molecules, respectively [108]. Therefore, the series was considered to be converged
at n ¼ 3 (green line in Fig. 18a) because the change in the Gibbs energy profile is not
significantly modified (by approximately 1 kcal mol
À1 ) with respect to n ¼ 4 (purple
line in Fig. 18a). The reductive elimination from Au(III) complex to form a C–C
bond was also found to be sensitive to the surrounding number of MeOH solvent
molecules. Thus, the reductive elimination barrier was modified from 18.5 kcal/mol
from pure continuum model, to 24.2 kcal/mol when including 12 MeOH molecules.
Last model approaches the experimental value and corresponds to the complete
solvation sphere observed on a MD simulation (green line in Fig. 18b). This effect
turned to be crucial to understand the difference between the reaction in solution and
inside the cavity of a metallocage [109]. The copper-mediated hydration of α,β-unsaturated 2-acylpyridines in water is a more challenging case because the
solvent is also the reagent. First, via QM calculations, the barrier associated with
the nucleophilic attack (TS N1 ) was computed using chains of (H 2 O) n water molecules, with n equal to 4, 5, 6, and 7 (Fig. 18c). The results show that the barrier is
essentially converged at n ¼ 6 [110]. The distribution of water molecules around the
copper complex was then assessed in an explicitly solvated system, by means of
classical MD simulations. The radial distribution function of water molecules around
the double bond shows a minimum around 5.25 Å. Within this distance, about
12 water molecules surround the double bond, six on each side, thus validating the
cluster-continuum model [110].
An organometallic reaction that challenges computational methods to describe
the solvent is the Grignard reaction. For this reason, and despite it has been
employed for more than 100 years, its mechanism has remained elusive until
recently. Difficulties in elucidating the Grignard’s mechanism have been mainly
related to speciation problems (a solution of Grignard reagents contains a variety of
chemical species), the existence of competing mechanisms (polar mechanism,
entailing nucleophilic addition or radical mechanism arising from the homolytic
Mg-C bond breaking), and the crucial, but not well-understood role of the solvent
(an ethereal solvent often THF) in both the Schlenk equilibrium and the C–C bond
formation mechanism. Recent ab initio molecular dynamics simulations with an
explicit model of the THF solvent, built up by placing the Grignard reagent in a box
with a large number of THF molecules (Fig. 19), have shed light to this longstanding
controversy [111, 112].
The Schlenk equilibrium implies the transformation of CH 3 MgCl into MgCl 2 and
Mg(CH 3 ) 2 . The AIMD study shown the way that the solvent (THF) plays a crucial
role in assisting Cl/Me exchange. The exchange is promoted by making the 2 Mg
atoms electronically different, and these differences are created by different solvation of the 2 Mg centers. Thus, it is the change in the solvation number what is
inducing the interchange of the methyl and chloride groups between two magnesium
centers [111]. Regarding the reaction of an organomagnesium species RMgX where
its organic residue R is added to an electrophilic substrate (Grignard reaction),
AIMD simulations revealed that the solvent needs to be considered as a reactant
for both the nucleophilic and the radical reactions. Solvent dynamics is essential for
representing the energy profile. [112] Only an explicit solvent model able to include
30
O. Eisenstein et al.
at n ¼ 3 (green line in Fig. 18a) because the change in the Gibbs energy profile is not
significantly modified (by approximately 1 kcal mol
À1 ) with respect to n ¼ 4 (purple
line in Fig. 18a). The reductive elimination from Au(III) complex to form a C–C
bond was also found to be sensitive to the surrounding number of MeOH solvent
molecules. Thus, the reductive elimination barrier was modified from 18.5 kcal/mol
from pure continuum model, to 24.2 kcal/mol when including 12 MeOH molecules.
Last model approaches the experimental value and corresponds to the complete
solvation sphere observed on a MD simulation (green line in Fig. 18b). This effect
turned to be crucial to understand the difference between the reaction in solution and
inside the cavity of a metallocage [109]. The copper-mediated hydration of α,β-unsaturated 2-acylpyridines in water is a more challenging case because the
solvent is also the reagent. First, via QM calculations, the barrier associated with
the nucleophilic attack (TS N1 ) was computed using chains of (H 2 O) n water molecules, with n equal to 4, 5, 6, and 7 (Fig. 18c). The results show that the barrier is
essentially converged at n ¼ 6 [110]. The distribution of water molecules around the
copper complex was then assessed in an explicitly solvated system, by means of
classical MD simulations. The radial distribution function of water molecules around
the double bond shows a minimum around 5.25 Å. Within this distance, about
12 water molecules surround the double bond, six on each side, thus validating the
cluster-continuum model [110].
An organometallic reaction that challenges computational methods to describe
the solvent is the Grignard reaction. For this reason, and despite it has been
employed for more than 100 years, its mechanism has remained elusive until
recently. Difficulties in elucidating the Grignard’s mechanism have been mainly
related to speciation problems (a solution of Grignard reagents contains a variety of
chemical species), the existence of competing mechanisms (polar mechanism,
entailing nucleophilic addition or radical mechanism arising from the homolytic
Mg-C bond breaking), and the crucial, but not well-understood role of the solvent
(an ethereal solvent often THF) in both the Schlenk equilibrium and the C–C bond
formation mechanism. Recent ab initio molecular dynamics simulations with an
explicit model of the THF solvent, built up by placing the Grignard reagent in a box
with a large number of THF molecules (Fig. 19), have shed light to this longstanding
controversy [111, 112].
The Schlenk equilibrium implies the transformation of CH 3 MgCl into MgCl 2 and
Mg(CH 3 ) 2 . The AIMD study shown the way that the solvent (THF) plays a crucial
role in assisting Cl/Me exchange. The exchange is promoted by making the 2 Mg
atoms electronically different, and these differences are created by different solvation of the 2 Mg centers. Thus, it is the change in the solvation number what is
inducing the interchange of the methyl and chloride groups between two magnesium
centers [111]. Regarding the reaction of an organomagnesium species RMgX where
its organic residue R is added to an electrophilic substrate (Grignard reaction),
AIMD simulations revealed that the solvent needs to be considered as a reactant
for both the nucleophilic and the radical reactions. Solvent dynamics is essential for
representing the energy profile. [112] Only an explicit solvent model able to include
30
O. Eisenstein et al.