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Topics in Current Chemistry (2020) 378:1
is possible to classify the transient enamines or iminium ions and compare them
to other well-known and established nucleophiles and electrophiles [7–9]. Mayr’s
equation, i.e., Log k = S N (E + N), relates the rate of a bimolecular reaction, involving an electrophile and a nucleophile, with the electrophilicity of the former and
the nucleophilicity of the latter, denoted with the parameters E and N, respectively.
Based on such an equation, a quite simple “rule of thumb” can be inferred: it is possible to observe a reaction between an electrophile and a nucleophile within 16 h
if E + N > –5 [7–9]. This powerful and simple rule is still effective also when dealing with organocatalytic processes [10–12]. The transient enamine intermediates,
formed in the enamine activation mode, feature nucleophilicity parameters ranging between 12 and 16 on the Mayr scale (a silyl enol ether is placed at 4–7 of the
same scale, for the sake of comparison) [13]. On the other hand, the electrophilicity
of iminium ions is 5–7 orders of magnitude higher than common Michael acceptors, such as unsaturated esters [14]. Hence, it is not surprising that many reactions
were developed with these activation modes [15]. The nucleophilicity parameters
(N) of the enamines derived from Hayashi–Jørgensen and MacMillan catalysts (for
the depiction displaying Hayashi–Jørgensen catalyst and MacMillan catalyst see
Fig. 3) have been evaluated [16], as well as the electrophilicity parameters (E) for
different reactions partners. Since a reaction between an enamine and an electrophile
will take place if E + N > –5, according to the Mayr equation [7–9], it is possible to
predict a variety of suited electrophiles able to react with enamines [17]. However,
although enamines are potent nucleophiles (N = 12–14), electrophiles with E < − 18
are unable to be employed. Moreover, side reactions, such as self-aldolization and
formation of unsaturated products, might occur during the organocatalytic process.
Also in the case of iminium activation, the electrophilicity of chiral iminium intermediates with Hayashi–Jørgensen and MacMillan catalysts has been reported, and
on the basis of the Mayr equation, suitable nucleophiles capable of observable reactions can be predicted. However, the possibilities to employ enamine or iminium
catalysis can be enhanced by the utilization of Lewis acids in synergistic catalysis.
1.1 General Activation of an Organic Substrate with a Lewis Acid
According to IUPAC recommendation, Mayr clarified that, unlike Lewis acidity and
basicity that are thermodynamic terms, electrophilicity (E) and nucleophilicity (N)
refer to kinetics [18]. In terms of general activation of substrates, the Lewis acid
activates a weak electrophile (for example a carbonyl) via coordination (Fig. 2),
enhancing its electrophilicity. This can be easily understood by envisioning the different electrophilicities of benzaldehyde and benzaldehyde coordinated to boron halides in the Mayr scale [19]. There are more than 11 orders of magnitude between
the electrophilicities of the two species (benzaldehyde E = − 12.90 in DMSO;
benzaldehyde·BCl 3 E = + 1.12), and this is the reason why Lewis acid compounds
are used to activate carbonyls towards nucleophiles. Therefore, Lewis acids can be
employed to form new electrophilic species, enhancing the scope of the reactions
promoted by organocatalysis. On the other hand, Lewis acids can activate electrophiles that have an insufficient electrophilicity to engage reactions with nucleophiles
Reprinted from the journal
31
Topics in Current Chemistry (2020) 378:1
is possible to classify the transient enamines or iminium ions and compare them
to other well-known and established nucleophiles and electrophiles [7–9]. Mayr’s
equation, i.e., Log k = S N (E + N), relates the rate of a bimolecular reaction, involving an electrophile and a nucleophile, with the electrophilicity of the former and
the nucleophilicity of the latter, denoted with the parameters E and N, respectively.
Based on such an equation, a quite simple “rule of thumb” can be inferred: it is possible to observe a reaction between an electrophile and a nucleophile within 16 h
if E + N > –5 [7–9]. This powerful and simple rule is still effective also when dealing with organocatalytic processes [10–12]. The transient enamine intermediates,
formed in the enamine activation mode, feature nucleophilicity parameters ranging between 12 and 16 on the Mayr scale (a silyl enol ether is placed at 4–7 of the
same scale, for the sake of comparison) [13]. On the other hand, the electrophilicity
of iminium ions is 5–7 orders of magnitude higher than common Michael acceptors, such as unsaturated esters [14]. Hence, it is not surprising that many reactions
were developed with these activation modes [15]. The nucleophilicity parameters
(N) of the enamines derived from Hayashi–Jørgensen and MacMillan catalysts (for
the depiction displaying Hayashi–Jørgensen catalyst and MacMillan catalyst see
Fig. 3) have been evaluated [16], as well as the electrophilicity parameters (E) for
different reactions partners. Since a reaction between an enamine and an electrophile
will take place if E + N > –5, according to the Mayr equation [7–9], it is possible to
predict a variety of suited electrophiles able to react with enamines [17]. However,
although enamines are potent nucleophiles (N = 12–14), electrophiles with E < − 18
are unable to be employed. Moreover, side reactions, such as self-aldolization and
formation of unsaturated products, might occur during the organocatalytic process.
Also in the case of iminium activation, the electrophilicity of chiral iminium intermediates with Hayashi–Jørgensen and MacMillan catalysts has been reported, and
on the basis of the Mayr equation, suitable nucleophiles capable of observable reactions can be predicted. However, the possibilities to employ enamine or iminium
catalysis can be enhanced by the utilization of Lewis acids in synergistic catalysis.
1.1 General Activation of an Organic Substrate with a Lewis Acid
According to IUPAC recommendation, Mayr clarified that, unlike Lewis acidity and
basicity that are thermodynamic terms, electrophilicity (E) and nucleophilicity (N)
refer to kinetics [18]. In terms of general activation of substrates, the Lewis acid
activates a weak electrophile (for example a carbonyl) via coordination (Fig. 2),
enhancing its electrophilicity. This can be easily understood by envisioning the different electrophilicities of benzaldehyde and benzaldehyde coordinated to boron halides in the Mayr scale [19]. There are more than 11 orders of magnitude between
the electrophilicities of the two species (benzaldehyde E = − 12.90 in DMSO;
benzaldehyde·BCl 3 E = + 1.12), and this is the reason why Lewis acid compounds
are used to activate carbonyls towards nucleophiles. Therefore, Lewis acids can be
employed to form new electrophilic species, enhancing the scope of the reactions
promoted by organocatalysis. On the other hand, Lewis acids can activate electrophiles that have an insufficient electrophilicity to engage reactions with nucleophiles
Reprinted from the journal
31