21 research outputs found
Insights into the Unexpected Chemoselectivity for the N‑Heterocyclic Carbene-Catalyzed Annulation Reaction of Allenals with Chalcones
Lewis
base N-heterocyclic carbene (NHC)-catalyzed annulation is
the subject of extensive interest in synthetic chemistry, but the
reaction mechanisms, especially the unexpected chemoselectivity of
some of these reactions, are poorly understood. In this work, a systematic
theoretical calculation has been performed on NHC-catalyzed annulation
between allenals and chalcone. Multiple possible reaction pathways
(A–E) leading to three different products have been characterized.
The calculated results reveal that NHC is more likely to initiate
the reaction by nucleophilic attack on the center carbon atom of the
allene group but not the carbonyl carbon atom in allenals leading
to the Breslow intermediate, which is remarkably different from the
other NHC-catalyzed annulations of unsaturated aldehydes with chalcones.
The computed energy profiles demonstrate that the most energetically
favorable pathway (A) results in polysubstituted pyranyl aldehydes,
which reasonably explains the observed chemoselectivity in the experiment.
The observed chemoselectivity is demonstrated to be thermodynamically
but not kinetically controlled, and the stability of the Breslow intermediate
is the key for the possibility of homoenolate pathway D and enolate
pathway E. This work can improve our understanding of the multiple
competing pathways for NHC-catalyzed annulation reactions of unsaturated
aldehydes with chalcones and provide valuable insights for predicting
the chemoselectivity for this kind of reaction
Computational Study on γ‑C–H Functionalization of α,β-Unsaturated Ester Catalyzed by N‑Heterocyclic Carbene: Mechanisms, Origin of Stereoselectivity, and Role of Catalyst
The N-heterocyclic
carbene (NHC)-catalyzed γ-C–H deprotonation/functionalization
of α,β-unsaturated esters with hydrazones leading to the
δ-lactams has been theoretically investigated by using density
functional theory. Three possible reaction mechanisms including Mechanism
A, for which the NHC catalyst serves as a nucleophilic catalyst to
attack on the carbonyl carbon atom to initiate the reaction, Mechanism
B, in which NHC triggers the reaction through the hydrogen bond, and
Mechanism C, which is the direct deprotonation/functionalization process
without the presence of NHC, have been suggested and studied in detail.
The most favorable Mechanism A was identified to proceed through the
following processes: nucleophilic attack on the carbonyl carbon of
the ester by NHC, γ-deprotonation, formal [4 + 2] cycloaddition
of dienolate with hydrazone, and regeneration of NHC. Multiple possible
deprotonation pathways were explored, and the additive base such as
K<sub>2</sub>CO<sub>3</sub> would significantly lower the energy barrier.
The formal [4 + 2] cycloaddition step is the stereoselectivity-determining
step, and <i>R</i>-configured rather than <i>S</i>-configured product was preferentially generated. In addition, the
C–H···O, C–H···N, LP···π,
and C–H···π interactions have been identified
in the most energetically favorable transition state involved in the
stereoselectivity-determining step. The additional analysis indicates
that NHC strengthens the acidity and electrophilicity to promote the
deprotonation, indicating this is not a simple NHC-catalyzed umpolung
carbonyl reaction. The mechanistic insights and the significant role
of NHC obtained in this study should provide valuable insights for
understanding the organocatalytic γ-C(sp<sup>3</sup>)–H
bond functionalization reaction
Theoretical Study on DBU-Catalyzed Insertion of Isatins into Aryl Difluoronitromethyl Ketones: A Case for Predicting Chemoselectivity Using Electrophilic Parr Function
The possible mechanisms
of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-catalyzed chemoselective
insertion of <i>N</i>-methyl isatin into aryl difluoronitromethyl
ketone to synthesize 3,3-disubstituted and 2,2-disubstituted oxindoles
have been studied in this work. As revealed by calculated results,
the reaction occurs via two competing paths, including α and
β carbonyl paths, and each path contains five steps, that is,
nucleophilic addition of DBU to ketone, C–C bond cleavage affording
difluoromethylnitrate anion and phenylcarbonyl–DBU cation,
nucleophilic addition of difluoromethylnitrate anion to carbonyl carbon
of <i>N</i>-methyl isatin, acyl transfer process, and dissociation
of DBU and product. The computational results suggest that nucleophilic
additions on different carbonyl carbons of <i>N</i>-methyl
isatin via α and β carbonyl paths would lead to different
products in the third step, and β carbonyl path associated with
the main product 3,3-disubstituted oxindole is more energetically
favorable, which is consistent with the experimental observations.
