other hand, the Raman spectrum of polymorph III is clearly distinctive from those
of polymorphs I and II, suggesting a significant dissimilarity in the H-bond network
of polymorph III compared to those of polymorphs I and II (no Raman spectrum
could be obtained for polymorph IV, which was found to be very labile, promptly
converting to other polymorphs).
7.4.3 Hydantoins: The Unusual Conformational Selection
in AAH upon Crystallization
Several polymorphs were also identified for AAH, which could be characterized by
DSC, PLTM, Raman spectroscopy, and XRD. Polymorph I corresponds to the
commercial sample used, while the remaining polymorphs (II-V) were obtained by
recrystallizations from different solvents. The melting points of polymorphs I, II,
III, and V were found to be 214.3 ± 0.8, 184–185, 175–178, and 198–200 °C,
respectively. Polymorph IV transforms into V at 180–185 °C. Until now, only in
the case of polymorph III suitable crystals could be produced for single crystal
structure determination. The crystal was found to be orthorhombic, P2 1 2 1 2 1 space
group, Z = 4, a = 7.6148(5) Å, b = 8.5592(6) Å, and c = 9.3406(6) Å. The
molecules form chains interconnected by H-bonds (N–H⋯OH), which define
parallel sheets of molecules.
Very interestingly, the molecules in the crystal assume the conformation of the
highest energy form predicted for the isolated molecule situation (Fig. 7.4), which
has a predicted relative energy of ca. 40 kJ mol
−1 . Considering that AAH has 13
conformers, it is impressive that the highest energy form is the one present in the
crystal. It is relatively frequent that crystallization takes place with selection of
conformers that are not the lowest energy form of the isolated molecule. However,
the selection of the most energetic among 13 conformers, with a relative energy as
high as 40 kJ mol
−1 is, certainly, a very rare case, implying a strongly favorable
packing of the molecules in the crystal that can overcome the intrinsic unfavorable
energetic requirements of the selected constituting unit. The Raman spectroscopy
data obtained for the different AAH polymorphs is in agreement with this conclusion. In fact, the spectra of the polymorphs (Fig. 7.13) exhibit notorious differences, which are compatible with substantially different crystal structures that, in
turn, can be correlated with existence of strong intermolecular interactions and
specific packing requisites. The accentuated dissimilarity between the Raman
spectra of the different polymorphs may also indicate that the conformation(s)
assumed by the individual molecules in each polymorph might be different.
Confirmation of this hypothesis requires the determination of the crystal structure of
the various polymorphs. Studies are on the way to achieve this goal.
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R. Fausto et al.
of polymorphs I and II, suggesting a significant dissimilarity in the H-bond network
of polymorph III compared to those of polymorphs I and II (no Raman spectrum
could be obtained for polymorph IV, which was found to be very labile, promptly
converting to other polymorphs).
7.4.3 Hydantoins: The Unusual Conformational Selection
in AAH upon Crystallization
Several polymorphs were also identified for AAH, which could be characterized by
DSC, PLTM, Raman spectroscopy, and XRD. Polymorph I corresponds to the
commercial sample used, while the remaining polymorphs (II-V) were obtained by
recrystallizations from different solvents. The melting points of polymorphs I, II,
III, and V were found to be 214.3 ± 0.8, 184–185, 175–178, and 198–200 °C,
respectively. Polymorph IV transforms into V at 180–185 °C. Until now, only in
the case of polymorph III suitable crystals could be produced for single crystal
structure determination. The crystal was found to be orthorhombic, P2 1 2 1 2 1 space
group, Z = 4, a = 7.6148(5) Å, b = 8.5592(6) Å, and c = 9.3406(6) Å. The
molecules form chains interconnected by H-bonds (N–H⋯OH), which define
parallel sheets of molecules.
Very interestingly, the molecules in the crystal assume the conformation of the
highest energy form predicted for the isolated molecule situation (Fig. 7.4), which
has a predicted relative energy of ca. 40 kJ mol
−1 . Considering that AAH has 13
conformers, it is impressive that the highest energy form is the one present in the
crystal. It is relatively frequent that crystallization takes place with selection of
conformers that are not the lowest energy form of the isolated molecule. However,
the selection of the most energetic among 13 conformers, with a relative energy as
high as 40 kJ mol
−1 is, certainly, a very rare case, implying a strongly favorable
packing of the molecules in the crystal that can overcome the intrinsic unfavorable
energetic requirements of the selected constituting unit. The Raman spectroscopy
data obtained for the different AAH polymorphs is in agreement with this conclusion. In fact, the spectra of the polymorphs (Fig. 7.13) exhibit notorious differences, which are compatible with substantially different crystal structures that, in
turn, can be correlated with existence of strong intermolecular interactions and
specific packing requisites. The accentuated dissimilarity between the Raman
spectra of the different polymorphs may also indicate that the conformation(s)
assumed by the individual molecules in each polymorph might be different.
Confirmation of this hypothesis requires the determination of the crystal structure of
the various polymorphs. Studies are on the way to achieve this goal.
218
R. Fausto et al.