A spontaneous single-crystal-to-single-crystal polymorphic transition involving major packing changes

Article abstract of DOI:10.1021/ja512697g

4,6-O-Benzylidene-α-d-galactosyl azide crystallizes into two morphologically distinct polymorphs depending on the solvent. While the α form appeared as thick rods and crystallized in P2₁ space group (monoclinic) with a single molecule in the asymmetric unit, the β form appeared as thin fibers and crystallized in P1 space group (triclinic) with six molecules in the asymmetric unit. Both the polymorphs appeared to melt at the same temperature. Differential scanning calorimetry analysis revealed that polymorph α irreversibly undergoes endothermic transition to polymorph β much before its melting point, which accounts for their apparently same melting points. Variable temperature powder X-ray diffraction (PXRD) experiments provided additional proof for the polymorphic transition. Single-crystal XRD analyses revealed that α to β transition occurs in a single-crystal-to-single-crystal (SCSC) fashion not only under thermal activation but also spontaneously at room temperature. The SCSC nature of this transition is surprising in light of the large structural differences between these polymorphs. Polarized light microscopy experiments not only proved the SCSC nature of the transition but also suggested nucleation and growth mechanism for the transition.

Full text of DOI:10.1021/ja512697g

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Article
A spontaneous single-crystal-to-single-crystal
polymorphic transition involving major packing changes
Baiju P Krishnan, and Kana M. Sureshan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja512697g • Publication Date (Web): 13 Jan 2015
Downloaded from http://pubs.acs.org on January 16, 2015
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Journal of the American Chemical Society
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A spontaneous single-crystal-to-single-crystal polymorphic
transition involving major packing changes
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Baiju P. Krishnan, and Kana M. Sureshan*
School of Chemistry, Indian Institute of Science Education and Research Thiruvananthapuram, Kerala, 695016,
India.
ABSTRACT: 4,6ꢀOꢀbenzylideneꢀβꢀDꢀgalactosyl azide crystallizes into two morphologically distinct polymorphs depending on the
solvent. While the α form appeared as thick rods and crystallized in P 21 space group (monoclinic) with a single molecule in the
asymmetric unit, the β form appeared as thin fibers and crystallized in P1 space group (triclinic) with six molecules in the asymmetꢀ
ric unit. Both the polymorphs appeared to melt at the same temperature. DSC analysis revealed that polymorph α irreversibly unꢀ
dergoes endothermic transition to polymorph β much before its melting point, which accounts for their apparently same melting
points. Variable temperature PXRD experiments provided additional proof for the polymorphic transition. Singleꢀcrystal XRD
analyses revealed that α to β transition occurs in a singleꢀcrystalꢀtoꢀsingleꢀcrystal (SCSC) fashion not only under thermal activation
but also spontaneously at room temperature. The SCSC nature of this transition is surprising in light of the large structural differꢀ
ences between these polymorphs. Polarized light microscopy experiments not only proved the SCSC nature of the transition but
also suggested nucleation and growth mechanism for the transition.
showed thin fibrillar morphology (form β, Figure 1C). NMR
characterization and combustion analyses of these crystals
INTRODUCTION
revealed the sample homogeneity and absence of any solvent
in the crystal lattice of both the forms suggesting that these
two forms are polymorphs of 1. Interestingly, FTIR spectra of
the two crystal forms were very distinct; The α form showed
two distinct OH stretching bands; a broad signal at frequency
3084ꢀ3493 cmꢀ1 suggestive of the presence of hydrogen bondꢀ
ed OH groups and a sharp signal at 3540 cmꢀ1 indicative of the
presence of nonꢀhydrogenꢀbonded OH group too (Figure 1D).
The β form showed only a broad OH stretching band at freꢀ
quency 3023ꢀ3633 cmꢀ1 suggesting that only hydrogenꢀbonded
OHs are present in this form (Figure 1E). Thus FTIR studies
suggest that in α form only one of the two hydroxyl groups is
involved in hydrogen bonding and in β form both the hydroxyl
groups are involved in hydrogen bonding.
