Directing the Solid-State Organization of Racemates via Structural Mutation and Solution-State Assembly Processes

Article abstract of DOI:10.1021/jacs.9b00452

Chirality plays a central role in biomolecular recognition and pharmacological activity of drugs and can even lead to new functions such as spin filters. Although there have been significant advances in understanding and controlling the helical organizati

Full text of DOI:10.1021/jacs.9b00452

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Article
Directing the solid-state organization of racemates via
structural mutation and solution-state assembly processes
Chidambar Kulkarni, Jose Augusto Berrocal, Martin Lutz, Anja R.A. Palmans, and Egbert Willem Meijer
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00452 • Publication Date (Web): 28 Mar 2019
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Directing the solid-state organization of racemates via structural
mutation and solution-state assembly processes
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Chidambar Kulkarni,† José Augusto Berrocal,† Martin Lutz,‡ Anja R. A. Palmans,*,†
E. W. Meijer*,†
† Laboratory of Macromolecular and Organic Chemistry and Institute for Complex Molecular Systems (ICMS), P.O.
Box 513, 5600 MB Eindhoven, The Netherlands
‡ Crystal and Structural Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, 3584 CH Utrecht,
The Netherlands
ABSTRACT: Chirality plays a central role in biomolecular recognition, pharmacological activity of drugs and can even lead
to new functions such as spin-filters. Although there have been significant advances in understanding and controlling the
helical organization of enantiopure synthetic molecular systems, rationally dictating the assembly of mixtures of
enantiomer (including racemates) is nontrivial. Here we demonstrate that a subtle change in molecular structure coupled
with the understanding of assembly processes of enantiomers and racemates, both in dilute solution and concentrated gels,
act as a stepping stone to rationally control the organization in the solid-state. We have studied trans-1,2-disubstituted
cyclohexanes as model systems with carboxamide, thioamide and their combination as functional groups. On comparing
the gelation propensity of individual enantiomers and racemates, we find that racemates of carboxamide, thioamide and
their combination adopt self-sorting, co-assembly and mixed organization, respectively. Remarkably, these modes of
assembly of racemates was also retained in solid-state. These results point out that studying the solution-phase assembly is
a key link for connecting molecular structure with the assembly in the solid-state, even for racemates.
INTRODUCTION
and has been extensively studied,14–20 it is highly dependent
on the system and still poorly understood.
Pasteur’s seminal work on the physical separation of
tartaric acid enantiomers in 1848 has heralded studies to
understand and apply the distinct properties of
enantiomers and their mixtures in a range of systems from
small molecules to polymers.1 An equimolar mixture of
enantiomers is called a “racemate” and it can exist as one
of the following; i) a physical mixture of two non-
interacting enantiomers (conglomerate), ii) a mixture of
Among a plethora of synthetic systems, trans-1,2-
disubstituted cyclohexane derivatives are an important
class of chiral compounds with utility in asymmetric
epoxidation catalysis,21,22 functional materials,23–25 and
organogels.26 At
a mesoscopic level, it has been
demonstrated that trans-1,2-bis(amido)cyclohexanes with
linear alkyl chain substituents on the amides undergo
head-to-tail inter-molecular hydrogen bonding leading to
long, one-dimensional aggregate which can further
entangle to gelate organic solvents at high solute
concentrations.26,27 Both the enantiomeric purity
(enantiopure vs racemic) of the sample26,28 and the nature
of substituents on amide (alkyl chain or perfluoroalkyl
chains)29,30 significantly affect the gelation behavior. On
the other hand, at dilute concentration in apolar solvents,
amide and urea derivatives of trans-1,2-cyclohexane
enantiomers mainly exist as self-sorted assemblies31,32 and
their co-assembly has been shown to be triggered by
enantiomers interacting at
a molecular level (true
racemate), or iii) a disordered mixture of enantiomers
(solid-solution).2,3 Conglomerates are ideally suited for
enriching one of the enantiomers through deracemization
to obtain optically active compounds for use in
pharmaceutical drugs.4–7 On the other hand, a true
racemate or stereo-complex exhibits higher melting
temperature (Tm) and improved material properties for
conventional polymers such as poly(lactide)s.8 Similar
organization for an organic semiconductor such as 1-
aza[6]helicene leads to over 80 fold enhancement in the
electronic properties of a racemate in thin-films compared
to its enantiomers.9 Finally, solid-solutions10,11 are known to
exhibit unique arrangements resembling plastic crystals
(rotatory phase) in the solid-state and such packings are
both fundamentally intriguing12 and technologically
relevant for applications such as proton conduction
channels in fuel cells.13 Although controlling the
organization of enantiomers in a racemate is paramount
specific
charge-transfer33
or
energy-transfer34,35
interactions. Although there are various examples of self-
sorting or co-assembly in solution-phase supramolecular
chemistry using elegant molecular designs,31,36–39
engineering the organization of enantiomers in solid-state
is still a challenging task.
