25 research outputs found
Calculating Free Energy Changes in Continuum Solvation Models
We recently showed for a large data
set of p<i>K</i><sub>a</sub>s and reduction potentials that
free energies calculated directly
within the SMD continuum model compares very well with corresponding
thermodynamic cycle calculations in both aqueous and organic solvents
[Phys. Chem. Chem. Phys. 2015, 17, 2859]. In this paper, we significantly expand the scope of our study
to examine the suitability of this approach for calculating <i>general</i> solution phase kinetics and thermodynamics, in conjunction
with several commonly used solvation models (SMD-M062X, SMD-HF, CPCM-UAKS,
and CPCM-UAHF) for a broad range of systems. This includes cluster-continuum
schemes for p<i>K</i><sub>a</sub> calculations as well as
various neutral, radical, and ionic reactions such as enolization,
cycloaddition, hydrogen and chlorine atom transfer, and SN2 and E2
reactions. On the basis of this benchmarking study, we conclude that
the accuracies of both approaches are generally very similarî—¸the
mean errors for Gibbs free energy changes of neutral and ionic reactions
are approximately 5 and 25 kJ mol<sup>–1</sup>, respectively.
In systems where there are significant structural changes due to solvation,
as is the case for certain ionic transition states and amino acids,
the direct approach generally afford free energy changes that are
in better agreement with experiment
Quantum Chemical Prediction of the Acidities of Sulfonamide Inhibitors of Carbonic Anhydrase
This study examined two pKa calculation
approaches (direct and proton exchange schemes) that employ high-level
quantum chemical methods and implicit solvent models to predict aqueous
Brønsted acidities of a large set of sulfonamides. For gas-phase
deprotonation energies, the DSD-PBEP86-D3(BJ) double-hybrid functional
provided the best agreement with the LNO-CCSD(T)/CBS benchmark with
a mean absolute deviation less than 2 kJ mol–1 when
the aug-cc-pVTZ or larger basis sets are used. For a large test set
of 54 primary and secondary sulfonamides, the use of the DSD-PBEP86-D3(BJ)/aug-cc-pVTZ
level of theory in conjunction with SM12 solvation free energies predict
their pKa values with a mean accuracy
of 0.9 units. In comparison, the SMD and ADF-COSMO-RS models have
slightly higher mean errors of 1.4 and 1.1 pKa units provided that the proton exchange scheme was employed
to cancel the systematic errors in these models. The performance of
these protocols was less ideal when applied to sulfonic acids, sulfamates,
and N-substituted sulfonamides, indicating that the
degree of error cancellation is sensitive to the chemical environment
around the −NH2 head group. The validated protocols
were then used to estimate the pKa values
of arylsulfonamide carbonic anhydrase inhibitors, which are used to
correct their experimentally measured binding free energies to account
for deprotonation of the sulfonamide group upon binding to the enzyme.
These corrected values did not have a significant impact on the correlation
with MMGBSA binding free energies obtained from classical MD simulations
where the ligand is usually considered in the deprotonated form
Quantum Chemical Prediction of the Acidities of Sulfonamide Inhibitors of Carbonic Anhydrase
This study examined two pKa calculation
approaches (direct and proton exchange schemes) that employ high-level
quantum chemical methods and implicit solvent models to predict aqueous
Brønsted acidities of a large set of sulfonamides. For gas-phase
deprotonation energies, the DSD-PBEP86-D3(BJ) double-hybrid functional
provided the best agreement with the LNO-CCSD(T)/CBS benchmark with
a mean absolute deviation less than 2 kJ mol–1 when
the aug-cc-pVTZ or larger basis sets are used. For a large test set
of 54 primary and secondary sulfonamides, the use of the DSD-PBEP86-D3(BJ)/aug-cc-pVTZ
level of theory in conjunction with SM12 solvation free energies predict
their pKa values with a mean accuracy
of 0.9 units. In comparison, the SMD and ADF-COSMO-RS models have
slightly higher mean errors of 1.4 and 1.1 pKa units provided that the proton exchange scheme was employed
to cancel the systematic errors in these models. The performance of
these protocols was less ideal when applied to sulfonic acids, sulfamates,
and N-substituted sulfonamides, indicating that the
degree of error cancellation is sensitive to the chemical environment
around the −NH2 head group. The validated protocols
were then used to estimate the pKa values
of arylsulfonamide carbonic anhydrase inhibitors, which are used to
correct their experimentally measured binding free energies to account
for deprotonation of the sulfonamide group upon binding to the enzyme.