Polymorphism, the phenomenon of existence of a particular
compound in two or more crystalline states, is of great scienꢀ
tific1 and commercial2 interest. Polymorphism arises from
different conformation or packing arrangement in the crystal
lattice.3 Though molecules in crystals have limited mobility,
often part or whole molecule undergo conformational change
or slight translational motion spontaneously or under activaꢀ
tion by heat, pressure, light etc. Such motion either leads to
chemical reactions within the crystal (topochemical reactions4)
or rearrangement to another polymorph of the same compound
(polymorphic transition5). Polymorphic transitions occur
mainly through (i) reconstructive mechanism (nucleation and
crystal growth) or (ii) topotactic/epitactic mechanism.6 Most
polymorphic transitions occur via reconstructive mechanism
leading to the disruption of packing continuity rendering the
resulting polymorphs unsuitable for single crystal XRD
(SCXRD) analysis.7 Singleꢀcrystalꢀtoꢀsingleꢀcrystal (SCSC)
polymorphic transitions,5a,5b,8 occur mainly via topotactic or
epitactic mechanism and usually in such cases both the polyꢀ
morphs (parent and daughter crystals) have close structural
relationship.9 SCSC polymorphic transition between two difꢀ
ferent polymorphs having large structural difference is one of
the rarest phenomena.8m,10 Herein, we report a spontaneous
SCSC polymorphic transition involving large packing changes
from a Zʹ = 1 polymorph to Zʹ = 6 polymorph.
RESULTS AND DISCUSSION
During our ongoing project of synthesizing various sugar
containing triazoles, we have observed that 4,6ꢀOꢀ
benzylideneꢀβꢀDꢀgalactosyl azide (1, Figure 1A) crystallizes
in different solvents to morphologically distinct crystals. For
instance, crystals formed from dichloromethane (DCM) soluꢀ
tion showed thick rodꢀlike morphology (form α, Figure 1B),
whereas the crystals obtained from benzene or ethyl acetate
Figure 1. Chemical structure of compound 1 (A). Photograph of
polymorphs, α (B) and β (C). FTIR spectra of polymorphs α (D)
and β (E).
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Single crystal XRD (SCXRD) analysis of both the forms reꢀ was observed when the preheated (to 145 °C) crystals of the α
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vealed they are polymorphs of 1. While the α form crystallized
in the space group P 21 (monoclinic) with a single molecule in
the asymmetric unit (Figure 2A), the β form crystallized in the
space group P1 (triclinic) with six molecules (conformers AꢀF)
in the asymmetric unit (Figure 2B & Table S1 in the Supportꢀ
ing Information). There are significant differences in the Hꢀ
bonding patterns of these two polymorphs. As expected from
the IR data, only one of the two hydroxyl groups is involved in
hydrogen bonding (O2ꢀH2ʹ…O2) in the crystal structure of
polymorph α forming a hydrogen bonded zigzag chain along
‘b’ direction (Figure 2C). The other hydroxyl group is inꢀ
volved in two relatively weaker interactions; an OH…π hyꢀ
drogen bond and a CꢀH…O hydrogen bond (Table S2 in the
Supporting Information). In polymorph β, all the hydroxyl
groups of all the six conformers are involved in intermolecular
hydrogen bonding, as was expected based on the IR studies,
forming an interlinked hydrogen bonded chains along ‘a’ diꢀ
rection (Figure 2D). In addition to these strong hydrogen
bonds, the polymorph β is further stabilized by several Cꢀ
H…O, CH…N and CH…π interactions (Table S3 in the Supꢀ
porting Information). Hirshfeld analysis also gave additional
proof for the presence of these interactions (Supporting Inforꢀ
mation).11 It is apparent from the crystal structures that the β
form having more hydrogen bonding interactions is more staꢀ
ble than α form.
form were cooled to ꢀ70 °C (Figure S17 in the Supporting
Information) or even after keeping the preheated crystals at
liquid nitrogen temperature for 4h, suggesting that the transiꢀ
tion is irreversible.
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Figure 2. Asymmetric unit of polymorphs, α (A) and β (B). Hyꢀ
drogen atoms are omitted for clarity. Packing arrangement of α
viewed along ‘a’ direction (C) and β viewed along ‘c’ direction.
Six conformers are colorꢀcoded as red, green, black, pink, cyan
and blue (D).
Figure 3. (A) DSC curves of polymorphs, α (i) and β (ii). (B)
TGA curves of polymorphs, α (i) and β (ii). (C) Comparison of
PXRD patterns of polymorph α (i), polymorph β (ii), form α preꢀ
heated to 140 ºC (iii) and polymorph α aged at room temperature
(iv).
