Acceleration of Diels-Alder reactions by mechanical distortion

Science, Год журнала: 2023, Номер 380(6649), С. 1053 - 1058

Опубликована: Июнь 8, 2023

Challenges in quantifying how force affects bond formation have hindered the widespread adoption of mechanochemistry. We used parallel tip-based methods to determine reaction rates, activation energies, and volumes force-accelerated [4+2] Diels-Alder cycloadditions between surface-immobilized anthracene four dienophiles that differ electronic steric demand. The rate dependences on pressure were unexpectedly strong, substantial differences observed dienophiles. Multiscale modeling demonstrated proximity a surface, mechanochemical trajectories ensued distinct from those solvothermally or under hydrostatic pressure. These results provide framework for anticipating experimental geometry, molecular confinement, directed contribute kinetics.

Язык: Английский

---

Formation of Isolable Dearomatized [4 + 2] Cycloadducts from Benzenes, Naphthalenes, and N-Heterocycles Using 1,2-Dihydro-1,2,4,5-tetrazine-3,6-diones as Arenophiles under Visible Light Irradiation

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(16), С. 9326 - 9333

Опубликована: Апрель 13, 2023

We report that the dearomative [4 + 2] cycloaddition between 1,2-dihydro-1,2,4,5-tetrazine-3,6-diones (TETRADs) and benzenes, naphthalenes, or N-heteroaromatic compounds under visible light irradiation affords corresponding isolable cycloadducts. Several synthetic transformations including transition-metal-catalyzed allylic substitution reactions using isolated cycloadducts at room temperature above were demonstrated. Computational studies revealed retro-cycloaddition of benzene–TETRAD adduct proceeds via an asynchronous concerted mechanism, while benzene–MTAD (MTAD = 4-methyl-1,2,4-triazoline-3,5-dione) a synchronous mechanism.

Язык: Английский

---

Substituent Effects in Bioorthogonal Diels–Alder Reactions of 1,2,4,5‐Tetrazines

Chemistry - A European Journal, Год журнала: 2023, Номер 29(29)

Опубликована: Фев. 28, 2023

1,2,4,5-Tetrazines are increasingly used as reactants in bioorthogonal chemistry due to their high reactivity Diels-Alder reactions with various dienophiles. Substituents the 3- and 6-positions of tetrazine scaffold known have a significant impact on rate cycloadditions; this is commonly explained basis frontier molecular orbital theory. In contrast, we show that differences between classes tetrazines not controlled by interactions. particular, demonstrate mono-substituted decreased Pauli repulsion, which leads more asynchronous approach associated reduced distortion energy. This follows recent Vermeeren-Hamlin-Bickelhaupt model increase asymmetric reactions. addition, reveal ethylene good compound for other alkenes

Язык: Английский

---

Computation-Guided Discovery of Diazole Monosubstituted Tetrazines as Optimal Bioorthogonal Tools

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(39), С. 26884 - 26896

Опубликована: Авг. 21, 2024

Monosubstituted tetrazines are important bioorthogonal reactive tools due to their rapid ligation with trans-cyclooctene. However, application is limited by the reactivity–stability paradox in biological environments. In this study, we demonstrated that steric effects crucial resolving through theoretical methods and developed a simple synthetic route validate our computational findings, leading discovery of 1,3-azole-4-yl 1,2-azole-3-yl monosubstituted as superior tools. These new surpass previous terms high reactivities elevated stabilities. The most stable tetrazine exhibits reasonable stability (71% remaining after 24 h incubation cell culture medium) an exceptionally reactivity (k2 > 104 M–1 s–1 toward trans-cyclooctene). Due its good systems, noncanonical amino acid containing such side chain was genetically encoded into proteins site-specifically via expanded genetic code. protein can be efficiently labeled using cyclopropane-fused trans-cyclooctene dyes living mammalian cells ultrafast reaction rate exceeding 107 s–1, making it one fastest labeling reactions reported date. Additionally, showed superiority vivo mice, achieving efficient local anchoring proteins. expected optimal within systems.

Язык: Английский

---

Enantioselective Povarov Reactions: An Update of a Powerful Catalytic Synthetic Methodology

European Journal of Organic Chemistry, Год журнала: 2021, Номер 2022(2)

Опубликована: Дек. 21, 2021

Abstract The enantioselective Povarov reaction is one of the most powerful synthetic strategy to synthesize chiral, highly functionalized 1,2,3,4‐tetrahydroquinolines. present Minireview aims collect significant successful examples efficient catalytic protocols for this reaction, since 2014. A comprehensive discussion different strategies employed in recent years realize provided; use chiral phosphoric acids, thio(urea) and proline derivatives, as well transition metal complexes will be presented. Additionally, critically discusses intriguing yet obscure mechanistic pathways well‐known controversial dispute between a concerted or polar two‐step process.