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One of the ways to profoundly influence the
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organization and properties of a system is by subtle
structural changes.40 A typical example of such a change is
the structural isomerism (o- vs p- substitution) coupled
with polymorphism to dictate the conglomerate or true
racemate organization as observed in mandelic acids.41,42
On the other hand, changing an urea group to a thiourea
group has resulted in highly efficient organocatalysts in
solution43 and self-healing polymeric materials in solid-
state.44 Moreover, thioamides exhibit strong inter-
molecular hydrogen-bonding,45,46 increased proteolytic
stability,47 and an opportunity to switch the conformation
from trans- to cis-thioamide with UV light.48 However, the
effect of the substitution of a carboxamide by thioamide
moiety has been rather underexplored to dictate solid-
state organization. Here we harness this subtle structural
effect of substitution of a carboxamide by thioamide in the
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trans-1,2-disubstituted
cyclohexane
systems
and
investigate the effect of such mutation at the molecular,
mesoscopic (gels) and the solid-state level. Remarkably, we
have observed conglomerate, true racemate and solid-
solution in a single molecular system in solid-state based
on changing one or two of the carboxamides into
thioamides.
RESULTS AND DISCUSSION
The system we have studied here is based on trans-1,2-
disubstituted cyclohexane derivatives with n-nonane side-
chains (Figure 1a). The carboxamide derivatives ((1S,2S)-1,
(1R,2R)-1 and (rac)-1) were synthesized by coupling the
corresponding commercially available diamines with
decanoyl chloride. The carboxamides were converted into
their corresponding thioamides (Figure 1a) using
phosphorus pentasulphide as the thionating agent under
reflux conditions in toluene. The detailed synthetic
procedures and characterization are provided in the
supporting information (SI Scheme 1). The purified
carboxamide derivatives (1) were all solid powders at room
temperature. However, the enantiopure thioamides
((1S,2S)-2 and (1R,2R)-2) were low melting solids, which
became solids only after prolonged standing at room
temperature. This already suggested that carboxamides (1)
and thioamides (2) show different properties in solid-state.
Figure 1: Comparison of assembly characteristics of trans-
1,2-cyclohexane carboxamide and thioamide from solution
to gels. a) Chemical structure of the carboxamides and
thioamides studied. b) Variable-temperature (VT) circular
dichroism (CD) spectra of (1R,2R)-1 in MCH (c = 435 µM).
Arrow indicates the spectral changes with decreasing
temperature. c) VT-CD spectra of (1R,2R)-2 in MCH (c = 868
µM). d) Atomic force microscopy height image of (1R,2R)-1
on a freshly cleaved mica surface by drop-casting from an
MCH solution (c = 383 µM). e) Partial VT-1H NMR spectra
of (1R,2R)-2 (c = 18 mM) in MCH-D14. Only the thioamide
N-H region is shown. Inset shows the optimized geometry
of a monomer (at B3LYP/6-31+G(d,p) level of theory) with
alkyl chains replaced by methyl group. The possible intra-
molecular hydrogen-bond is depicted in the inset. f)
Photographs of gelation tests of (1R,2R)-1 and (rac)-1 in
MCH. At 77 mM in MCH, (rac)-1 forms a weak gel, which
upon gentle shaking turns into a dispersion (right photo).
g) Photographs of gelation tests of (1R,2R)-2 and (rac)-2 in
n-heptane as the solvent. (1R,2R)-2 dissolved readily in n-
heptane on sonication and no noticeable change in viscosity
of the solution was observed.
