.4,5 the centrosymmetric patterns observed in their analogous
Because the form of chemical systems is derived from a complex racemic counterparts.9,10,14 This thermodynamic preference
blend of covalent and non-bonded contacts, codifying each provides a key entry point for the study since the complementary
contributor has become essential for recognizing the functions shapes of the quasienantiomeric building blocks serve as the
and potential applications of materials.6–8 While considerable primary driving force for these assemblies. Such a notion is
progress in this area has been realized by isolating and identifying supported by the diversity of molecular architectures and
molecular contacts and the structural details of their conditional functional groups represented by the collection of racemic and
exceptions, insight to the entire landscape of molecular associa- quasiracemic crystal structures. It should also be noted that non-
tions remains an ongoing effort. Some of this challenge rests bonded contacts (e.g., hydrogen bonds), while often important
with chemical features that produce less manageable motifs via to the overall molecular recognition process, cannot explain the
ill-defined or weak contacts. Molecular shape is one such crystal growth events of racemates or quasiracemates since
feature. Although generally recognized as an important contri- comparable stabilization may be achieved from homomeric
butor to molecular assembly, the systematic use of topological [(R)-Xꢀꢀꢀ(R)-X] or heteromeric [(S)-Xꢀꢀꢀ(R)-X or (S)-Xꢀꢀꢀ(R)-X0] contacts.
features as a design element for supramolecular synthesis
remains a relatively unexplored area.9–11 The lack of direct
attention to molecular shape largely relates to the intractable
Department of Chemistry, Eastern Illinois University, 600 Lincoln Avenue,
Charleston, Illinois, 61910, USA. E-mail: kawheeler@eiu.edu
† Electronic supplementary information (ESI) available: Synthetic procedures,
hot stage micrographs, X-ray powder and NMR spectroscopic data for Cl/Br,
CH3/CF3, Br/CF3, and Cl/I pairs, and full crystal structure and hydrogen bond
tables for quasiracemates H/F, NO2/CF3, NO2/Br, CH3/CF3, and CF3/I, and group/
framework volume and surface area comparisons. CCDC 1534589–1534594. For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
Scheme 1 Chiral diarylamides used in the present study.
c7cc01638g
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Moving beyond the current collection of known quasiracemic distinct interface between the crystalline phases. Video recording
systems where component selection often follows pairs of closely with increasing temperature provided an opportunity to view the
related quasienantiomers, our investigation examined a topo- thermal behavior of cocrystallization in real-time. The onset of
logically diverse set of related compounds to understand the melting of the (S)-Br and (R)-Br adducts occurs at 112 1C with the
structural boundaries of quasiracemate formation. A homologous emergence of the racemic phase at the component interface
family of R and S diarylamides that differ incrementally in the size (Fig. 2A, center and right micrographs). The identity of this
and shape of the pendant substituents was selected for this racemic phase was further supported by comparing its X-ray
study – a total of 22 compounds (Scheme 1). The collection of powder pattern to those calculated from the known crystal
2-substituted components range from X = H to C6H5 with the structures of (S)-Br and (ꢁ)-Br (ESI†).20
topological features of these groups approximated using their
The success of this method as applied to racemic Br suggests
volumes and surface areas.15,16 To exclude the challenges that that the strategy could also be amenable to probing the molecular
arise from solvent-assisted crystal growth processes, cocrystal- recognition profiles of quasiracemic systems. Similar to enantiomers
lization of pairs of quasienantiomers was pursued from the (S)-Br and (R)-Br, quasienantiomers (S)-Cl and (R)-Br were thermally
melt using the Kofler contact fusion method.17–19 A utility of processed with video capture using the hot stage technique. Several
this technique draws attention to the formation of new crystalline micrographs of this process are provided in Fig. 2B with results
phases during the heating cycle as indicated by the emergence of showing the onset of melting near 113 1C for both the (S)-Cl (left)
melting regions (eutectic regions) in the viewing area. In the case and (R)-Br (right) components. The complete thermal signature
of racemic and quasiracemic mixtures, distinguishing between of this process offers an important glimpse into the molecular
the various modes of crystallization (i.e., racemic/quasiracemic assembly of this material and highlights the formation of the
compounds, conglomerates, and solid solutions) is possible (S)-Cl/(R)-Br quasiracemic phase at the interface region.
