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R. Tamura et al.
20.1 Introduction
The ‘complexity theory’ developed rapidly since the 1970s is regarded as one of
the paradigm shifts or epoch-making revolutions of natural science in the twentieth
century [1, 2], together with the birth and establishment of ‘quantum mechanics’
and ‘Einsteinian general theory of relativity’ at the beginning of the same century
[3]. Nowadays, a concept of the nonlinear complexity theory is recognized to govern
a variety of dynamic behaviors observed in both natural and social sciences [4–
8]. In the ‘nonequilibrium (or out of equilibrium) complexity system,’ symmetry
breaking occurs easily in concert with a phase transition of a chaotic or dissipative
state to another one. In other words, fluctuation in a nonequilibrium state induces
a phase transition to trigger the symmetry breaking, and eventually, the nonlinear
amplification of fluctuation leads to dissymmetric circumstances [4–8]. A typical
example is the birth of the universe by the cosmic inflation followed by big bang
starting from a quantum fluctuation according to the ‘uncertainty principle of energy
and time’ as a hypothetical explanation [3]. Other familiar and important examples
include many body interactions of multiple elements responsible for the nonlinearity
[9]; intermolecular interactions can give nonequilibrium objects such as cells [10],
bubbles [11], and metastable crystals [12], which may have strong links to the origin
of the selected chirality of life.
In this context, twenty-five years ago, we discovered an unprecedented, spontaneous chiral resolution phenomenon, referred to as ‘preferential enrichment (PE),’
which was applicable to a certain kind of racemic organic salt crystals [13, 14]. Since
that time, it has been proved that generally, PE originates from regular chiral fluctuation and symmetry breaking which occurs immediately after polymorphic transition
during crystallization. In more detail, by repeating simple recrystallization of certain
kinds of racemic mixed crystals (solid solutions) under nonequilibrium conditions
using high supersaturation, a regularly alternating enrichment of two enantiomers
occurs largely in the mother liquor and slightly in the deposited crystals with full
reproducibility in the absence of an external chiral source (Fig. 20.1a) [15–19]. This
is, in essence, a completely opposite phenomenon to the well-known ‘preferential
crystallization (PC)’ of racemic conglomerates composed of a mixture of homochiral
R and S crystals [20–22]. PC discovered by Gernez in the nineteenth century has been
recognized to be a common chiral resolution method by seeding a nearly racemic
solution with a very small amount of enantiomerically pure crystals (Fig. 20.1b)
[23, 24]. In PC, it is in the deposited crystals that substantial enrichment occurs by
recrystallization, and at the same time, slight enrichment of the opposite enantiomer
always takes place in the mother liquor. Please refer to the cited literatures [15–22]
for the comparison of PE with PC and the significance of these complementary two
phenomena in the field of chiral separation by crystallization.
Here, at first, we focus on the history and features, and the recently clarified mechanism, requirements and generality concerning PE. Then, our strategy and the outcome
with respect to the recent application of PE to racemic dimorphic (two components)
cocrystals are introduced. Eventually, we have recognized that PE is ascribed to an
R. Tamura et al.
20.1 Introduction
The ‘complexity theory’ developed rapidly since the 1970s is regarded as one of
the paradigm shifts or epoch-making revolutions of natural science in the twentieth
century [1, 2], together with the birth and establishment of ‘quantum mechanics’
and ‘Einsteinian general theory of relativity’ at the beginning of the same century
[3]. Nowadays, a concept of the nonlinear complexity theory is recognized to govern
a variety of dynamic behaviors observed in both natural and social sciences [4–
8]. In the ‘nonequilibrium (or out of equilibrium) complexity system,’ symmetry
breaking occurs easily in concert with a phase transition of a chaotic or dissipative
state to another one. In other words, fluctuation in a nonequilibrium state induces
a phase transition to trigger the symmetry breaking, and eventually, the nonlinear
amplification of fluctuation leads to dissymmetric circumstances [4–8]. A typical
example is the birth of the universe by the cosmic inflation followed by big bang
starting from a quantum fluctuation according to the ‘uncertainty principle of energy
and time’ as a hypothetical explanation [3]. Other familiar and important examples
include many body interactions of multiple elements responsible for the nonlinearity
[9]; intermolecular interactions can give nonequilibrium objects such as cells [10],
bubbles [11], and metastable crystals [12], which may have strong links to the origin
of the selected chirality of life.
In this context, twenty-five years ago, we discovered an unprecedented, spontaneous chiral resolution phenomenon, referred to as ‘preferential enrichment (PE),’
which was applicable to a certain kind of racemic organic salt crystals [13, 14]. Since
that time, it has been proved that generally, PE originates from regular chiral fluctuation and symmetry breaking which occurs immediately after polymorphic transition
during crystallization. In more detail, by repeating simple recrystallization of certain
kinds of racemic mixed crystals (solid solutions) under nonequilibrium conditions
using high supersaturation, a regularly alternating enrichment of two enantiomers
occurs largely in the mother liquor and slightly in the deposited crystals with full
reproducibility in the absence of an external chiral source (Fig. 20.1a) [15–19]. This
is, in essence, a completely opposite phenomenon to the well-known ‘preferential
crystallization (PC)’ of racemic conglomerates composed of a mixture of homochiral
R and S crystals [20–22]. PC discovered by Gernez in the nineteenth century has been
recognized to be a common chiral resolution method by seeding a nearly racemic
solution with a very small amount of enantiomerically pure crystals (Fig. 20.1b)
[23, 24]. In PC, it is in the deposited crystals that substantial enrichment occurs by
recrystallization, and at the same time, slight enrichment of the opposite enantiomer
always takes place in the mother liquor. Please refer to the cited literatures [15–22]
for the comparison of PE with PC and the significance of these complementary two
phenomena in the field of chiral separation by crystallization.
Here, at first, we focus on the history and features, and the recently clarified mechanism, requirements and generality concerning PE. Then, our strategy and the outcome
with respect to the recent application of PE to racemic dimorphic (two components)
cocrystals are introduced. Eventually, we have recognized that PE is ascribed to an