Crystal Growth & Design
ARTICLE
Figure 2c,e) were confirmed by the measured Raman spectra
assuming that the heat capacity of the materials is temperature
independent.
(Figure 5) which show identical spectra for the enantiomer and
the conglomerate while that of the racemic compound, form R,
shows clear differences in both the hydroxyl and carbonyl stretch-
ing regions.
Overall these studies confirm the conclusions of He et al. and
show conclusively the existence of the metastable conglomerate.
!
f
T
f
E
R
f
f
R
ΔG° ¼ ΔH 1 ꢀ
ꢀ T R ln 2
ð1Þ
T
E
10
ꢀ
1
Using our measured values eq 1 gives a ΔG° of ꢀ0.30 kJ mol .
3
5
3
.2. Crystallization from Melts and Solutions. In this
Collet points out that the most stable racemic compounds have
ꢀ
1
section, we report on preliminary crystallization experiments,
which reproducibly led to the appearance of the conglomerate.
Melting and rapid solidification of (Sigma-Aldrich) racemic
values for this free energy change over ꢀ8.4 kJ mol ; for the
3
ꢀ
1
majority of racemic compounds ΔG° is smaller than ꢀ4.2 kJ mol .
3
A zero value would indicate that the formation of a conglomerate is
equally as probable as the formation of a racemic compound. In our
case, the Gibbs free energy for the racemic compound is negative but
very close to zero indicating a low relative stability of the racemic
compound.
2
-chloromandelic acid on a Petri dish yielded a solid having the
XRPD of the pure enantiomer.
This appears to be consistent with observations made both by
hot stage microscopy and DSC. Figure 6, for example, shows hot
stage microscopy images of the recrystallization of a racemic melt
prepared by heating form R of the racemic compound to 120 °C.
Cooling to 25 °C and reheating yielded first the growth of the
conglomerate, seen in Figure 6a,b at 48 and 64 °C followed by
the transformation to the racemic compound illustrated in
Figure 6c,d at 76 and 83 °C.
The evidence of the presence of a conglomerate of 2-chloro-
mandelic acid that is metastable compared to the (stable)
racemic compound, together with the diminutive existence
region of the racemic compound in the phase diagram (Figure 8)
are thus consistent with this very low free energy gain. Practically,
this situation leads to the observation that the occurrence of the
racemic compound versus the conglomerate can depend on the
crystallization (reaction) conditions.
Figure 7 shows an associated DSC heating experiment using
an equimolar mixture of conglomerate and racemic compound
form R. Here the melting of the metastable conglomerate
starts at 83 °C, and the racemic compound recrystallizes
almost instantly from the melt and finally melts at 90 °C
The binary phase diagram of the (R,S)-2-chloromandelic acid
system is shown in Figure 8. The liquidus lines were calculated
according to the Schr €o der-van Laar and Prigogine-Defay
4
(peak onsets).
equations. The phase diagram clearly emphasizes the existence
This metastable conglomerate was also accessible by solu-
of a racemic compound that melts at a slightly higher tempera-
ture than the racemic conglomerate, ca. 90 °C vs 83 °C. The
intersection of the liquidus lines of the pure enantiomer and the
racemic compound determines the eutectic composition at a
mole fraction of 0.56 and the corresponding eutectic temper-
ature at 87.5 °C. The eutectic composition observed in the
vicinity of the racemic composition specifies a small existence
region for the racemic compound and therefore, a comparatively
low or limited stability of this compound as mentioned already
above. The part of the liquidus curve that falls below this eutectic
line characterizes metastable states matching the melting tem-
perature of the metastable conglomerate at racemic composition
of ca. 82 °C. The measured values for the corresponding eutectic
temperature vary between 78 and 83.5 °C (mean value 80 °C), a
feature that may be attributed to the different sources of the
2-chloromandelic acid containing different amounts and identi-
ties of impurities. Attempts to identify the impurities using a
tion crystallization using material prepared by the synthetic
route described above in which the crude synthetic racemate
was recrystallized from toluene to yield a material melting
at 83 °C and again having the XRPD pattern of the pure
enantiomer. On the other hand, a cooling crystallization from
water produced the stable racemic compound on stirring for
one week at 5 °C. Finally, suspension experiments confirmed
the metastability of the conglomerate versus the racemic
compound. A 50:50 mixture of conglomerate and racemic
compound form R slurried in water, toluene, or ethylacetate,
always yielded the racemic compound form R after approxi-
mately two days. The conglomerate was fully transformed into
the racemic compound.
3
.3. Phase Diagram Studies. Table 2 summarizes the ther-
mophysical properties of the metastable conglomerate, the stable
racemic compound, and the pure enantiomer. The melting point
of the conglomerate is 83.0 °C, only slightly lower than for the
racemic compound at 90.2 °C. The pure enantiomer melts
at 119.2 °C. The melting enthalpy of the pure enantiomer is
1
range of analytical methods (HPLC, H NMR, XRPD) were
unsuccessful. Most data for the conglomerate equilibria in the
phase diagram have been determined via the conglomerate or
mixtures of the pure enantiomer with the conglomerate. How-
ever, sometimes mixtures prepared with the racemic compound
form R (via dissolution and recrystallization from acetone)
provided a conglomerate exemplified with samples of composi-
tion 0.833 and 0.85 in Figures 8 and 9. In Figure 9, examples of
DSC curves are given to illustrate the melting behavior of the
pure enantiomer, the racemic compound, the conglomerate, and
the mixtures mentioned above. The sample containing 85 mol %
of (S)-2-chloromandelic acid (curve 3) shows eutectic melting
at 81 °C, which can clearly be assigned to the conglomerate.
This is followed by dissolution of the excess enantiomer in the
melt (liquidus temperature obtained from the peak maximum
∼111 °C). On the other hand, a sample of similar composition
of 83.3 mol % (S) (curve 4) exhibits an initial melting of
a conglomerate in the mixture at 82 °C, followed by
ꢀ
1
ꢀ1
2
4.3 kJ mol , slightly higher than 23.2 kJ mol for the
3
3
racemic compound. The 29 K difference in melting point
between the pure enantiomer and the racemic compound together
with the heat of melting of the pure enantiomer can be used,
4
following the methodology of Jacques & Collet, to calculate the
Gibbs free energy (ΔG°) for the conversion of conglomerate to
compound. This calculation assumes the formation of the racemic
compound by a “reaction” of the enantiomers (in a mixture, i.e., a
conglomerate); thus ΔG°-values are positive for conglomerates
and negative for the formation of racemic compounds. For a
system where the racemic compound has a lower melting point
than the enantiomers then eq 1 is used to calculate ΔG°, where
f
f
ΔH is the enthalpy of fusion for the enantiomer, T is the
E
R
f
melting temperature of the racemic compound and T E is the
melting temperature of the enantiomer. This gives ΔG° at T
f
R
1
554
dx.doi.org/10.1021/cg1015077 |Cryst. Growth Des. 2011, 11, 1549–1556