22 Molecular Recognition by Inclusion …
459
Choosing reversible and convenient covalent bonding formation in the functional
groups of amides, sulfoxides, nitrile, and so on is more difficult than with alcohols
and ketones. The inclusion crystal method must conveniently separate one enantiomer from racemic compounds for all of these neutral compounds, including alcohols and ketones (Fig. 22.1c) [5–7]. Because inclusion crystals are obtained by cocrystallization without a covalent bonding formation between hosts and guests, the
recovery of optically separated guests—in which guests are released by dissolution
or heating of inclusion crystals—is quite easy.
However, inclusion crystals consist of weaker intermolecular interactions such
as hydrogen bonds and van der Waals interactions instead of ion pairs and covalent
bonds. Therefore, the molecular design of the host is an important consideration in
the construction of inclusion crystals with guest molecules.
22.2 Recent Examples of Molecular Recognition
by Inclusion Crystals
22.2.1 Chiral Recognition by Inclusion Crystals
In 1983, Toda reported on optical resolution by the inclusion crystal method using a
chiral 1,6-bis(2-chlorophenyl)-1,6-diphenylhexa-2,4-diyne-1,6-diol, which is classified as a wheel-and-axle type (Fig. 22.2a) [8]. This chiral diol host included
3-methylcyclohexanone and 3-methylcyclopentanone enantioselectively.
More recently, Nassibeni and Weber reported on a borneol dumb-bell
host with methylcyclohexanones and 2-butanols (Fig. 22.2b) [9]. Achiral 4methylcyclohexanones formed 1:2 (host/guest) inclusion crystals. With other
methylcyclohexanones, 1:1 inclusion crystals were obtained and 2- and 3methylcyclohexanones were included in 72% ee (S) and 57% ee (S) with statistic
disorder of these guest molecules.
Barton and Caira’s group reported on the inclusion of TETROL with cyclohexanone and 2-, 3-, and 4-methylcyclohexanone (abbreviation: Cy, 2-MeCy, 3-MeCy,
and 4-MeCy) that form 1:1 complexes (Fig. 22.2c) [10]. Notably, the 2- and 3-MeCys
were included in the axial conformation of their methyl groups. But the methyl group
of the included 4-MeCy took the more favorable equatorial conformation. Enantiomeric excesses of 2- and 3-MeCys in the inclusion crystals are 13% and 20%
ee for (R)-enantiomer, respectively. The reason for this low selectivity is confirmed
by the single-crystal X-ray analysis that showed both (R)- and (S)-enantiomers were
observed as a statistically disordered structure in the same void space. In addition,
Barton found interesting inclusion phenomena of these cyclohexanones concerning
TETROL in the competition experiments [11]. Crystallization of TETROL in the
presence of an equimolar mixture of 2-, 3-, and 4-MeCy gave inclusion crystals with
a mixture of three guests, where the ratios were 79: 14: 7, respectively. The host’s
selectivity might be described as 2-MeCy > > 3- MeCy > 4-MeCy. Conversely,
459
Choosing reversible and convenient covalent bonding formation in the functional
groups of amides, sulfoxides, nitrile, and so on is more difficult than with alcohols
and ketones. The inclusion crystal method must conveniently separate one enantiomer from racemic compounds for all of these neutral compounds, including alcohols and ketones (Fig. 22.1c) [5–7]. Because inclusion crystals are obtained by cocrystallization without a covalent bonding formation between hosts and guests, the
recovery of optically separated guests—in which guests are released by dissolution
or heating of inclusion crystals—is quite easy.
However, inclusion crystals consist of weaker intermolecular interactions such
as hydrogen bonds and van der Waals interactions instead of ion pairs and covalent
bonds. Therefore, the molecular design of the host is an important consideration in
the construction of inclusion crystals with guest molecules.
22.2 Recent Examples of Molecular Recognition
by Inclusion Crystals
22.2.1 Chiral Recognition by Inclusion Crystals
In 1983, Toda reported on optical resolution by the inclusion crystal method using a
chiral 1,6-bis(2-chlorophenyl)-1,6-diphenylhexa-2,4-diyne-1,6-diol, which is classified as a wheel-and-axle type (Fig. 22.2a) [8]. This chiral diol host included
3-methylcyclohexanone and 3-methylcyclopentanone enantioselectively.
More recently, Nassibeni and Weber reported on a borneol dumb-bell
host with methylcyclohexanones and 2-butanols (Fig. 22.2b) [9]. Achiral 4methylcyclohexanones formed 1:2 (host/guest) inclusion crystals. With other
methylcyclohexanones, 1:1 inclusion crystals were obtained and 2- and 3methylcyclohexanones were included in 72% ee (S) and 57% ee (S) with statistic
disorder of these guest molecules.
Barton and Caira’s group reported on the inclusion of TETROL with cyclohexanone and 2-, 3-, and 4-methylcyclohexanone (abbreviation: Cy, 2-MeCy, 3-MeCy,
and 4-MeCy) that form 1:1 complexes (Fig. 22.2c) [10]. Notably, the 2- and 3-MeCys
were included in the axial conformation of their methyl groups. But the methyl group
of the included 4-MeCy took the more favorable equatorial conformation. Enantiomeric excesses of 2- and 3-MeCys in the inclusion crystals are 13% and 20%
ee for (R)-enantiomer, respectively. The reason for this low selectivity is confirmed
by the single-crystal X-ray analysis that showed both (R)- and (S)-enantiomers were
observed as a statistically disordered structure in the same void space. In addition,
Barton found interesting inclusion phenomena of these cyclohexanones concerning
TETROL in the competition experiments [11]. Crystallization of TETROL in the
presence of an equimolar mixture of 2-, 3-, and 4-MeCy gave inclusion crystals with
a mixture of three guests, where the ratios were 79: 14: 7, respectively. The host’s
selectivity might be described as 2-MeCy > > 3- MeCy > 4-MeCy. Conversely,