Assembly characteristics of carboxamides and
thioamides from dilute solutions to gels:
We first investigated the assembly characteristics of
both
1 and 2 in dilute apolar solvents, as both
carboxamide49 and thioamide45 motifs are known to
assemble via inter-molecular hydrogen bonding leading to
elongated one-dimensional (1-D) structures in solution.
Circular dichroism (CD) spectra of (1R,2R)-1 in
methylcyclohexane (MCH) (c = 435 µM) exhibit a negative
Cotton effect at 220 nm (Figure 1b). Variable-temperature
(VT) CD measurements show that the molar circular
dichroism (Δε) decreases at higher temperatures but does
not completely vanish at 95 °C, indicative of an
asymmetrically
perturbed
chromophore.
The
temperature-dependence of the molar circular dichroism
suggests that carboxamide groups engage in inter-
molecular interactions. Atomic force microscopy of a
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(1R,2R)-1 film on mica obtained by drop-casting a solution the hydrogen of N-H on C1 of cyclohexane and sulphur of
1
of MCH (c = 383 µM) shows a network of fibers (Figure 1d).
The fiber formation is mainly driven by inter-molecular
hydrogen bonding between monomers of (1R,2R)-1.
However, it has been previously observed for 1,2-
bis(ureido)cyclohexane derivatives that different alkyl
substituents on the two urea groups in the monomer
results in a two dimensional assembly rather than the thin
1-D fibers observed for monomers containing two identical
alkyl substituents on bisurea.50 We anticipate that similar
van der Waals interactions between the side chains are also
important to achieve long 1-D fibers observed for (1R,2R)-1.
Furthermore, at higher concentration (15 mM) (1R,2R)-1
forms stable, transparent gels in MCH. On the contrary,
the racemic carboxamide ((rac)-1), forms only a weak gel
which turns into a suspension on gentle shaking even at
much higher concentration (77 mM, Figure 1f) compared
to its enantiopure counterpart. Similar VT-CD and gelation
characteristics have also been observed for trans-1,2-
bis(amido)cyclohexane with longer alkyl chains on the
carboxamide group.26 Thus enantiomers of 1 form long, 1-
D helical fibers through inter-molecular hydrogen bonding
assisted by the van der Waals interaction between the side
chains. Enantiomers of 1 form stable gels, whereas (rac)-1
forms a weaker assembly compared to its enantiopure form
in apolar solvents.
C=S on C2 of the cyclohexane ring (Inset of Figure 1e). Such
N-H…S distances have been ascribed to hydrogen bonding
in various systems.52 Juxtaposing the downfield shift and
sharpening of thioamide N-H proton with lowering in
temperature and the quantum chemical calculations, we
can conclude that enantiopure thioamides (2) undergo
intra-molecular hydrogen bonding contrary to the inter-
molecular hydrogen bonding observed for carboxamides
(1) in solution state. We further tested the gelation of
thioamides in n-heptane as a solvent which promotes
assembly through enhanced van der Waals interactions
between the solute-solute and solute-solvent. Enantiopure
thioamide (1R,2R)-2 was highly soluble even at 250 mM
concentration in n-heptane. However, (rac)-2 forms an
opaque gel/solid already at 112 mM in n-heptane (Figure 1f).
This indicates that (rac)-2 forms a stronger assembly
compared to enantiopure (1R,2R)-2. The difference in
gelation ability of enantiomers and racemates of
carboxamides (1) and thioamides (2) is completely
contrasting and this triggered our attention to further
study the organization of these systems in solid-state.
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Assembly characteristics of carboxamides and
thioamides in solid-state:
The assembly characteristics of carboxamides (1) and
thioamides (2) in solid-state was studied through
differential scanning calorimetry (DSC), FT-IR and X-ray
scattering techniques, as a combination of these methods
has been shown to be essential to ascertain the
organization of enantiomeric mixtures.53 First we
examined the solid-state assembly of carboxamides (1).
The enantiopure carboxamides (1) exhibit a melting
temperature (Tm) around 192 – 195 °C (determined by
DSC), whereas the (rac)-1 shows a Tm at 156 °C (Figure 2a).
