8 research outputs found
Mechanism and Site Selectivity in Visible-Light Photocatalyzed C–H Functionalization: Insights from DFT Calculations
Visible-light
photocatalyzed (VLPC) late-stage C–H functionalization
is a powerful addition to the chemical synthesis toolkit. VLPC has
a demonstrated potential for discovery of elusive and valuable transformations,
particularly in functionalization of bioactive heterocycles. In order
to fully harvest the potential of VLPC in the context of complex molecule
synthesis, a thorough understanding of the elementary processes involved
is crucial. This would enable more rational design of suitable reagents
and catalysts, as well as prediction of activated C–H sites
for functionalization. Such knowledge is essential when VLPC is to
be employed in retrosynthetic analysis of complex molecules. Herein,
we present a density functional theory (DFT) study of mechanistic
details in the C–H functionalization of bioactive heterocycles
exemplified by the methylation of the antifungal agent voriconazole.
Moreover, we show that readily computed atomic charges can predict
major site-selectivity in good agreement with experimental studies
and thus be informative tools for the identification of active C–H
functionalization sites in synthetic planning
Cryptophanes for Methane and Xenon Encapsulation: A Comparative Density Functional Theory Study of Binding Properties and NMR Chemical Shifts
The
host–guest chemistry of cryptophanes is an active research
area because of its applications in sensor design, targeting small
molecules and atoms in environmental and medical sciences. As such,
the computational prediction of binding energies and nuclear magnetic
resonance (NMR) properties of different cryptophane complexes are
of interest to both theoreticians and experimentalists working in
host–guest based sensor development. Herein we present a study
of 10 known and some newly proposed cryptophanes using density functional
theory (DFT) calculations. We benchmark the description of nonbonding
interactions by different DFT functionals against spin-component-scaled,
second-order Møller–Plesset theory (SCS-MP2) and predict
novel host molecules with enhanced affinity toward methane and Xenon,
two representative systems of high interest. We demonstrate the power
and limitations of the different computational methods in describing
the binding and NMR properties of these established and novel host
systems. The results show the importance of including dispersion corrections
in the DFT functionals. The overall analysis of the dispersion corrections
indicated that results obtained from pure DFT functionals should be
used cautiously when conclusions are drawn for molecular systems
with considerable weak interactions. Proposed analogues of cryptophane-A,
where the alkoxy bridges are replaced by alkyl chains, are predicted
to display enhanced affinity toward both methane and Xenon
DFT as a Powerful Predictive Tool in Photoredox Catalysis: Redox Potentials and Mechanistic Analysis
Visible-light
photoredox catalysis has come forth as a powerful
activation mode in chemical synthesis, affording the development of
a multitude of new strategies for molecular construction. However,
detailed mechanistic knowledge of the various subprocesses involved
is lacking, and new tools for addressing this are needed to drive
innovation forward in the area. Herein, we describe predictions of
ground- and excited-state redox potentials of ruthenium and iridium
photocatalysts using nonrelativistic and scalar relativistic zero-order
regular approximation density functional theory (DFT) methods. The
computed redox potentials were correlated with experimental values
and found to reproduce them well. Relativistic corrections were found
to be important to reproduce experimental data. Moreover, the computational
protocol allows us to estimate redox potentials that are not currently
available in the literature or are difficult to determine experimentally.
The mechanistic details of the photocatalyzed C–H functionalization
of 1-methylindole with diethyl bromomalonate were also studied using
the validated DFT method. We demonstrate how DFT can predict the experimentally
observed redox behavior of common photocatalysts and mechanistic details
of the C–H functionalization process. This work demonstrates
that DFT can be a powerful tool for innovation and design in the field
of visible-light photoredox catalysis by predicting redox properties
and mechanistic behavior
Metal-Free N–H Insertions of Donor/Acceptor Carbenes
Synthetically useful transformations arise from the thermal decomposition of aryldiazoacetates in the presence of primary and secondary amines without the use of a metal catalyst. Thermally generated, free donor/acceptor carbenes directly undergo N–H insertion with amines through selective aza-ylide formation to afford a variety of α-amino esters in 53–96% yields
Scope and Mechanistic Analysis of the Enantioselective Synthesis of Allenes by Rhodium-Catalyzed Tandem Ylide Formation/[2,3]-Sigmatropic Rearrangement between Donor/Acceptor Carbenoids and Propargylic Alcohols
Rhodium-catalyzed reactions of tertiary propargylic alcohols
with
methyl aryl- and styryldiazoacetates result in tandem reactions, consisting
of oxonium ylide formation followed by [2,3]-sigmatropic rearrangement.