Язык: Английский

---

Computational Organic Chemistry: The Frontier for Understanding and Designing Bioorthogonal Cycloadditions

Topics in Current Chemistry, Год журнала: 2024, Номер 382(2)

Опубликована: Май 10, 2024

Computational organic chemistry has become a valuable tool in the field of bioorthogonal chemistry, offering insights and aiding progression this branch chemistry. In review, I present an overview computational work field, including exploration both primary analysis methods used their application main areas chemistry: (3 + 2) [4 2] cycloadditions. context cycloadditions, detailed studies electronic effects have informed evolution cycloalkyne/1,3-dipole Through techniques, researchers found ways to adjust structure via hyperconjugation enhance reactions without compromising stability. For such as distortion/interaction energy decomposition been beneficial, leading development reactants with improved reactivity creation orthogonal reaction pairs. To conclude, touch upon emerging fields cheminformatics machine learning, which promise play role future discovery optimization.

Язык: Английский

---

How Lewis Acids Catalyze Ene Reactions

European Journal of Organic Chemistry, Год журнала: 2021, Номер 2021(37), С. 5275 - 5283

Опубликована: Сен. 12, 2021

Abstract The catalytic effect of various Lewis acids (LAs) on the ene reaction between propene (ene) and but‐3‐en‐2‐one (enophile) was studied quantum chemically using density functional theory with coupled‐cluster theory. LAs efficiently accelerate by lowering barrier up to 12 kcal mol −1 compared uncatalyzed reaction. Our detailed activation strain Kohn‐Sham molecular orbital analyses reveal that coordination a LA catalyst enophile decreases inducing an asymmetry in π‐electronic system, which increases asynchronicity hence relieves otherwise highly destabilizing Pauli repulsion closed‐shell filled π ‐ orbitals enophile. In all, these findings further demonstrate generality Pauli‐lowering catalysis concept.

Язык: Английский

---

NHC-catalysed [3 + 2]-asymmetric annulation between pyrazolin-4,5-diones and enals: synthesis of novel spirocyclic pyrazolone γ-butyrolactones and computational study of mechanism and stereoselectivity

Organic Chemistry Frontiers, Год журнала: 2021, Номер 9(2), С. 420 - 427

Опубликована: Дек. 6, 2021

Herein we present the first asymmetric synthesis of spiropyrazolone γ-butyrolactones from 1 H -pyrazol-4,5-diones and enals by an NHC-catalysed [3 + 2] annulation. DFT calculations carried out predict experimental configuration final adducts.

Язык: Английский

---

Understanding the Mechanism of Diels–Alder Reactions with Anionic Dienophiles: A Systematic Comparison of [ECX]⁻ (E = P, As; X = O, S, Se) Anions

Inorganic Chemistry, Год журнала: 2022, Номер 61(20), С. 7922 - 7934

Опубликована: Май 9, 2022

While Diels-Alder (DA) reactions involving neutral or cationic dienophiles are well-known, the characteristics of analogous with anionic practically unexplored. Herein we present first comparative computational investigations on DA cycloadditions basis [ECX]- anions (E = P, As; X O, S, Se) 2H-pyran-2-one. All these were found to be both kinetically and thermodynamically feasible, enabling synthetic access toward 2-phosphaphenolate arsaphenolate derivatives in future. This study also reveals that [ECO]- show clear regioselectivity, while for [ECS]- [ECSe]- anions, two possible reaction channels have very similar energetics. Additionally, activation barriers lower than those heavier analogues. The observed differences can traced back starkly differing nucleophilic character pnictogen center leading a barrier-lowering effect case anions. Furthermore, analysis geometries electron distributions corresponding transition states revealed structure-property relationships, thus direct comparison cycloaddition reactivity was achieved. Along one pathways, good correlation between suitable nucleophilicity descriptors (nucleophilic Parr function global nucleophilicity). tendency energies explained by changing aromaticity products.

Язык: Английский

---

Computational molecular refinement to enhance enantioselectivity by reinforcing hydrogen bonding interactions in major reaction pathway

Chemical Science, Год журнала: 2023, Номер 14(21), С. 5712 - 5721

Опубликована: Янв. 1, 2023

In the chiral phosphoric acid-catalysed Diels–Alder reaction of 2-vinylquinolines and dienylcarbamates, an "interaction strategy" aided by computational studies resulted in a remarkable improvement enantioselectivity rate.

Язык: Английский

---