Noteworthy, electrophilic Parr function can be successfully applied
for exactly predicting the activity of reaction site and reasonably
explaining the chemoselectivity. In addition, the distortion/interaction
and noncovalent interaction analyses show that much more hydrogen
bond interactions should be responsible for the lower energy of the
transition state associated with β carbonyl path. The obtained
insights would be valuable for the rational design of efficient organocatalysts
for this kind of reactions with high selectivities
Insights into Stereoselective Aminomethylation Reaction of α,β-Unsaturated Aldehyde with N,O-Acetal via N‑Heterocyclic Carbene and Brønsted Acid/Base Cooperative Organocatalysis
A theoretical
investigation has been performed to interrogate the
mechanism and stereoselectivities of aminomethylation reaction of
α,β-unsaturated aldehyde with N,O-acetal, which is initiated
by N-heterocyclic carbene and Brønsted acid (BA). The calculated
results disclose that the reaction contains several steps, i.e., formation
of the actual catalysts NHC and Brønsted acid Et<sub>3</sub>N·H<sup>+</sup> coupled with activation of C–O bond of N,O-acetal,
nucleophilic attack of NHC on α,β-unsaturated aldehyde,
formation of Breslow intermediate, β-protonation for the formation
of enolate intermediate, nucleophilic addition on the Re/Si face to
enolate by the activated iminium cation, esterification coupled with
regeneration of Et<sub>3</sub>N·H<sup>+</sup>, and dissociation
of NHC from product. Addition on the prochiral face of enolate should
be the stereocontrolling step, in which the chiral <i>α-</i>carbon is formed. Furthermore, NBO, GRI, and FMO analyses have been
performed to explore the roles of catalysts and origin of stereoselectivity.
Surprisingly, the added Brønsted base (BB) Et<sub>3</sub>N plays
an indispensable role in the esterification process, indicating the
reaction proceeds under NHC-BA/BB multicatalysis rather than NHC-BA
dual catalysis proposed in the experiment. This theoretical work provides
a case on the exploration of the special roles of the multicatalysts
in NHC chemistry, which is valuable for rational design on new cooperative
organocatalysis
Theoretical Investigations toward the Asymmetric Insertion Reaction of Diazoester with Aldehyde Catalyzed by N‑Protonated Chiral Oxazaborolidine: Mechanisms and Stereoselectivity
In recent years, the N-protonated
chiral oxazaborolidine has been
utilized as the Lewis acid catalyst for the asymmetric insertion reaction,
which is one of the most challenging topics in current organic chemistry.
Nevertheless, the reaction mechanism, stereoselectivity, and regioselectivity
of this novel insertion reaction are still unsettled to date. In this
present work, the density functional theory (DFT) investigation has
been performed to interrogate the mechanisms and stereoselectivities
of the formal C–C/H insertion reaction between benzaldehyde
and methyl α-benzyl diazoester catalyzed by the N-protonated
chiral oxazaborolidine. For the reaction channel to produce the <i>R</i>-configured C–C insertion product as the predominant
isomer, the catalytic cycle can be characterized by four steps: (i)
the complexation of the aldehyde with catalyst, (ii) addition of the
other reactant methyl α-benzyl diazoester, (iii) the removal
of nitrogen concerted with the migration of phenyl group or hydrogen,
and (iv) the dissociation of catalyst from the products. Our computational
results show that the carbon–carbon bond formation step is
the stereoselectivity determining step, and the reaction pathways
associated with [1, 2]-phenyl group migration occur preferentially
to those pathways associated with [1, 2]-hydrogen migration. The pathway
leading to the <i>R</i>-configured product is the most favorable
pathway among the possible stereoselective pathways. All these calculated
outcomes align well with the experimental observations. The novel
mechanistic insights should be valuable for understanding this kind
of reaction
Fundamental Reaction Pathway and Free Energy Profile for Inhibition of Proteasome by Epoxomicin
First-principles quantum mechanical/molecular mechanical
free energy
calculations have been performed to provide the first detailed computational
study on the possible mechanisms for reaction of proteasome with a
representative peptide inhibitor, Epoxomicin (EPX). The calculated
results reveal that the most favorable reaction pathway consists of
five steps. The first is a proton transfer process, activating Thr1-O<sup>γ</sup> directly by Thr1-N<sup>z</sup> to form a zwitterionic
intermediate. The next step is nucleophilic attack on the carbonyl
carbon of EPX by the negatively charged Thr1-O<sup>γ</sup> atom,
followed by a proton transfer from Thr1-N<sup>z</sup> to the carbonyl
oxygen of EPX (third step). Then, Thr1-N<sup>z</sup> attacks on the
carbon of the epoxide group of EPX, accompanied by the epoxide ring-opening
(S<sub>N</sub>2 nucleophilic substitution) such that a zwitterionic
morpholino ring is formed between residue Thr1 and EPX. Finally, the
product of morpholino ring is generated via another proton transfer.