These corrected values did not have a significant impact on the correlation
with MMGBSA binding free energies obtained from classical MD simulations
where the ligand is usually considered in the deprotonated form
Quantum Chemical Prediction of the Acidities of Sulfonamide Inhibitors of Carbonic Anhydrase
This study examined two pKa calculation
approaches (direct and proton exchange schemes) that employ high-level
quantum chemical methods and implicit solvent models to predict aqueous
Brønsted acidities of a large set of sulfonamides. For gas-phase
deprotonation energies, the DSD-PBEP86-D3(BJ) double-hybrid functional
provided the best agreement with the LNO-CCSD(T)/CBS benchmark with
a mean absolute deviation less than 2 kJ mol–1 when
the aug-cc-pVTZ or larger basis sets are used. For a large test set
of 54 primary and secondary sulfonamides, the use of the DSD-PBEP86-D3(BJ)/aug-cc-pVTZ
level of theory in conjunction with SM12 solvation free energies predict
their pKa values with a mean accuracy
of 0.9 units. In comparison, the SMD and ADF-COSMO-RS models have
slightly higher mean errors of 1.4 and 1.1 pKa units provided that the proton exchange scheme was employed
to cancel the systematic errors in these models. The performance of
these protocols was less ideal when applied to sulfonic acids, sulfamates,
and N-substituted sulfonamides, indicating that the
degree of error cancellation is sensitive to the chemical environment
around the −NH2 head group. The validated protocols
were then used to estimate the pKa values
of arylsulfonamide carbonic anhydrase inhibitors, which are used to
correct their experimentally measured binding free energies to account
for deprotonation of the sulfonamide group upon binding to the enzyme.
These corrected values did not have a significant impact on the correlation
with MMGBSA binding free energies obtained from classical MD simulations
where the ligand is usually considered in the deprotonated form
Molecular Geometries and Vibrational Contributions to Reaction Thermochemistry Are Surprisingly Insensitive to the Choice of Basis Sets
Calculation
of molecular geometries and harmonic vibrational frequencies
are pre-requisites for thermochemistry calculations. Contrary to conventional
wisdom, this paper demonstrates that quantum chemical predictions
of the thermochemistry of many gas and solution phase chemical reactions
appear to be very insensitive to the choice of basis sets. For a large
test set of 80 diverse organic and transition-metal-containing reactions,
variations in reaction free energy based on geometries and frequencies
calculated using a variety of double and triple-zeta basis sets from
the Pople, Jensen, Ahlrichs, and Dunning families are typically less
than 4 kJ mol–1, especially when the quasiharmonic
oscillator correction is applied to mitigate the effects of low-frequency
modes. Our analysis indicates that for many organic molecules and
their transition states, high-level revDSD-PBEP86-D4 and DLPNO-CCSD(T)/(aug-)cc-pVTZ
single-point energies usually vary by less than 2 kJ mol–1 on density functional theory geometries optimized using basis sets
ranging from 6-31+G(d) to aug-pcseg-2 and aug-cc-pVTZ. In cases where
these single-point energies vary significantly, indicating sensitivity
of molecular geometries to the choice of basis set, there is often
substantial cancellation of errors when the reaction energy or barrier
is calculated. The study concludes that the choice of basis set for
molecular geometry and frequencies, particularly those considered
in this study, is not critical for the accuracy of thermochemistry
calculations in the gas or solution phase
N‑Heterocyclic Olefin Catalyzed Silylation and Hydrosilylation Reactions of Hydroxyl and Carbonyl Compounds
N-Heterocyclic
olefins (NHOs), the alkylidene derivatives of N-heterocyclic
carbenes (NHCs), have recently emerged as a new family of promising
organocatalysts with strong nucleophilicity and Brønsted basicity.