Though morphologically and structurally different, both the
polymorphs showed apparently same melting point (Tm = 165
°C). However, Differential Scanning Calorimetry (DSC) curve
of α form showed an endothermic peak at 140 °C (ꢁH = 2.21
kJ/mol) well before its melting point, suggestive of some
chemical or physical change in the solid state (Figure 3A). The
TGA profile of α form did not show any weight loss at 140 °C,
Powder XRD (PXRD) of both the polymorphs were very
distinct as anticipated (Figure 3C:i&ii). Interestingly, the polꢀ
ymorph α upon heating transforms to the polymorph β as eviꢀ
dent from the PXRD pattern of a sample of polymorph α heatꢀ
ed to 140 ºC (Figure 3C:iii). FTIR spectrum of this heated
sample was also indistinguishable from that of polymorph β,
suggesting that the nonꢀhydrogenꢀbonded OH group become
hydrogenꢀbonded after transition (Figure S18 in the Supportꢀ
ing Information). This also suggests that a more stable form is
being formed after the transition. Variable temperature PXRD
of polymorph α also suggested its transition to polymorph β
(Figure 4A). In light of this polymorphic transition before
melting point, it is not surprising that both the polymorphs
showed apparently same melting point.
1
ruling out any possible loss of its fragments (Figure 3B). H
NMR spectrum of a sample of α form heated to 145 °C was
1
indistinguishable from the H NMR of a fresh sample of 1
ruling out the possibility of any chemical change being reꢀ
sponsible for the endothermic peak at 140 °C (Figure S16 in
the Supporting Information). These results suggest that some
possible phase change occurs prior to the melting, possibly a
polymorphic transition. However, no polymorphic transition
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This suggests that the polymorphic transition from polymorph
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α to polymorph β could be a SCSC transition. In order to
probe this, we have carried out SCXRD analysis of same crysꢀ
tal of polymorph α before and after the transition. We have
mounted a single crystal of polymorph α on a glass fiber and
collected its Xꢀray data (and solved as polymorph α) and then
taken out of the goniometer along with the glass fiber and
heated in a test tube kept at a constant temperature bath (140
°C) for 5 minutes. Again the Xꢀay data was collected for this
heated sample and solved its structure, which showed that the
crystal has undergone polymorphic transition to βꢀform. This
clearly supports that it is a SCSC transition (Figure S20 in the
Supporting Information). In order to understand the structural
changes during transition from polymorph α to β, we have
compared their crystal packing.
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From an analysis of crystal packing, it is clear that polyꢀ
morph β has a twoꢀfold modulation arising from minor conꢀ
formational changes; A & A', B & B' and C & C' are nearly
superimposable pairs (Figure 4C). For a comparison of packꢀ
ing, this can be simplified as three conformers, A, B & C
(Figure 4D). Figure 4F shows a comparison of packing of
polymorph α viewed along ‘b’ direction and polymorph β
along ‘a’ direction. In polymorph α, molecules in the alternate
columns are color coded as red and blue and the molecules
below the blue are coded in green for convenience. Due to the
zigꢀzag hydrogen bonded assembly along ‘b’ direction, moleꢀ
cules in alternate columns fall on the same plane (red moleꢀ
cules on any two different columns) and molecules on adjaꢀ
cent columns are out of plane (red and blue molecules on adꢀ
jacent columns) as shown in Figure 4G. The representative A,
B and C conformers of polymorph β are color coded as green,
blue and red respectively. It is clear that both green and blue
molecules of α, which are Hꢀbonded to red molecules, have to
undergo considerable rotation (green by 55° clockwise about
‘a’ axis & blue by 90° clockwise about ‘a’ and 180° clockwise
about ‘c’) to transform into β (Figure 4F).
It is surprising that despite having major structural changes,
the polymorphic transition is happening in an SCSC fashion.
Rarely occurring SCSC transitions between polymorphs havꢀ
ing large structural difference8m,10 are known to occur via nuꢀ
cleation and growth mechanism and can easily be distinꢀ
guished by polarized light microscopy. In order to see, whethꢀ
er the transition from α to β, occurs via such a mechanism, the
crystals of polymorph α was heated on a hotꢀstage polarizing
microscope until melting. The color of the birefringence of the
crystal changed during transition, and the growth of the new
phase could be seen from a nucleation point (Figure 5A). At
the melting point (165 °C), the interference pattern disapꢀ
peared as expected (Supporting Information). Thus the hotꢀ
stage polarizing microscopy (HSM) experiments provide addiꢀ
tional proof for the SCSC nature of the transition and for the
nucleation and growth (reconstructive) mechanism.
Figure 4. (A) Variable temperature PXRD patterns of polymorph α.
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Photographs of single crystal of polymorph α (B) before and (C) after
heating at 140 ˚C for 5 minutes. (D) Two fold modulation of polyꢀ
morph β viewed along the ‘a’ direction. (E) Three representative
conformers of polymorph β in ‘bc’ plane. (F) Comparison of packing
of polymorphs α (‘ac’ plane) and β (‘bc’ plane). (G) Comparison of
packing arrangements of polymorph α (‘bc’ plane) with that of polyꢀ
morph β (‘ac’ plane) showing the gain in number of hydrogen bonds
after transition.