Noteworthy, Thr1-O<sup>γ</sup> can be activated directly by
Thr1-N<sup>z</sup> to form the zwitterionic intermediate (with a free
energy barrier of only 9.9 kcal/mol), and water cannot assist the
rate-determining step, which is remarkably different from the previous
perception that a water molecule should mediate the activation process.
The fourth reaction step has the highest free energy barrier (23.6
kcal/mol) which is reasonably close to the activation free energy
(∼21–22 kcal/mol) derived from experimental kinetic
data. The obtained novel mechanistic insights should be valuable for
not only future rational design of more efficient proteasome inhibitors
but also understanding the general reaction mechanism of proteasome
with a peptide or protein
Fundamental Reaction Pathway for Peptide Metabolism by Proteasome: Insights from First-Principles Quantum Mechanical/Molecular Mechanical Free Energy Calculations
Proteasome
is the major component of the crucial non-lysosomal
protein degradation pathway in the cells, but the detailed reaction
pathway is unclear. In this study, first-principles quantum mechanical/molecular
mechanical free energy calculations have been performed to explore,
for the first time, possible reaction pathways for proteasomal proteolysis/hydrolysis
of a representative peptide, succinyl-leucyl-leucyl-valyl-tyrosyl-7-amino-4-methylcoumarin
(Suc-LLVY-AMC). The computational results reveal that the most favorable
reaction pathway consists of six steps. The first is a water-assisted
proton transfer within proteasome, activating Thr1-O<sup>γ</sup>. The second is a nucleophilic attack on the carbonyl carbon of a
Tyr residue of substrate by the negatively charged Thr1-O<sup>γ</sup>, followed by the dissociation of the amine AMC (third step). The
fourth step is a nucleophilic attack on the carbonyl carbon of the
Tyr residue of substrate by a water molecule, accompanied by a proton
transfer from the water molecule to Thr1-N<sup>z</sup>. Then, Suc-LLVY
is dissociated (fifth step), and Thr1 is regenerated <i>via</i> a direct proton transfer from Thr1-N<sup>z</sup> to Thr1-O<sup>γ</sup>. According to the calculated energetic results, the overall reaction
energy barrier of the proteasomal hydrolysis is associated with the
transition state (TS3<sup>b</sup>) for the third step involving a
water-assisted proton transfer. The determined most favorable reaction
pathway and the rate-determining step have provided a reasonable interpretation
of the reported experimental observations concerning the substituent
and isotopic effects on the kinetics. The calculated overall free
energy barrier of 18.2 kcal/mol is close to the experimentally derived
activation free energy of ∼18.3–19.4 kcal/mol, suggesting
that the computational results are reasonable
Theoretical Investigations toward the [4 + 2] Cycloaddition of Ketenes with <i>N</i>‑Benzoyldiazenes Catalyzed by N‑Heterocyclic Carbenes: Mechanism and Enantioselectivity
Density functional theory (DFT) calculations have been
performed
to provide the first detailed computational study on the mechanism
and enantioselectivity for the [4 + 2] cycloaddition reaction of ketenes
with <i>N</i>-benzoyldiazenes catalyzed by N-heterocyclic
carbenes (NHCs). Two possible mechanisms have been studied: first
is the “ketene-first” mechanism (mechanism A), and second
is the novel “diazene-first” mechanism (mechanism B).