The Tm for both (1R,2R)-1 and (rac)-1 was independent of
the heating rate and only the transition became sharper at
slower heating rates (Figure S5 and S6). The enthalpy of
fusion for both enantiopure ((1R,2R)-1, (1S,2S)-1) and
racemic ((rac)-1) carboxamides are comparable (22 – 25 kJ
mol-1), indicating that the lowering in Tm for (rac)-1 might
be due to entropic factors caused by the packing of alkyl
side chains. DSC analysis of scalemic mixtures (mixture of
enantiomers in ratios other than 1:1) indicate a gradual
transition of Tm from 192 °C (at 0.947 mole fraction of
(1R,2R)-1) to 156 °C (at 0.519 mole fraction of (1R,2R)-1)
(Figure S7 & S8, Table S1), thus reaffirming the lowering of
melting point for the mixture of enantiomers.
Furthermore, FT-IR spectra of enantiopure 1 shows peaks
at 3278 cm-1 and 1634 cm-1 corresponding to hydrogen-
bonded N-H and C=O stretching, respectively (Figure 2b).
The FT-IR spectrum of (rac)-1 also shows peaks at exactly
the same wavenumber as that of the enantiopure 1 (Figure
2b), suggesting that in the solid-state both enantiomers in
the racemate do not interact at a molecular level. To
investigate if the mixing of individual enantiomers has any
influence on their overall packing, we have studied their X-
On the other hand, enantiopure thioamide (1R,2R)-2 was
readily soluble in MCH and the CD spectrum at 25 °C
shows maxima in the Cotton effects at 356 nm (Δε = + 4 L
mol-1 cm-1) and 270 nm (Δε = + 23 L mol-1 cm-1), assigned to
n→π* and π→π* transitions of the thioamide moiety,
respectively (Figure 1c).51 On increasing the temperature of
the solution to 95 °C, the CD spectrum did not decrease in
intensity. Even at a concentration of 868 µM, only minor
shifts were observed (Figure 1c). A similar observation was
made at a much lower concentration of 6 µM (SI, Figure
S1). The invariance of CD spectra (|Δε| = 25 ± 2 L mol-1 cm-
1
at 270 nm) with variation in temperature, concentration
and solvent polarity (SI, Figure S2) strongly suggests that
the Cotton effect arises exclusively from an asymmetrically
perturbed chromophore (thioamide moiety) rather than
due to helical supramolecular arrangement of inter-
molecular hydrogen bonds between the monomers. To
1
further verify this hypothesis, VT H-NMR studies were
carried out on (1R,2R)-2 (c = 18 mM) in MCH-D14 (Figure
S3). The thioamide protons remain sharp even at such high
concentration and this peak undergoes downfield shift
(from 7.83 to 9.41 δ ppm) and sharpens (FWHM lowers,
Figure S4) with lowering the temperature from 90 to -50 °C
1
(Figure 1e). These H-NMR changes clearly suggest; i)
hydrogen bond formation on lowering the temperature
and ii) lack of assembly due to the sharp nature of the peak
down to -50 °C.
To understand the spectroscopic changes observed in VT
1H-NMR, we carried out quantum chemical computations
on a monomer of (1R,2R)-2 with alkyl chains replaced by
methyl groups for computational tractability. The
optimized structure shows close contacts (2.60 Å) between
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Figure 2: Comparison of solid-state assembly of 1 and 2: a) and d) Binary phase diagram of 1 and 2, respectively obtained from
differential scanning calorimetric studies. The melting temperature (Tm) and eutectic temperature (Teu) are determined from the
second heating run at 2 °C min-1. The black solid lines in (a) and (d) represent simulated Tm curves with simplified Schröder-Van
Laar and Prigogine-Defay equations, respectively (See supporting information Table S1 and S2 for details). The dashed line
indicates the variation in Teu and it is a guide to the eye. b) and e) Solid-state FT-IR spectra of 1 and 2, respectively. Important
vibrations are marked in the graph. e) and f) Solid-state powder X-ray scattering profile of 1 and 2, respectively. The first four
major peaks in the scattering profile of 1 are marked along with their corresponding relation to principal peak (q*). The FT-IR
spectra and X-ray scattering profiles are vertically shifted for clarity, thus the transmittance and intensities are relative values.