given the unique thermal signature of each phase (Fig. 1). Fig. 2A
The appearance of the Cl/Br diarylamide quasiracemic phase
demonstrates proof-of-concept as applied to the (ꢁ)-N-(2-bromo- was largely anticipated given the crystal structure was previously
benzoyl)methylbenzylamine system. The first snapshot indicates reported.20 Furthermore, combining quasienantiomers that
the two racemic components [(S)-Br (left), (R)-Br (right)] with a differ in Cl and Br substitutions has provided a common theme
for other quasiracemate studies.9,21,22 Though similar in topo-
logical features (spherical), a change from Cl to Br represents a
41% increase in substituent volume and an overall increase in
diarylamide framework volume of 3%. Evidently, the structural
difference imposed by the Cl and Br substituents does not
present a sufficient deterrent to quasiracemate formation. Even
so, we wondered if expanding the margin of shape space using
the Cl/I pair would also achieve similar molecular recognition.
The absence of reports featuring Cl/I quasiracemates, signifi-
cantly different volumes (77% increase for Cl/I and 6% when
considering the entire diarylamide framework), and our lack of
success with growing single crystals of (S)-I/(R)-Cl via solution
methods initially suggested that the spatial difference of this
substituent pair was beyond the structural boundary for quasi-
racemate formation. However, pursuing recognition behavior
of the (S)-I/(R)-Cl quasienantiomeric pair from the melt yielded
key insight to the recognition profile of this system. Inspection
of Fig. 2C reveals a small, but distinct quasiracemic phase
appearing at the boundary of the starting materials. This result,
like that for the (S)-Cl/(R)-Br quasiracemic phase, underscores
the importance of the recognition profile of quasienantiomers
in forming quasiracemates from the melt.
Fig. 1 Melting point phase diagrams of idealized racemic and quasiracemic
mixtures.
Considering the success of the (S)-Cl/(R)-Br and (S)-I/(R)-Cl
systems, could our hot stage approach be broadly applied as a
diagnostic tool for mapping the shape space of quasiracemate
assemblies? The collection of diarylamides selected for this
study differ incrementally in size and shape and provided
55 unique bimolecular combinations (Scheme 1 and Fig. 3A).
Thermally processing all possible sets as before and tabulating
these results provided a comprehensive view of the topological
landscape for this diarylamide family. It is initially worth noting
that heating each enantiomeric pair resulted in, without exception,
Fig. 2 Hot stage polarized light microscopy using the (A) (S)-Br (left) and
(R)-Br (right), (B) (S)-Cl and (R)-Br and (C) (S)-I and (R)-Br pairs showing the
emergence of new racemic and quasiracemic crystalline phases.
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approximate inversion symmetry in these systems and in several
cases provided calculated PXRD patterns for comparison with the
hot stage samples.
As shown, the attraction between pairs of quasienantiomers
results from their complementary topologies and the thermo-
dynamic consequence of constructing approximate inversion
related motifs. Close-packing arrangements achieved from
these near symmetry motifs are significant and provide sufficient
incentive for quasiracemate formation. Even so, what would be the
impact by exchanging the handedness of one component of
a quasiracemate to give (R)-X and (R)-X0 pair [or (S)-X and (S)-X0]
and then assessed using the hot stage method? If the pairs were
Fig. 3 Hot stage microscopy results from combining diarylamide (A)
quasienantiomers and (B) molecular pairs with the same chirality
[e.g. (R)-X and (R)-X0].
