Dynamics and the Regiochemistry of Nitration of Toluene

Nieves‐Quinones, Yexenia; Singleton, Daniel A.

doi:10.1021/jacs.6b07328

Cited by 73 publications

(90 citation statements)

References 73 publications

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“…This enables the unraveling of the role of solvents and enzymes on control of single-molecule reaction pathways involving ambimodal transition states and potential energy surface (PES) bifurcations (5,18). Quasi-classical trajectories have been employed previously in the gas phase to understand and predict selectivities of reactions with post-TS bifurcations on the PES (5,(19)(20)(21), such as for the cationic rearrangements occurring in terpene biosynthesis (22,23). We report how solvent and enzyme influence the dynamical behavior of a bifurcating reaction path in the SpnF-catalyzed DA reaction.…”

Section: Significancementioning

confidence: 99%

Influence of water and enzyme SpnF on the dynamics and energetics of the ambimodal [6+4]/[4+2] cycloaddition

Yang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SpnF is the first monofunctional Diels-Alder/[6+4]-ase that catalyzes a reaction leading to both Diels-Alder and [6+4] adducts through a single transition state. The environment-perturbed transition-state sampling method has been developed to calculate free energies, kinetic isotope effects, and quasi-classical reaction trajectories of enzyme-catalyzed reactions and the uncatalyzed reaction in water. Energetics calculated in this way reproduce the experiment and show that the normal Diels-Alder transition state is stabilized by H bonds with water molecules, while the ambimodal transition state is favored in the enzyme SpnF by both intramolecular hydrogen bonding and hydrophobic binding. Molecular dynamics simulations show that trajectories passing through the ambimodal transition state bifurcate to the [6+4] adduct and the Diels-Alder adduct with a ratio of 1:1 in the gas phase, 1:1.6 in water, and 1:11 in the enzyme. This example shows how an enzyme acts on a vibrational time scale to steer post-transition state trajectories toward the Diels-Alder adduct.

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Section: Significancementioning

confidence: 99%

Influence of water and enzyme SpnF on the dynamics and energetics of the ambimodal [6+4]/[4+2] cycloaddition

Yang

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Notably in recent years, direct molecular dynamics simulations [5][6][7][8][9][10][11] have found broad applications in interpreting unusual profiles of organic reactions whose product distribution and stereochemistry are determined by the shape of the potential energy surface (PES) or non-statistical dynamics effects, rather than by the relative heights of energetic barriers, and therefore cannot be well described by classic transition state theory (TST). [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] Pictet-Spengler reactions are among the most extensively utilized methods in the synthesis of various indole alkaloids. [30][31][32][33][34] Moreover, their mechanistic aspect is intriguing and has been a topic of intensive research for quite a long time.…”

Section: Introductionmentioning

confidence: 99%

Unified Mechanistic Understandings of Pictet-Spengler Reactions

Zheng

Xia

You

2018

Chem

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Pictet-Spengler reactions have widely been employed in the synthesis of polycyclic-indole-derived natural products. However, the mechanism of this reaction has remained as a controversial research topic. In this article, You and coworkers performed combined density functional theory calculations and direct molecular dynamics simulations to provide unified mechanistic understandings of Pictet-Spengler reactions with an emphasis on the divergent role played by spiroindolenine intermediates. The key theoretical predictions are well supported by further experiments.

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“…Electrophilic aromatic nitration is one of the most thoroughly studied classes of organic reactions, and its mechanism has been intensely debated over many decades [ 1 – 7 ]. Still it continues to fascinate.…”

Section: Introductionmentioning

confidence: 99%

Mechanism and regioselectivity of electrophilic aromatic nitration in solution: the validity of the transition state approach

2017

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The potential energy surfaces in gas phase and in aqueous solution for the nitration of benzene, chlorobenzene, and phenol have been elucidated with density functional theory at the M06-2X/6-311G(d,p) level combined with the polarizable continuum solvent model (PCM). Three reaction intermediates have been identified along both surfaces: the unoriented π-complex (I), the oriented reaction complex (II), and the σ-complex (III). In order to obtain quantitatively reliable results for positional selectivity and for modeling the expulsion of the proton, it is crucial to take solvent effects into consideration. The results are in agreement with Olah’s conclusion from over 40 years ago that the transition state leading to (II) is the rate-determining step in activated cases, while it is the one leading to (III) for deactivated cases. The simplified reactivity approach of using the free energy for the formation of (III) as a model of the rate-determining transition state has previously been shown to be very successful for halogenations, but problematic for nitrations. These observations are rationalized with the geometric and energetic resemblance, and lack of resemblance respectively, between (III) and the corresponding rate determining transition state. At this level of theory, neither the σ-complex (III) nor the reaction complex (II) can be used to accurately model the rate-determining transition state for nitrations.

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Dynamics and the Regiochemistry of Nitration of Toluene

Cited by 73 publications

References 73 publications

Influence of water and enzyme SpnF on the dynamics and energetics of the ambimodal [6+4]/[4+2] cycloaddition

Influence of water and enzyme SpnF on the dynamics and energetics of the ambimodal [6+4]/[4+2] cycloaddition

Unified Mechanistic Understandings of Pictet-Spengler Reactions

Mechanism and regioselectivity of electrophilic aromatic nitration in solution: the validity of the transition state approach

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