ray scattering profiles. The powder X-ray scattering
profiles for both enantiopure 1 and (rac)-1 are identical
(Figure 2c) and the ratio of first four peaks follows in all
cases ((1R,2R)-1, (1S,2S)-1 and (rac)-1) a lamellar packing
(q*, √4, √9, and √16 times q*). The thickness of the lamellae
obtained from X-ray studies of 1.9 nm matches well with
the interdigitated packing of alkyl chain of two
cyclohexane moieties. The identical scattering profile for
both individual enantiomers of 1 and (rac)-1, points to the
fact that mixing of the enantiopure compounds does not
alter their packing in solid-state. Thus, the following
observations; i) lowering of Tm for the (rac)-1 compared to
its enantiopure analogue by ~ 37 °C, ii) lack of interaction
between the two individual enantiomers in (rac)-1, as seen
by FT-IR spectroscopy and iii) identical packing for both
individual enantiomers of 1 and (rac)-1 suggests that
indicating that the racemate of thioamide is more stable
compared to individual enantiopure compounds. For
(1R,2R)-2 and (rac)-2, the Tm was found to be independent
of the rate of heating, only the crystallization was affected
by the rate of cooling (Figure S9 and S10). Further DSC
analysis of scalemic mixtures shows the gradual evolution
of Tm from 37.2 °C (at 0.937 mole fraction of (1R,2R)-2) to
81.8 °C (at 0.521 mole fraction of (1R,2R)-2) (Figure S11 & S12
and Table S2), confirming the increased stability for
scalemic and racemic mixture of 2. To investigate if the
apparent stability of racemic thioamide is due to
interaction between the individual enantiomers, FT-IR
studies were carried out. The FT-IR spectra of enantiopure
thioamide show a peak at 3220 cm-1, corresponding to
hydrogen-bonded N-H stretching (Figure 2e). Another
prominent peak at 755 cm-1 was observed and this arises
mostly due to the C=S stretching with contribution from
coupled N-C=S stretching mode.54 The FT-IR spectrum of
(rac)-2, shows the N-H stretching at 3200 cm-1 and the 755
cm-1 mode almost vanishes. A 20 cm-1 shift of N-H
stretching to lower wavenumber for the (rac)-2 (Figure 2e)
indicates a stronger hydrogen-bonding for the racemate
compared to its individual enantiomers. This is in
mixture of enantiomers of
1
exist as individual
components, or in other words form conglomerates or self-
sort in solid-state.
The enantiopure thioamides (2) exhibit a Tm around ~
35 – 37 °C, much lower (by ~ 150 °C) than that observed for
their carboxamide counterpart. However, the racemic
thioamide ((rac)-2) exhibits a Tm at 82 °C (Figure 2d),
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carried out single-crystal X-ray structure determination on
1
2
model compounds.
We have synthesized model thioamide derivatives
((1S,2S)-t-butyl-thioamide and (rac)-t-butyl-thioamide,
Figure 3a) comprising t-butyl groups as substituents in
place of n-nonane to promote the crystallization. The
single-crystals of (1S,2S)-t-butyl-thioamide grown from
slow evaporation of n-heptane with few drops of toluene
crystallize in the non-centrosymmetric triclinic space
group P1 with four independent molecules in the unit cell
(Figure 3b). Interestingly, each of the four molecules have
a unique arrangement with both inter- and intra-molecular
hydrogen bonds involving N-H…S atoms. Both inter- and
intra-molecular hydrogen bond distances (between the
hydrogen and sulphur atoms) were in the range of 2.65 –
2.95 Å, without a clear preference for one of the two modes
of hydrogen bonding. Since both the modes of hydrogen
bonding are equally likely, we anticipate that in the
solution phase intra-molecular hydrogen bonding
dominates and only in the solid-state inter-molecular
hydrogen bonding and steric or van der Waals interactions
of side chains become prominent. Furthermore, single-
crystals of (rac)-t-butyl-thioamide grown from slow
diffusion of n-pentane into toluene solution crystallize in
the triclinic space group P1with one independent molecule
in the asymmetric unit. The unit cell comprises one
molecule of each individual enantiomer related by a
crystallographic inversion center. They interact via both
inter- and intra-molecular hydrogen-bonding. This
unequivocally proves that in the racemate of thioamides,
the individual enantiomers interact with one another
resulting in a co-assembly, or in other words a true-
racemate is formed.
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organization of thioamides: a) Chemical structures of model
thioamide derivatives studied. b) Packing of (1S,2S)-t-butyl-
thioamide in the crystal viewed along the [1,0,0] direction.