This process competes favorably with the standard O–H insertion
reaction of carbenoids. The resulting allenes are produced with high
enantioselectivity (88–98% ee) when the reaction is catalyzed
by the dirhodium tetraprolinate complex, Rh<sub>2</sub>(<i>S</i>-DOSP)<sub>4</sub>. Kinetic resolution is possible when racemic tertiary
propargylic alcohols are used as substrates. Under the kinetic resolution
conditions, the allenes are formed with good diastereoselectivity
and enantioselectivity (up to 6.1:1 dr, 88–93% ee), and the
unreacted alcohols are enantioenriched to 65–95% ee. Computational
studies reveal that the high asymmetric induction is obtained via
an organized transition state involving a two-point attachment: ylide
formation between the alcohol oxygen and the carbenoid and hydrogen
bonding of the alcohol to a carboxylate ligand. The 2,3-sigmatropic
rearrangement proceeds through initial cleavage of the O–H
bond to generate an intermediate with close-lying open-shell singlet,
triplet, and closed-shell singlet electronic states. This intermediate
would have significant diradical character, which is consistent with
the observation that the 2,3-sigmatropic rearrangement is favored
with donor/acceptor carbenoids and more highly functionalized propargylic
alcohols
Scope and Mechanistic Analysis of the Enantioselective Synthesis of Allenes by Rhodium-Catalyzed Tandem Ylide Formation/[2,3]-Sigmatropic Rearrangement between Donor/Acceptor Carbenoids and Propargylic Alcohols
Rhodium-catalyzed reactions of tertiary propargylic alcohols
with
methyl aryl- and styryldiazoacetates result in tandem reactions, consisting
of oxonium ylide formation followed by [2,3]-sigmatropic rearrangement.
This process competes favorably with the standard O–H insertion
reaction of carbenoids. The resulting allenes are produced with high
enantioselectivity (88–98% ee) when the reaction is catalyzed
by the dirhodium tetraprolinate complex, Rh<sub>2</sub>(<i>S</i>-DOSP)<sub>4</sub>. Kinetic resolution is possible when racemic tertiary
propargylic alcohols are used as substrates. Under the kinetic resolution
conditions, the allenes are formed with good diastereoselectivity
and enantioselectivity (up to 6.1:1 dr, 88–93% ee), and the
unreacted alcohols are enantioenriched to 65–95% ee. Computational
studies reveal that the high asymmetric induction is obtained via
an organized transition state involving a two-point attachment: ylide
formation between the alcohol oxygen and the carbenoid and hydrogen
bonding of the alcohol to a carboxylate ligand. The 2,3-sigmatropic
rearrangement proceeds through initial cleavage of the O–H
bond to generate an intermediate with close-lying open-shell singlet,
triplet, and closed-shell singlet electronic states. This intermediate
would have significant diradical character, which is consistent with
the observation that the 2,3-sigmatropic rearrangement is favored
with donor/acceptor carbenoids and more highly functionalized propargylic
alcohols
<i>D</i><sub>2</sub>-Symmetric Dirhodium Catalyst Derived from a 1,2,2-Triarylcyclopropanecarboxylate Ligand: Design, Synthesis and Application
Dirhodium tetrakis-(<i>R</i>)-(1-(4-bromophenyl)-2,2-diphenylcyclopropanecarboxylate) (Rh<sub>2</sub>(<i>R</i>-BTPCP)<sub>4</sub>) was found to be an effective chiral catalyst for enantioselective reactions of aryl- and styryldiazoacetates. Highly enantioselective cyclopropanations, tandem cyclopropanation/Cope rearrangements and a combined C–H functionalization/Cope rearrangement were achieved using Rh<sub>2</sub>(<i>R</i>-BTPCP)<sub>4</sub> as catalyst. The advantages of Rh<sub>2</sub>(<i>R</i>-BTPCP)<sub>4</sub> include its ease of synthesis, its tolerance to the size of the ester group in the styryldiazoacetates, and its compatibility with dichloromethane as solvent. Computational studies suggest that the catalyst adopts a <i>D</i><sub>2</sub>-symmetric arrangement, but when the carbenoid binds to the catalyst, two of the <i>p</i>-bromophenyl groups on the ligands rotate outward to make room for the carbenoid and the approach of the substrate to the carbenoid
<i>D</i><sub>2</sub>-Symmetric Dirhodium Catalyst Derived from a 1,2,2-Triarylcyclopropanecarboxylate Ligand: Design, Synthesis and Application
Dirhodium tetrakis-(<i>R</i>)-(1-(4-bromophenyl)-2,2-diphenylcyclopropanecarboxylate) (Rh<sub>2</sub>(<i>R</i>-BTPCP)<sub>4</sub>) was found to be an effective chiral catalyst for enantioselective reactions of aryl- and styryldiazoacetates. Highly enantioselective cyclopropanations, tandem cyclopropanation/Cope rearrangements and a combined C–H functionalization/Cope rearrangement were achieved using Rh<sub>2</sub>(<i>R</i>-BTPCP)<sub>4</sub> as catalyst. The advantages of Rh<sub>2</sub>(<i>R</i>-BTPCP)<sub>4</sub> include its ease of synthesis, its tolerance to the size of the ester group in the styryldiazoacetates, and its compatibility with dichloromethane as solvent. Computational studies suggest that the catalyst adopts a <i>D</i><sub>2</sub>-symmetric arrangement, but when the carbenoid binds to the catalyst, two of the <i>p</i>-bromophenyl groups on the ligands rotate outward to make room for the carbenoid and the approach of the substrate to the carbenoid