fluorine reagents, including hypervalent iodines and nitrogen-based reagents, in
combination with silver, zinc, and dirhodium catalysts [21, 23–27]. The developed
reactions are very interesting because they are typically fast and take place at mild
conditions with high regioselectivities and good yields, providing thus excellent latestage strategies to introduce fluorine-containing substituents to bioactive molecules.
Mechanistic details of reactions using electrophilic reagents have been studied
using both experimental [33–38] and computational [39–53] methodologies. A
number of computational studies have also been reported on the activation mechanisms of the fluoro-benziodoxole 1 [54–57] and Togni reagent 2 [58–64], which has
certainly provided deeper insights into the characteristics of these compounds.
However, the level of understanding of the reactions involving electrophilic
reagents, in particular in combination with metal catalysts, is still rather poor,
which is an obstacle to the further development of these reactions and to finding
new protocols to control and enhance the regio- and stereoselectivities.
To this end, quantum chemical calculations can be used to fill this knowledge
gap. Quantum chemistry, most importantly density function theory (DFT), is today
an essential tool for mechanistic studies of organic and organometallic reactions. The
steady improvements of the computational methodologies and the computing
resources have made it possible to treat ever-larger systems with ever-increasing
accuracy [65–71]. We have in recent years embarked the study of mechanisms of
fluorination reactions using computational methodology. In this contribution, we
will summarize our experiences by discussing a number of examples. We expect that
the detailed understanding of the mechanisms and the origin of selectivity gained
from the calculations will facilitate the development of new and improved catalytic
systems in this interesting field of chemistry.
2 Technical Details
All results discussed were obtained using that B3LYP functional [72, 73], a method
that has been used extensively to explore a vast number of organic and organometallic reactions. The free energies represent Gibbs energies, where the rigid-rotor
harmonic oscillator (RRHO) approximation has been employed based on analytical
frequency calculations. Solvation effects were evaluated by single-point calculations
on the optimized structures using implicit solvent models, such as the conductor-like
polarizable continuum model (CPCM) [74, 75] and the solvation model based on
density (SMD) method [76]. In addition, dispersion effects were included by the D3
or D3(BJ) versions of Grimme’s dispersion method [77, 78].
An important issue that must be noted here is that when the size of the model
increases, a thorough conformational search is very important, because each structure can have a number of possible conformers. One has therefore to be careful and
perform many calculations in order to identify the lowest-energy conformation for
each individual intermediate and transition state. In the examples discussed below,
typically 10–20 geometries were optimized for each reported structure by explicitly
Mechanisms of Metal-Catalyzed Electrophilic F/CF 3 /SCF 3 Transfer Reactions. . .
41
combination with silver, zinc, and dirhodium catalysts [21, 23–27]. The developed
reactions are very interesting because they are typically fast and take place at mild
conditions with high regioselectivities and good yields, providing thus excellent latestage strategies to introduce fluorine-containing substituents to bioactive molecules.
Mechanistic details of reactions using electrophilic reagents have been studied
using both experimental [33–38] and computational [39–53] methodologies. A
number of computational studies have also been reported on the activation mechanisms of the fluoro-benziodoxole 1 [54–57] and Togni reagent 2 [58–64], which has
certainly provided deeper insights into the characteristics of these compounds.
However, the level of understanding of the reactions involving electrophilic
reagents, in particular in combination with metal catalysts, is still rather poor,
which is an obstacle to the further development of these reactions and to finding
new protocols to control and enhance the regio- and stereoselectivities.
To this end, quantum chemical calculations can be used to fill this knowledge
gap. Quantum chemistry, most importantly density function theory (DFT), is today
an essential tool for mechanistic studies of organic and organometallic reactions. The
steady improvements of the computational methodologies and the computing
resources have made it possible to treat ever-larger systems with ever-increasing
accuracy [65–71]. We have in recent years embarked the study of mechanisms of
fluorination reactions using computational methodology. In this contribution, we
will summarize our experiences by discussing a number of examples. We expect that
the detailed understanding of the mechanisms and the origin of selectivity gained
from the calculations will facilitate the development of new and improved catalytic
systems in this interesting field of chemistry.
2 Technical Details
All results discussed were obtained using that B3LYP functional [72, 73], a method
that has been used extensively to explore a vast number of organic and organometallic reactions. The free energies represent Gibbs energies, where the rigid-rotor
harmonic oscillator (RRHO) approximation has been employed based on analytical
frequency calculations. Solvation effects were evaluated by single-point calculations
on the optimized structures using implicit solvent models, such as the conductor-like
polarizable continuum model (CPCM) [74, 75] and the solvation model based on
density (SMD) method [76]. In addition, dispersion effects were included by the D3
or D3(BJ) versions of Grimme’s dispersion method [77, 78].
An important issue that must be noted here is that when the size of the model
increases, a thorough conformational search is very important, because each structure can have a number of possible conformers. One has therefore to be careful and
perform many calculations in order to identify the lowest-energy conformation for
each individual intermediate and transition state. In the examples discussed below,
typically 10–20 geometries were optimized for each reported structure by explicitly
Mechanisms of Metal-Catalyzed Electrophilic F/CF 3 /SCF 3 Transfer Reactions. . .
41