N-aryl pyrazoles: DFT calculations of CH acidity and deprotonative metallation using a combination of lithium and zinc amides

Chevallier, Floris; Halauko, Yury S.; Pecceu, Christelle; Nassar, Ibrahim F.; Dam, To Uyen; Roisnel, Thierry; Матулис, Вадим Э.; Ивашкевич, Олег А.; Mongin, Florence

doi:10.1039/c1ob05267e

Cited by 53 publications

(40 citation statements)

References 51 publications

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“…We chose this reagent as a focus for attention because of: 1) the blurred nature of the base as a contacted lithium zinc species and therefore of its ’ate formulation and 2) the possibility that LiCl, also present in the reaction media, has a role in the constitution of the base. In relation to reason (1) the authors were led to interpret the base in different ways, it being generally treated as a simple 1:1 mixture of LiTMP and Zn(TMP) 2 , where its synergistic performance is explained according to the in situ trapping of generated lithio species with zinc compounds 8a–c. This agrees with the detection of free LiTMP and Zn(TMP) 2 in 13 C NMR spectra of the base8d and with calculations predicting that LiTMP and Zn(TMP) 2 are more stable separately than their co‐complex 8c.…”

Section: Dosy Sizes Estimated (Expressed In Fw; G Mol−1) For Every Comentioning

confidence: 99%

“LiZn(TMP)₃”, a Zincate or a Turbo‐Lithium Amide Reagent? DOSY NMR Spectroscopic Evidence

2011

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LiCl counts! DOSY NMR studies (see picture; TMP=2,2,6,6‐tetramethylpiperidide; TMEDA=N,N,N′,N′‐tetramethylethylenediamine) reveal the true nature of the synthetically useful basic mixture formed by reacting three equivalents of LiTMP with one of (TMEDA)⋅ZnCl2 in THF. Surprisingly, Zn(TMP)2 is just a spectator of the mutual interactions shown between LiTMP and the LiCl coproduct released from the transmetalation/“salt elimination” reaction.

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Section: Dosy Sizes Estimated (Expressed In Fw; G Mol−1) For Every Comentioning

confidence: 99%

“LiZn(TMP)₃”, a Zincate or a Turbo‐Lithium Amide Reagent? DOSY NMR Spectroscopic Evidence

2011

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“…In the study of their intrinsic basicities and regioselectivity, however, an interesting phenomenon emerges, that is, the adjacent lone pair (ALP) effect, which states that “a ring‐nitrogen atom bearing an sp 2 lone pair provides a sizable electrostatic obstacle (not Pauli repulsion) to the generation of an sp 2 carbanion at an adjacent ring‐carbon atom” . Notable examples with the ALP effect include the absence of lithiation of 1‐methylpyrazole and 1‐phenylpyrazole at the 3‐position (Scheme ), the higher CH acidity at the 5‐position in a series of N ‐aryl, N ‐methylpyrazoles and N ‐methylimidazole, the lower acidity of the 4‐position of pyrazole demonstrated by both experimental and density function theory studies, and no evidence for any halogen‐metal exchange of imidazole at the 4‐position or of pyrazole at the 3‐position –…”