Symmetry-independent molecules are drawn in different
colors. Only the major disorder form is shown. c) Hydrogen
bonded dimer in the crystal structure of (rac)-t-butyl-
thioamide. There is only one independent molecule in the
asymmetric unit. Since both the molecules in the unit cell are
related by inversion symmetry, they are depicted with same
color. The minor disorder form is omitted for clarity. In both
(b) and (c), inter- and intra-molecular hydrogen bonds in the
unit cell are shown. The C-H hydrogen atoms are omitted for
clarity.
agreement with the higher Tm observed for the (rac)-2
compared to its enantiopure counterpart. Furthermore,
powder X-ray scattering studies showed that both
enantiopure compounds and racemate of thioamides were
highly crystalline (Figure S13). Due to the highly complex
powder X-ray pattern, the peaks could not be indexed to
any particular crystal packing. However, it can be clearly
observed that (rac)-2 has a completely different powder X-
ray profile in the low scattering vector region compared to
its enantiopure form (Figure 2f), indicating that the (rac)-
2 has a different packing compared to enantiopure
compounds.
Assembly of mixed carboxamide-thioamide system:
The contrasting assembly properties of carboxamide (1)
and thioamide (2) derivatives in solution, gel and solid-
state lead us to an intriguing question “will the mixed
carboxamide-thioamide system (3) exhibit
a mixed
organization (solid-solution) due to the mutual opposing
tendencies of carboxamide and thioamide in solid-state”?
To investigate this, we have synthesized and studied such
mixed systems comprising both carboxamide and
thioamide functional groups within a single enantiomer of
the molecule (3, Figure 4a). The synthesis of mixed system
was carried out by first mono-protecting the trans-1,2-
diamino-cyclohexane with tert-butyloxycarbonyl (t-Boc)
group and further conversion of the unprotected amine
into the corresponding carboxamide using decanoyl
chloride. The crucial synthetic step involved the
conversion of this carboxamide into thioamide without
affecting the t-Boc group and this transformation was
successfully achieved using Lawesson’s reagent. Further
the t-Boc group was deprotected and the resulting amine
was coupled with another equivalent of decanoyl chloride
to obtain the final mixed systems (3, see supporting
information Scheme 3 for details). Both the enantiopure
compounds and racemate of mixed systems (3) were fully
Single-crystal X-ray analysis:
In order to get a thorough understanding of the packing
of individual enantiomers and racemate, we have
performed single-crystal X-ray structure determination.
The crystal structure of an enantiopure carboxamide with
n-butyl side chains has been reported.27 Here, the
carboxamides engage in inter-molecular hydrogen-
bonding between monomers leading to 1-D antiparallel
hydrogen-bonded array. On the other hand, the
unsubstituted, racemic trans-1,2-diaminocyclohexane has
been observed to crystallize as conglomerates,55,56
indicating the strong propensity of these systems to form
conglomerates. This is agreement with our findings that
the (rac)-1 exhibits self-sorting or conglomerate behavior,
as noted in the previous section. However, insights into the
crystal packing of thioamides are scarce and thus we have
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Figure 4: Solid-state assembly study of mixed carboxamide-thioamide system (3): a) Chemical structure of mixed carboxamide-
thioamide systems studied. b) DSC thermograms of 3 with a scan rate of 0.5 °C min-1. The exact Tm for 3 are mentioned in the
graph and the gray bar represents the region of Tm for 3. c) Solid-state powder X-ray profiles of 3. The scattering vector (q)
relationship between the first four major peaks is shown in the graph. The peaks which are distinctly observed for (1S,2S)-3 and
(1R,2R)-3 but become broad or masked in (rac)-3 are marked with an asterisk sign. d) Partial FT-IR spectra of 3 in solid-state.
Prominent vibrations are marked with dashed lines and the corresponding exact values of the vibration are mentioned in the
graph. e) Optimized geometry (at B3LYP/6-31+G(d,p) level of theory) of (1S,2S)-3 model compound (alkyl chains replaced by
methyl groups). Important hydrogen-bond distances and the two kinds of N-H stretching are marked. f) Computed IR spectrum
from the geometry obtained in (e). The FWHM of the peaks was chosen to be 4 cm-1.
characterized by various techniques to confirm their
structural integrity and purity (see SI for synthetic details).
carboxamides and thioamides. With this initial indication
from solution-state studies that mixed systems (3) might
behave in a unique way, we have further studied their
solid-state organization.