The crystals of polymorph α heated to 145 °C, which unꢀ
derwent transition to polymorph β, were transparent and morꢀ
phologically indistinguishable from fresh unheated crystals.
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pected, the experimental results gave a negative value for the
free energy change of the transition (ꢁG = ꢀ0.459 kJmolꢀ1 at
room temperature), justifying the spontaneity of polymorphic
transition. However, the ꢁH of the transition (ꢁH = 1.879
kJmolꢀ1) was found to be positive even at room temperature.
This suggests that the positive TꢁS term offsets the positive
ꢁH term to make the process spontaneous.
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CONCLUSION
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In summary, we report a pair of polymorphs of a sugar deꢀ
rived molecule, obtainable by crystallization from different
solvents. The metastable polymorph irreversibly transforms
into the thermodynamically stable polymorph not only under
thermal activation but also spontaneously at ambient temperaꢀ
ture. Notably, this transition happens in an SCSC fashion even
though they don’t have very similar orientation relationship.
SCSC polymorphic transitions usually occur when both the
polymorphs have close structural relationship. Polymorphic
transition between polymorphs having large structural differꢀ
ences usually proceeds through nucleation and growth, leading
to the loss of singleꢀcrystalline nature. Polarized light microsꢀ
copy studies show that this SCSC polymorphic transition from
polymorph α to polymorph β occurs through nucleation and
crystal growth. To the best of our knowledge, this is the first
report on the spontaneous SCSC polymorphic transition from
a Zʹ = 1 structure to a Zʹ = 6 structure which are not closely
related in their packing. Our results suggest that polymorphic
transitions involving large structural changes can occur in an
SCSC fashion.
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Figure 5. (A) Hotꢀstage polarizing microscopy images of polyꢀ
morph α showing the nucleation and growth. (B) DSC profiles of
polymorph α carried out at different heating rates 25 °C/min (i),
15 °C/min (ii), 10 °C/min (iii) and 5 °C/min (iv). (C) Crystal
packing arrangement of an aged sample (kept at r.t. for 2 months)
of polymorph α.
According to heat of transition rule,12 if endothermic phase
transition is involved, the polymorphs are related enantiotropiꢀ
cally and such polymorphic transitions are reversible and their
thermodynamic transition temperature lies below the experiꢀ
mental transition temperature. There are cases where the enanꢀ
tiotrops are not reversible due to kinetic factors13 and in such
cases the experimental transition temperature varies with the
heating rate.14The endothermic and unidirectional polymorphic
transition from α to β form suggests that this is a kinetically
irreversible enantiotropic transition. DSC analyses with differꢀ
ent scan rate revealed that the transition temperature varied
with the heating rate as anticipated (Figure 5B) proving that it
is indeed a case of kinetically irreversible enantiotropic transiꢀ
tion.
ASSOCIATED CONTENT
Supporting Information
Details of synthesis & characterization of 1, DSC, PXRD, singleꢀ
crystal XRD, IR, NMR and Thermodynamic parameters determiꢀ
nation. “This material is available free of charge via the Internet at
http://pubs.acs.org.”
Interestingly we have observed a slow conversion of polyꢀ
morph α into polymorph β even at ambient temperature.
PXRD pattern of an aged sample of polymorph α (stored at
room temperature for 3 weeks) showed the presence of both
the polymorphs, α and β (Figure 3C:iv). Singleꢀcrystal Xꢀray
analysis of an aged crystal of polymorph α kept at rt for one
month revealed that it underwent spontaneous SCSC transꢀ
formation to polymorph β (Figure 5C). The spontaneous forꢀ
mation of polymorph β from polymorph α at room temperaꢀ
ture suggests that the actual transition temperature must be
below room temperature. It is clear that the polymorph β (Z′ =
6) is thermodynamically more stable than the polymorph α (Z′
= 1). It is noteworthy that the high Z′ polymorphs are generalꢀ
AUTHOR INFORMATION
Corresponding Author
kms@iisertvm.ac.in
ACKNOWLEDGMENT
We thank Mr. Alex P. Andrews for his technical help in executing
this project. B. P. K. thanks University Grants Commission
(UGC) for Junior Research Fellowship assistance. K.M.S. thanks
Department of Science and Technology (DST, India) for a Ramaꢀ
nujan Fellowship, Swarnajayanti Fellowship and a Fast Track
grant and CSIR for an EMR project grant.
ly considered as thermodynamically less stable or metastable
15 16
kinetic polymorphs
. A CSD analysis of polymorphic pairs
with different Z′ revealed that the low Z′ forms are stable in
majority of the cases (Supporting Information).17 High Z′
structures and the factors that determine their formation are of
current interest.18
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