Browse
Submit Data
Databases
API
Help

Dataset Information

42 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Geminal Repulsion Disrupts Diels-Alder Reactions of Geminally Substituted Cyclopentadienes and 4H-Pyrazoles.

ABSTRACT: We have experimentally and computationally explored the sluggish Diels-Alder reactivities of the geminally substituted 5,5-dimethylcyclopentadiene and 5,5-dimethyl-2,3-diazacyclopentadiene (4,4-dimethyl-4H-pyrazole) scaffolds. We found that geminal dimethylation of 1,2,3,4-tetramethylcyclopentadiene to 1,2,3,4,5,5-hexamethylcyclopentadiene decreases the Diels-Alder reactivity towards maleimide by 954-fold. Quantum mechanical calculations revealed that the decreased Diels-Alder reactivities of gem-dimethyl substituted cyclopentadienes and 2,3-diazacyclopentadienes are not a consequence of unfavorable steric interactions between the diene and dienophile as reported previously, but a consequence of the increased repulsion within the gem-dimethyl group in the transition state. The findings have implications for the use of cyclopentadienes in "click" chemistry.

SUBMITTER: Levandowski BJ

PROVIDER: S-EPMC8291746 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Geminal Repulsion Disrupts Diels-Alder Reactions of Geminally Substituted Cyclopentadienes and 4H-Pyrazoles.

Levandowski Brian J BJ Abularrage Nile S NS Raines Ronald T RT

Tetrahedron 20210424

We have experimentally and computationally explored the sluggish Diels-Alder reactivities of the geminally substituted 5,5-dimethylcyclopentadiene and 5,5-dimethyl-2,3-diazacyclopentadiene (4,4-dimethyl-4H-pyrazole) scaffolds. We found that geminal dimethylation of 1,2,3,4-tetramethylcyclopentadiene to 1,2,3,4,5,5-hexamethylcyclopentadiene decreases the Diels-Alder reactivity towards maleimide by 954-fold. Quantum mechanical calculations revealed that the decreased Diels-Alder reactivitie ...[more]

PMID: 34290459

Similar Datasets

Spirocyclization enhances the Diels-Alder reactivities of geminally substituted cyclopentadienes and 4H-pyrazoles.

Project description:The Diels-Alder reactivity of 5-membered dienes is tunable through spirocyclization at the saturated center. As the size of the spirocycle decreases, the Diels-Alder reactivity increases with the cyclobutane spirocycle, spiro[3.4]octa-5,7-diene, being the most reactive. Density functional theory calculations suggest that spiro[3.4]octa-5,7-diene dimerizes 220,000-fold faster than 5,5-dimethylcyclopentadiene and undergoes a Diels-Alder reaction with ethylene 1,200-fold faster than 5,5-dimethylcyclopentadiene. These findings show that spirocyclization is an effective way to enhance the Diels-Alder reactivity of geminally substituted 5-membered dienes.

| S-EPMC10038129 | biostudies-literature

Hyperconjugative Antiaromaticity Activates 4H-Pyrazoles as Inverse-Electron-Demand Diels-Alder Dienes.

Project description:The Diels-Alder reactivity of 4,4-difluoro-3,5-diphenyl-4H-pyrazole was investigated experimentally and computationally with endo-bicyclo[6.1.0]non-4-yne. The computationally predicted rate enhancement from hyperconjugative antiaromaticity induced by fluorination of cyclopentadienes at the 5-position extends to five-membered heterocyclic dienes containing a saturated center. 4,4-Difluoro-4H-pyrazoles are new electron-deficient dienes with rapid reactivities toward strained alkynes.

| S-EPMC7015664 | biostudies-literature

Additivity of Diene Substituent Gibbs Free Energy Contributions for Diels-Alder Reactions between Me2C=CMe2 and Substituted Cyclopentadienes.

Project description:Systematic computational studies of pericyclic Diels-Alder reactions between (H3C)2C=C(CH3)2, 1, and all permutations of substituted cyclopentadienes c-C5R1R2R3R4R5aR5b (R = H, CH3, CF3, F) allowed isolation of substitutional effects on Gibbs free energy barrier heights and reaction Gibbs free energies. "Average Substitution Gibbs Free Energy Correction" ΔG ASC# ‡/ΔG ASC# values for each substituent in each position appeared to be additive. Substituent effects on barriers showed interesting contrasts. Methyl substitution at positions 5a and 5b increased barriers significantly, while substitution at all other positions had essentially no impact. In contrast, fluoro substitution at positions 5a and 5b lowered barriers more than substitution at other positions. Trifluoromethyl substitution mixed these effects, in that substitution at positions 5a and 5b increased barriers, but substitution at other positions lowered them. Despite the variances, ΔG ASC# ‡/ΔG ASC# values allowed reliable prediction of barriers and exergonicities for reactions between 1 and highly substituted cyclopentadienes, and between 1 and cyclopentadienes with random mixtures of CH3/CF3/F substituents. ΔG ASC# ‡/ΔG ASC# values were correlated with steric considerations and quantum theory of atoms in molecules (QTAIM) calculations. Overall, the ASC values provide a resource for predicting which Diels-Alder reactions of this type should occur at rapid rates and/or give stable bicyclic products.

| S-EPMC10116529 | biostudies-literature

Regioselectivity of Diels-Alder Reactions Between 6,7-Dehydrobenzofuran and 2-Substituted Furans.