First, we have studied the solution-state assembly of
(1S,2S)-3 by using circular dichroism spectroscopy. CD
spectrum of (1S,2S)-3 (c = 50 µM) in MCH at 95 °C shows
two negative peaks at 357 and 277 nm corresponding to
n→π* and π→π* transitions, respectively. On cooling such
a solution till 40 °C, no change in CD spectra was observed.
On further cooling, the Cotton effect increases in
magnitude (Figure S14). These spectral changes indicate
that from 95 to 40 °C, the Cotton effect is mainly due to
asymmetrical perturbation of chromophore and below 40
°C the increase in magnitude of Cotton effect can be
interpreted as due to assembly of monomeric units leading
to helical aggregates. While the carboxamide ((1R,2R)-1)
and thioamide ((1R,2R)-2) show monotonic changes and
temperature-independent Cotton effect, respectively
(Figure 1b and c), the mixed system ((1S,2S)-3) shows a two-
stage temperature-dependent CD changes in solution-
state. Furthermore, it was observed that the critical
gelation concentration for both (1S,2S)-3 and (rac)-3 in n-
heptane was around 275 mM (Figure S15). This indicates
that the assembly characteristics of individual enantiomers
The thermal behavior of enantiopure (1S,2S)-3 was first
studied using DSC at various scan rates. At the faster scan
rate of 10 °C min-1, we observed an endothermic transition
around 75 °C, just below the melting temperature of 79 °C.
On slower heating/cooling at 0.5 °C min-1, the transition
around 75 °C decreases considerably and a sharp Tm at 79.1
°C (ΔHf = 18.78 kJ mol-1) was observed (Figure S16).
Moreover, the crystallization temperature shifts from 62 °C
to 66 °C on decreasing the scan rate from 10 to 0.5 °C min-
1. For (rac)-3, a Tm at 70 °C was observed at scan rates of 10
and 20 °C min-1. However, at 0.5 °C min-1, the Tm drastically
shifts completely to 79 °C and moreover the crystallization
temperature shifts to 40 °C and becomes broad (Figure
S17). Similar DSC runs on (1R,2R)-3 at slow scan rate
showed a Tm of 78.9 °C (Figure 4b). The remarkably
concurrent and single Tm of 79 ± 0.1 °C for both the
enantiopure 3 and (rac)-3 suggests that mixed systems
might exhibit solid-solution organization. Furthermore, it
is worth noting here that the Tm of enantiopure
and racemate of
3
are intermediate to those of
compounds of 3 (79 °C) falls in-between that of
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Here we have studied the assembly processes of trans-
1
1,2-disubstituted cyclohexane systems with carboxamide
(1), thioamide (2) and their combination (3) as functional
groups from dilute solution to solid-state. We have
observed that both enantiopure compounds and racemate
of 1 and 2 exhibit contrasting assembly in dilute solution
and gelation behavior. Such an assembly behavior is also
reflected in the solid-state organization, with racemates of
1 and 2 showing self-sorting or conglomerate and
coassembly or true-racemate, respectively (Figure 5).
Detailed crystallographic studies on model compounds of
2 showed the existence of both inter- and intra-molecular
hydrogen bonding. The intra-molecular hydrogen bonding
observed for thioamides (2) is mainly responsible for their
unique assembly characteristics in different phases such as
solution and solid-state. The mixed carboxamide-
thioamide system (3) showed intermediate assembly
characteristics in both dilute solution and solid-state.
Moreover, racemate of 3 form mixed organization or solid-
solution in solid-state, mostly due to the competing
assembly characteristics of carboxamide and thioamide
functional units (Figure 5). Although solid-solutions of
multicomponent crystals are extensively studied,10 reports
on solid solutions of enantiomeric mixtures are scarce.11
Thus, we have shown a complete control over the solid-
state organization of racemates by subtle structural
variation of the molecular building blocks. We envisage
that the above outlined approach of understanding the
assembly of molecules in dilute solution and more
concentrated gels as a guiding principle to gain control
over solid-state assembly is a powerful methodology which
can be applied to various systems.
