1 3
Topics in Current Chemistry (2020) 378:1
the organocatalyst. The organocatalyst is normally used in 20 mol% and the presence of
a co-catalyst—normally a Brønsted acid—is mandatory. The obtainment of a relevant
concentration of chiral enamines is forced by the employment of acidic co-catalysts and
it is influenced by the aldehydes used in the organocatalytic reaction. The acidity of the
Brønsted acid is relevant to the catalytic cycle, influencing the rate-determining step of
the reaction. In addition, in some cases, even the basicity of the Brønsted base associated with the acid can have an influence on the progress of the reaction, especially when
the C–C bond formation is not the rate-determining step [29]. Since water is present in
organocatalytic-mediated processes, both in enamine and iminium activation modes,
the compatibility of Lewis acids and electrophiles with water is a key point for the synergistic use of Lewis acids and organocatalysis. Many chiral Lewis acids that are not
compatible with the presence of water were developed in the past years for asymmetric
catalytic reactions [30]. Therefore, the first step towards the concerted use of a Lewis
acid in an organocatalytic process is recognizing which Lewis acids are compatible
with the presence of water. If the Lewis acid does not interact with the water present in
the reaction media, the recycling of the organocatalyst becomes possible. On the other
hand, if the Lewis acid reacts with water, the recycling of the organocatalyst becomes
slow and difficult, since water is consumed as it hydrolyses the Lewis acid leading to
inactive oxo-species. Furthermore, since amines are normally employed in the enamine
and iminium activation modes, the Lewis acid used in the synergistic reaction needs
to be able to selectively activate electrophiles in the presence of amines. Alternatively,
it needs free coordination sites, determining a reversible equilibrium in the presence
of basic amine donors. Under these important standpoints, it is worth mentioning that
Kobayashi tested the use of rare-Earth metal triflates [31] in the fundamental studies
about Lewis acid catalysts in water or water-containing solvents [32]. The research carried out by Kobayashi established empirical criteria to define a Lewis acid that is compatible with water [33]. Based on a test performed on a standard Lewis acid-promoted
reaction, Kobayashi screened many Lewis acids (Group 1–15 metal chlorides, perchlorates, and triflates) finding that Fe(II), Cu(II), Zn(II), Cd(II), and Pb(II) salts were able
to perform Lewis acid activation of electrophiles in aqueous media. The catalytic activity of the metals was correlated both to their hydrolysis constants in water (K h ), and the
exchange rate constants for coordination of water molecules in the inner ligand sphere
of the Lewis acid (water exchange rate constants, i.e., WERC) [34]. The active metals
have pK h values between 4.3 and 10.08. If the pK h is less than 4, a rapid reaction of the
Lewis acid with water occurs, with the release of protons that can cause the protonation
of the amine organocatalyst. On the other hand, a strong Lewis acid can strongly interact with the amine (a Lewis base) or the nucleophile present in the reaction conditions.
If the value of pK h is too high, the Lewis acid is unable to activate the less Lewis basic
organic substrate. The ability of water to coordinate the Lewis acid and to saturate all
the available coordination sites determines the rate of the reaction in the presence of
water, or when water is used as reaction solvent. If a large (and fast) exchange rate of
the coordinated water is possible, the Lewis acid can be an effective catalyst in water.
A large WERC value, i.e., > of 10
6
, allows a sufficiently rapid exchange between the
coordinated water molecules and the Lewis acid. Metals with suitable values of pK h
and WERC could be used for organocatalytic Lewis acid-promoted reactions, but they
are less efficient. Nevertheless, indium(III) salts, despite not featuring optimal values to
Reprinted from the journal
33
Topics in Current Chemistry (2020) 378:1
the organocatalyst. The organocatalyst is normally used in 20 mol% and the presence of
a co-catalyst—normally a Brønsted acid—is mandatory. The obtainment of a relevant
concentration of chiral enamines is forced by the employment of acidic co-catalysts and
it is influenced by the aldehydes used in the organocatalytic reaction. The acidity of the
Brønsted acid is relevant to the catalytic cycle, influencing the rate-determining step of
the reaction. In addition, in some cases, even the basicity of the Brønsted base associated with the acid can have an influence on the progress of the reaction, especially when
the C–C bond formation is not the rate-determining step [29]. Since water is present in
organocatalytic-mediated processes, both in enamine and iminium activation modes,
the compatibility of Lewis acids and electrophiles with water is a key point for the synergistic use of Lewis acids and organocatalysis. Many chiral Lewis acids that are not
compatible with the presence of water were developed in the past years for asymmetric
catalytic reactions [30]. Therefore, the first step towards the concerted use of a Lewis
acid in an organocatalytic process is recognizing which Lewis acids are compatible
with the presence of water. If the Lewis acid does not interact with the water present in
the reaction media, the recycling of the organocatalyst becomes possible. On the other
hand, if the Lewis acid reacts with water, the recycling of the organocatalyst becomes
slow and difficult, since water is consumed as it hydrolyses the Lewis acid leading to
inactive oxo-species. Furthermore, since amines are normally employed in the enamine
and iminium activation modes, the Lewis acid used in the synergistic reaction needs
to be able to selectively activate electrophiles in the presence of amines. Alternatively,
it needs free coordination sites, determining a reversible equilibrium in the presence
of basic amine donors. Under these important standpoints, it is worth mentioning that
Kobayashi tested the use of rare-Earth metal triflates [31] in the fundamental studies
about Lewis acid catalysts in water or water-containing solvents [32]. The research carried out by Kobayashi established empirical criteria to define a Lewis acid that is compatible with water [33]. Based on a test performed on a standard Lewis acid-promoted
reaction, Kobayashi screened many Lewis acids (Group 1–15 metal chlorides, perchlorates, and triflates) finding that Fe(II), Cu(II), Zn(II), Cd(II), and Pb(II) salts were able
to perform Lewis acid activation of electrophiles in aqueous media. The catalytic activity of the metals was correlated both to their hydrolysis constants in water (K h ), and the
exchange rate constants for coordination of water molecules in the inner ligand sphere
of the Lewis acid (water exchange rate constants, i.e., WERC) [34]. The active metals
have pK h values between 4.3 and 10.08. If the pK h is less than 4, a rapid reaction of the
Lewis acid with water occurs, with the release of protons that can cause the protonation
of the amine organocatalyst. On the other hand, a strong Lewis acid can strongly interact with the amine (a Lewis base) or the nucleophile present in the reaction conditions.
If the value of pK h is too high, the Lewis acid is unable to activate the less Lewis basic
organic substrate. The ability of water to coordinate the Lewis acid and to saturate all
the available coordination sites determines the rate of the reaction in the presence of
water, or when water is used as reaction solvent. If a large (and fast) exchange rate of
the coordinated water is possible, the Lewis acid can be an effective catalyst in water.
A large WERC value, i.e., > of 10
6
, allows a sufficiently rapid exchange between the
coordinated water molecules and the Lewis acid. Metals with suitable values of pK h
and WERC could be used for organocatalytic Lewis acid-promoted reactions, but they
are less efficient. Nevertheless, indium(III) salts, despite not featuring optimal values to
Reprinted from the journal
33