The development of a novel method is shown using NHOs as efficient
promoters for the direct dehydrogenative silylation of alcohols or
hydrosilylation of carbonyl compounds. Preliminary results of the
first NHO-promoted asymmetric synthesis are also discussed
Molecular Geometries and Vibrational Contributions to Reaction Thermochemistry Are Surprisingly Insensitive to the Choice of Basis Sets
Calculation
of molecular geometries and harmonic vibrational frequencies
are pre-requisites for thermochemistry calculations. Contrary to conventional
wisdom, this paper demonstrates that quantum chemical predictions
of the thermochemistry of many gas and solution phase chemical reactions
appear to be very insensitive to the choice of basis sets. For a large
test set of 80 diverse organic and transition-metal-containing reactions,
variations in reaction free energy based on geometries and frequencies
calculated using a variety of double and triple-zeta basis sets from
the Pople, Jensen, Ahlrichs, and Dunning families are typically less
than 4 kJ mol–1, especially when the quasiharmonic
oscillator correction is applied to mitigate the effects of low-frequency
modes. Our analysis indicates that for many organic molecules and
their transition states, high-level revDSD-PBEP86-D4 and DLPNO-CCSD(T)/(aug-)cc-pVTZ
single-point energies usually vary by less than 2 kJ mol–1 on density functional theory geometries optimized using basis sets
ranging from 6-31+G(d) to aug-pcseg-2 and aug-cc-pVTZ. In cases where
these single-point energies vary significantly, indicating sensitivity
of molecular geometries to the choice of basis set, there is often
substantial cancellation of errors when the reaction energy or barrier
is calculated. The study concludes that the choice of basis set for
molecular geometry and frequencies, particularly those considered
in this study, is not critical for the accuracy of thermochemistry
calculations in the gas or solution phase
Molecular Geometries and Vibrational Contributions to Reaction Thermochemistry Are Surprisingly Insensitive to the Choice of Basis Sets
Calculation
of molecular geometries and harmonic vibrational frequencies
are pre-requisites for thermochemistry calculations. Contrary to conventional
wisdom, this paper demonstrates that quantum chemical predictions
of the thermochemistry of many gas and solution phase chemical reactions
appear to be very insensitive to the choice of basis sets. For a large
test set of 80 diverse organic and transition-metal-containing reactions,
variations in reaction free energy based on geometries and frequencies
calculated using a variety of double and triple-zeta basis sets from
the Pople, Jensen, Ahlrichs, and Dunning families are typically less
than 4 kJ mol–1, especially when the quasiharmonic
oscillator correction is applied to mitigate the effects of low-frequency
modes. Our analysis indicates that for many organic molecules and
their transition states, high-level revDSD-PBEP86-D4 and DLPNO-CCSD(T)/(aug-)cc-pVTZ
single-point energies usually vary by less than 2 kJ mol–1 on density functional theory geometries optimized using basis sets
ranging from 6-31+G(d) to aug-pcseg-2 and aug-cc-pVTZ. In cases where
these single-point energies vary significantly, indicating sensitivity
of molecular geometries to the choice of basis set, there is often
substantial cancellation of errors when the reaction energy or barrier
is calculated. The study concludes that the choice of basis set for
molecular geometry and frequencies, particularly those considered
in this study, is not critical for the accuracy of thermochemistry
calculations in the gas or solution phase
Corey–Chaykovsky Reactions of Nitro Styrenes Enable <i>cis</i>-Configured Trifluoromethyl Cyclopropanes
Trifluoromethyl-substituted
cyclopropanes are an attractive family
of building blocks for the construction of pharmaceutical and agrochemical
agents. This work demonstrated the utilization of fluorinated sulfur
ylides as versatile reagents for Corey–Chaykovsky cyclopropanation
reactions of nitro styrenes. This protocol favored the synthesis of <i>cis</i>-configured trifluoromethyl cyclopropanes for a broad
range of substrates with excellent yields and good diastereoselectivities
Iron-Catalyzed C—H Insertions: Organometallic and Enzymatic Carbene Transfer Reactions
<p>C—H insertion reactions with organometallic and enzymatic catalysts based on earth-abundant iron complexes remain one of the major challenges in organic synthesis. In this report, we describe the development and application of these iron-based catalysts in the reaction of two different carbene precursors with <i>N-</i>heterocycles for the first time. While FeTPPCl showed excellent reactivity in the Fe(III) state with diazoacetonitrile, the highest activities of the YfeX enzyme could be achieved upon heme-iron reduction to Fe(II) with both diazoacetonitrile and ethyl diazoacetate. This highlights unexpected and subtle differences in reactivity of both iron catalysts. Deuterium labeling studies indicated a C—H insertion pathway and a marked kinetic isotope effect. This transformation features mild reaction conditions, excellent yields or turnover numbers with broad functional group tolerance, including gram-scale applications giving a unique access to functionalized <i>N</i>-heterocycles.</p