Project description:We describe the first report of the generation of 6,7-dehydrobenzofuran (6,7-benzofuranyne) from 6,7-dihalobenzofurans via metal-halogen exchange and elimination, in a manner similar to our previous work with 6,7-indole arynes. This benzofuranyne undergoes highly regioselective Diels-Alder cycloadditions with 2-substituted furans.

| S-EPMC4179875 | biostudies-literature

Preparation and Diels-Alder/cross coupling reactions of a 2-diethanolaminoboron-substituted 1,3-diene.

Project description:A 2-diethanolamine boronyl substituted 1,3-diene has been synthesized in high yield and characterized spectroscopically as well as by X-ray crystallography. This diene has then subsequently been used in a number of fast, high yielding Diels-Alder/cross coupling reactions.

| S-EPMC2779738 | biostudies-literature

How Ionization Catalyzes Diels-Alder Reactions.

Project description:The catalytic effect of ionization on the Diels-Alder reaction between 1,3-butadiene and acrylaldehyde has been studied using relativistic density functional theory (DFT). Removal of an electron from the dienophile, acrylaldehyde, significantly accelerates the Diels-Alder reaction and shifts the reaction mechanism from concerted asynchronous for the neutral Diels-Alder reaction to stepwise for the radical-cation Diels-Alder reaction. Our detailed activation strain and Kohn-Sham molecular orbital analyses reveal how ionization of the dienophile enhances the Diels-Alder reactivity via two mechanisms: (i) by amplifying the asymmetry in the dienophile's occupied π-orbitals to such an extent that the reaction goes from concerted asynchronous to stepwise and thus with substantially less steric (Pauli) repulsion per reaction step; (ii) by enhancing the stabilizing orbital interactions that result from the ability of the singly occupied molecular orbital of the radical-cation dienophile to engage in an additional three-electron bonding interaction with the highest occupied molecular orbital of the diene.

| S-EPMC9400981 | biostudies-literature

Irreversible endo-selective diels-alder reactions of substituted alkoxyfurans: a general synthesis of endo-cantharimides.

Project description:The [4+2] cycloaddition of 3-alkoxyfurans with N-substituted maleimides provides the first general route for preparing endo-cantharimides. Unlike the corresponding reaction with 3H furans, the reaction can tolerate a broad range of 2-substitued furans including alkyl, aromatic, and heteroaromatic groups. The cycloaddition products were converted into a range of cantharimide products with promising lead-like properties for medicinal chemistry programs. Furthermore, the electron-rich furans are shown to react with a variety of alternative dienophiles to generate 7-oxabicyclo[2.2.1]heptane derivatives under mild conditions. DFT calculations have been performed to rationalize the activation effect of the 3-alkoxy group on a furan Diels-Alder reaction.

| S-EPMC4406157 | biostudies-literature

Dual Activation of Aromatic Diels-Alder Reactions.

Project description:The unusually fast Diels-Alder reactions of [5]cyclophanes were analyzed by DFT at the BLYP-D3(BJ)/TZ2P level of theory. The computations were guided by an integrated activation-strain and Kohn-Sham molecular orbital analysis. It is revealed why both [5]metacyclophane and [5]paracyclophane exhibit a significant rate enhancement compared to their planar benzene analogue. The activation strain analyses revealed that the enhanced reactivity originates from 1)?predistortion of the aromatic core resulting in a reduced activation strain of the aromatic diene, and/or 2)?enhanced interaction with the dienophile through a distortion-controlled lowering of the HOMO-LUMO gap within the diene. Both of these physical mechanisms and thus the rate of Diels-Alder cycloaddition can be tuned through different modes of geometrical distortion (meta versus para bridging) and by heteroatom substitution in the aromatic ring. Judicious choice of the bridge and heteroatom in the aromatic core enables effective tuning of the aromatic Diels-Alder reactivity to achieve activation barriers as low as 2?kcal?mol-1 , which is an impressive 35?kcal?mol-1 lower than that of benzene.

| S-EPMC6771859 | biostudies-literature

Intramolecular Diels-Alder reactions of cyclopropenone ketals.

Project description:The first intramolecular cycloaddition reactions of cyclopropenone ketals with tethered electron-deficient, electron-rich, and neutral 1-substituted dienes are reported, constituting inverse electron demand, normal, and neutral Diels-Alder reactions, that provide exclusively the exo [4 + 2] cycloaddition products without the intervention of [1 + 2], [3 + 2], or [3 + 4] cycloadducts in reactions whose courses do not depend on the reaction conditions, the diene activating substituent, or the nature of the tethering.

| S-EPMC2912946 | biostudies-literature

How Lewis Acids Catalyze Diels-Alder Reactions.

Project description:The Lewis acid(LA)-catalyzed Diels-Alder reaction between isoprene and methyl acrylate was investigated quantum chemically using a combined density functional theory and coupled-cluster theory approach. Computed activation energies systematically decrease as the strength of the LA increases along the series I2 <SnCl4 <TiCl4 <ZnCl2 <BF3 <AlCl3 . Emerging from our activation strain and Kohn-Sham molecular orbital bonding analysis was an unprecedented finding, namely that the LAs accelerate the Diels-Alder reaction by a diminished Pauli repulsion between the π-electron systems of the diene and dienophile. Our results oppose the widely accepted view that LAs catalyze the Diels-Alder reaction by enhancing the donor-acceptor [HOMOdiene -LUMOdienophile ] interaction and constitute a novel physical mechanism for this indispensable textbook organic reaction.

| S-EPMC7187354 | biostudies-literature