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Figure 5: A schematic illustration of the solid-state assembly
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of the racemates of three trans-1,2-disubstituted cyclohexanes
investigated in this study (1 – 3). For each of the systems light
and dark shades are used to depict the (1R,2R) and (1S,2S)
enantiomers, respectively.
carboxamide (1, 192 °C) and thioamide (2, 37 °C)
enantiopure compounds, indicating that the mutation at
the molecular level affects the macroscopic properties in a
predictable manner.
We have further looked into the FT-IR spectra of
enantiopure 3 and (rac)-3 to ascertain their organization.
FT-IR spectra of the enantiopure 3 shows two prominent
peaks at 3304 cm-1 and 3230 cm-1 in the N-H stretching
region (Figure 4d). Based on quantum chemical
computations of a dimer of (1S,2S)-3 with alkyl chains
replaced by methyl, we assign the peaks at 3304 cm-1 and
3230 cm-1 to arise from the N-H stretching peak of the
C=S…N-H (ν1) and C=O…N-H (ν2) hydrogen-bonded motifs,
respectively (Figure 4e and 4f). Also, for the enantiopure 3,
the C=O stretching is observed at 1647 cm-1, again pointing
to hydrogen-bonded carbonyl motif. For (rac)-3, both the
N-H stretching vibrations shift to higher wavenumbers
(3414 cm-1 and 3256 cm-1) and the C=O stretching shifts to
1621 cm-1. The weakening of the N-H and strengthening of
C=O hydrogen-bonded vibrations in the (rac)-3 suggests a
rearrangement in the hydrogen-bonding pattern.
Furthermore, powder X-ray scattering profiles of
enantiopure 3 and (rac)-3 are very comparable (Figure 4c).
The small difference between the X-ray profiles of
ASSOCIATED CONTENT
Supporting Information. Synthetic procedures, Additional
DSC thermograms, Single crystal structure determination
details and Spectral copies. “This material is available free of
charge via the Internet at http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
enantiopure and racemic
3 might be due to the
* e.w.meijer@tue.nl
a.palmans@tue.nl
polymorphism of the system.57–59 Detailed analysis
suggests that both enantiopure 3 and (rac)-3 form lamellar
arrangement with d-spacing of 3.9 nm. The observations
such as i) remarkably identical Tm for both enantiopure 3
and (rac)-3, and ii) similar packing as evidenced by powder
X-ray scattering profile and FT-IR spectra suggests that
mixed carboxamide-thioamide system (3) forms solid-
solution with polymorphism. Due to the rather complex
polymorphism and scan rate dependence of DSC profiles,
here we refrain from definitely assigning the present
system (3) to one of the three kinds of solid-solution
possible.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
ACKNOWLEDGMENT
We thank NWO (TOP-PUNT Grant 10018944) and the Dutch
Ministry of Education, Culture, and Science (Gravitation
program 024.001.035) for financial support. C.K. acknowledges
Marie Skłodowska-Curie postdoctoral fellowship (704830) for
financial support. We thank Dr. Bas van Genabeek and
Brigitte Lamers for powder X-ray measurements. We thank
OGO molecules and materials 2017-batch students for their
help with synthesis in the initial phase of this work. C.K.
CONCLUSIONS
1
thanks Marcin L. Ślęczkowski for help with VT H-NMR
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Page 8 of 10
racemates in the same assemblies. Chem. Commun. 2013, 49, 9320,
DOI: 10.1039/c3cc45806g.
(17) Palmans, A. R. A. Deracemisations under kinetic and
thermodynamic control. Mol. Syst. Des. Eng. 2017, 2, 34, DOI:
10.1039/C6ME00088F.
(18) Pérez-García, L.; Amabilino, D. B. Spontaneous resolution,
whence and whither: From enantiomorphic solids to chiral liquid
crystals, monolayers and macro- and supra-molecular polymers
and assemblies. Chem. Soc. Rev. 2007, 36, 941, DOI:
10.1039/b610714a.
(19) Lorenz, H.; Seidel-Morgenstern, A. Processes to separate
enantiomers. Angew. Chem. Int.Ed. 2014, 53, 1218, DOI:
10.1002/anie.201302823.
measurements, Ralf Bovee for elemental analysis, and Dr.
Xianwen Lou for assistance with chiral-HPLC analysis. We
thank Prof. Richard M. Kellogg for fruitful discussions.
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