the growth of racemic phases where similar shapes of opposing altogether incompatible, then a thermal signature corresponding
chirality influence crystal formation. Such a structural bias during to a conglomerate should result. However, if comparable affinities
the heating stage is significant and indicates the relative thermo- of the (R)-X or (R)-X0 molecules exist for the same compound and
dynamic stability of the racemic phase compared to that of the the other component then the hot stage event will reflect that of a
starting components. This same structural preference should also solid solution. Fig. 4 shows the results from thermally processing
apply to the formation of the diarylamide quasiracemates. The the (R)-Cl/(R)-Br and (R)-I/(R)-Cl systems. The lack of eutectic region
remaining entries in Fig. 3A correspond to the thermal signatures for (R)-Cl/(R)-Br (Fig. 4A, solid solution), but its presence in
of each quasienantiomeric pair. This data offers critical insight to (R)-I/(R)-Cl (Fig. 4B, conglomerate) clearly shows the variation with
those systems where a quasiracemic phase forms, but also high- these thermal signatures. Fig. 3B provides the hot stage results
lights instances where quasiracemates fail to form as indicated by from processing the entire diarylamide family using pairs of
the appearance of a single eutectic region. Several important components of the same chirality. Interestingly, only five of
trends emerge from this data. Combining (S)-H and (R)-F these entries – H/F, Cl/CH3 Cl/NO2, Cl/Br, and NO2/Br – exhibit
diarylamides produced a quasiracemic phase, but conglomerates solid solution behavior. Because the structural principles that
formed upon thermal processing using the other building blocks govern quasiracemic materials do not apply with these systems,
in the series, presumably owing to a greater difference in func- hot stage results from (R)-X/(R)-X0 binary mixtures offer a more
tional group/molecular shape profiles. It is not surprising the subtle assessment tool of molecular topology.
Cl/Br, Cl/CH3, Br/CH3, NO2/CH3 pairs gave new quasiracemic
In summary, we have developed experimental methods
phases since these sets are topologically similar and have been for assessing the structural boundary of molecular shape to
successfully used with other quasiracemic systems.9,20,21,23,24 Of molecular recognition. This strategy probes the complementary
interest are also pairs that result in quasiracemates, but are less spatial features for a sizable family of diarylamide (R)-X/(S)-X0
prevalent in the literature or consist of significantly different and (R)-X/(R)-X0 pairs via hot stage microscopy. Without access
shape spaces (e.g. Cl/I, CN/CF3).
to effective methods for evaluating molecular shape, this study
One outlier in this study is the OCH3 entry where molecular represents a step forward in determining the role of topology
assembly with the second component only occurs with its features to molecules assembly.
enantiomer. This distinct hot stage behavior is consistent with
We gratefully acknowledge financial support of the National
the unique conformational topology of the OCH3 adduct. Unlike Science Foundation (DMR1505717 and CHE0722547) and Eastern
other crystal structures of 2-substituted diarylamides, the struc- Illinois University for Research Activity Awards (ICT and JMS).
ture of (S)-OCH3 shows an intramolecular N–Hꢀꢀ ꢀOCH3 contact
(Nꢀ ꢀ ꢀO, 2.669(3) Å; N–Hꢀ ꢀꢀO, 139(3)1). This interaction controls
the conformation, and thus topological features of (S)-OCH3 as
indicated by a significantly smaller N–C(QO)–CAr–CAr torsion
angle (18.41) compared to other 2-substituted diarylamides
(47.5–79.91).‡
Since the formation of new crystalline phases does not
necessarily signify quasiracemate formation, additional infor-
mation was also retrieved for several sets of these thermally
processed systems (ESI†). Both NMR and powder X-ray diffrac-
tion (PXRD) data were collected for the Cl/Br, CH3/CF3, NO2/CF3,
Br/CF3, and Cl/I pairs and crystal structures were determined or
retrieved from the extant database for the H/F, Cl/Br, NO2/CF3,
NO2/Br, CH3/CF3, and CF3/I quasiracemates. This collective
information offers key support for the assignment of the
Fig. 4 Hot stage polarized light microscopy using the (A) (R)-Cl (left) and
quasiracemic phases generated from these hot stage experi-
ments. Additionally, the crystal structures confirmed the role of
(R)-Br (right) and (B) (R)-I/(R)-Br pairs and showing the characteristics of
solid solution and conglomerate crystalline phase formation.
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‡ N–C(QO)–CAr–CAr torsion angles were retrieved from the CSD entries
LUNPOZ, LUNPOZ01, LUNPUF, LUNQAM, LUNQEQ, and LUNQIU and
crystal structures of quasiracemates H/F, NO2/CF3, NO2/Br, CH3/CF3,
and CF3/I determined for this study.
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