The calculated results reveal that mechanism B is more favorable than
mechanism A because it is not only of lower energy barrier but also
more consistent with the provided general experimental procedure (Huang,
X.-L.; He, L.; Shao, P.-L.; Ye, S. <i>Angew. Chem., Int. Ed.</i> <b>2009</b>, <i>48</i>, 192–195). The enantioselectivity-determining
step is demonstrated to present during the first process of cycloaddition,
and the main product configuration is verified to agree with the experimental
ee values very well. This study should be of some worth on forecasting
how different substituent groups of catalysts and/or reactants affect
the enantioselectivity of products. The obtained novel mechanistic
insights should be valuable for not only rational design of more efficient
NHC catalysts but also understanding the general reaction mechanism
of [4 + 2] cycloaddition of ketenes
N‑Heterocyclic Carbene (NHC)-Catalyzed sp<sup>3</sup> β‑C–H Activation of Saturated Carbonyl Compounds: Mechanism, Role of NHC, and Origin of Stereoselectivity
Activation
of inert sp<sup>3</sup> β-C–H bonds has
attracted widespread attention and been developed with significant
progress in recent years, but understanding the mechanism of this
kind of reaction continues to be one of the most challenging topics
in organic chemistry. In this paper, the possible reaction mechanisms
and origin of stereoselectivity in the reaction between saturated
carbonyl compounds with enones generating cyclopentenes catalyzed
by N-heterocyclic carbene (NHC) have been investigated using density
functional theory. The computational results show that the additive
DBU plays an important role in NHC-catalyzed C–H activation.
Analyses of the natural bond orbital charge and global reaction index
indicate that NHC can lower the energy barrier of the entire reaction
by activating the α/β-C–H bond rather than by strengthening
the nucleophilicity of the reactant as a Lewis base. This is remarkably
at variance from previous reports. In addition, the π···π
stacking between the phenyl of the enone and the conjugated system
of the NHC-bounded enolate intermediate has been found by the analyses
of distortion/interaction and atom-in-molecule to be responsible for
the stereoselectivity. These results shed light on the detailed reaction
mechanism and the significant role of the NHC organocatalyst and offer
valuable insights into the rational design of potential catalysts
for this kind of highly stereoselective reaction
DFT Study on the Mechanisms and Diastereoselectivities of Lewis Acid-Promoted Ketene–Alkene [2 + 2] Cycloadditions: What is the Role of Lewis Acid in the Ketene and C = X (X = O, CH<sub>2</sub>, and NH) [2 + 2] Cycloaddition Reactions?
The
detailed mechanisms and diastereoselectivities of Lewis acid-promoted
ketene–alkene [2 + 2] cycloaddition reactions have been studied
by density functional theory (DFT). Four possible reaction channels,
including two noncatalyzed diastereomeric reaction channels (channels
A and B) and two Lewis acid (LA) ethylaluminum dichloride (<b>EtAlCl</b><sub><b>2</b></sub>) catalyzed diastereomeric reaction channels
(channels C and D), have been investigated in this work. The calculated
results indicate that channel A (associated with product R-configurational
cycloputanone) is more energy favorable than channel B (associated
with the other product S-configurational cyclobutanone) under noncatalyzed
condition, but channel D leading to S-configurational cyclobutanone
is more energy-favorable than channel C, leading to R-configurational
cycloputanone under a LA-promoted condition, which is consistent with
the experimental results. And Lewis acid can make the energy barrier
of ketene–alkene [2 + 2] cycloaddition much lower. In order
to explore the role of LA in ketene and C = X (X = O, CH<sub>2</sub>, and NH) [2 + 2] cycloadditions, we have tracked and compared the
interaction modes of frontier molecular orbitals (FMOs) along the
intrinsic reaction coordinate (IRC) under the two different conditions.
Besides by reducing the energy gap between the FMOs of the reactants,
our computational results demonstrate that Lewis acid lowers the energy
barrier of the ketene and C = X [2 + 2] cycloadditions by changing
the overlap modes of the FMOs, which is remarkably different from
the traditional FMO theory. Furthermore, analysis of global reactivity
indexes has also been performed to explain the role of LA catalyst
in the ketene–alkene [2 + 2] cycloaddition reaction