Section: Introductionmentioning

confidence: 99%

Adjacent Lone Pair (ALP) Effect: A Computational Approach for Its Origin

Zhang

Ahmed

et al. 2016

Chemistry A European J

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In one word,h ow would you describe your research? Unexpected. What is the most significant result of this study? It has been common knowledge in chemistry that when two lone pairs are close, the molecular system is less stable than when the pairs are far away from each other,a nd the instability comes from the Pauli exchange or simply electronic repulsion. When the adjacent lone pair (ALP) effect in nitrogenous heterocyclic compounds was experimentally identified, the same interpretation was applied. However,t here have been few theoretical methods, which can quantify the magnitude of the pair-pair repulsion. Using our recently developed generalized block-localized wavefunction (BLW) method, we can precisely probe the pair-pair repulsion and other electronic interactions by optimally deriving the electron-localized state wavefunction. Significantly,w ef ound that two-electron inte-grals between adjacent lone pairs are not consistent with the explanation of the ALP effect in terms of pair-pair repulsion. Instead, the reduced p conjugation and nucleus-electron electrostatic attraction in the deprotonated anion with two lone pairs adjacent are the true causes for the ALP effect. What was the inspiration for this cover design? Using cartoon figures to represent electron pairs, we try to show that the p electron pairs (in white) are happier and move around more (conjugate) when the s lone pairs (in red) are comfortably separated. Is your current researchm ainly curiosity driven (fundamental) or rather applied? Our theoretical research is mostly curiosity driven. Chemical theory is built on an umber of fundamental and intuitive concepts and am olecule is considered in terms of atoms or functional groups. Modern computational chemistry,h owever,a dopts at op-down strategy in terms of molecular orbitals (MOs) which are extended over the whole molecule. To explore bonding natures and quantify conventional chemical concepts, we have been developing an alternative theory,t hat is, the ab initio valence bond (VB) theory.T he BLWm ethod used in this work is the simplest variant of the VB theory,a nd can provide bonding information which is supplement to MO computations. Invited for the cover of this issue are the teams led by Wei Wu (Xiamen University) and Yirong Mo (Universityo fW estern Michigan). The image depicts how p electron pairs (white figures) are more stable when the s lone pairs (red figures)a re separated. Read the full text of the article at

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“…1 ). We showed earlier, for related substrates, the impact of the different hydrogen acidities on the regioselectivity of the reaction [ 37 – 38 40 , 42 – 43 ]. Based on these results, we here use CH acidities of the aromatic substrates in THF (calculated using the homodesmic reaction approach within the density functional theory (DFT) framework) to attempt a rationalization of the practical results.…”

Section: Introductionmentioning

confidence: 99%

Deproto-metallation of N-arylated pyrroles and indoles using a mixed lithium–zinc base and regioselectivity-computed CH acidity relationship

Messaoud¹,

Bentabed‐Ababsa²,

Hedidi³

et al. 2015

Beilstein J. Org. Chem.

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SummaryThe synthesis of N-arylated pyrroles and indoles is documented, as well as their functionalization by deprotonative metallation using the base in situ prepared from LiTMP and ZnCl2·TMEDA (1/3 equiv). With N-phenylpyrrole and -indole, the reactions were carried out in hexane containing TMEDA which regioselectively afforded the 2-iodo derivatives after subsequent iodolysis. With pyrroles and indoles bearing N-substituents such as 2-thienyl, 3-pyridyl, 4-methoxyphenyl and 4-bromophenyl, the reactions all took place on the substituent, at the position either adjacent to the heteroatom (S, N) or ortho to the heteroatom-containing substituent (OMe, Br). The CH acidities of the substrates were determined in THF solution using the DFT B3LYP method in order to rationalize the experimental results.

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N-aryl pyrazoles: DFT calculations of CH acidity and deprotonative metallation using a combination of lithium and zinc amides

Cited by 53 publications

References 51 publications

“LiZn(TMP)₃”, a Zincate or a Turbo‐Lithium Amide Reagent? DOSY NMR Spectroscopic Evidence

“LiZn(TMP)₃”, a Zincate or a Turbo‐Lithium Amide Reagent? DOSY NMR Spectroscopic Evidence

Adjacent Lone Pair (ALP) Effect: A Computational Approach for Its Origin

Deproto-metallation of N-arylated pyrroles and indoles using a mixed lithium–zinc base and regioselectivity-computed CH acidity relationship

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N-aryl pyrazoles: DFT calculations of CH acidity and deprotonative metallation using a combination of lithium and zinc amides

Cited by 53 publications

References 51 publications

“LiZn(TMP)3”, a Zincate or a Turbo‐Lithium Amide Reagent? DOSY NMR Spectroscopic Evidence

“LiZn(TMP)3”, a Zincate or a Turbo‐Lithium Amide Reagent? DOSY NMR Spectroscopic Evidence

Adjacent Lone Pair (ALP) Effect: A Computational Approach for Its Origin

Deproto-metallation of N-arylated pyrroles and indoles using a mixed lithium–zinc base and regioselectivity-computed CH acidity relationship

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Product

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“LiZn(TMP)₃”, a Zincate or a Turbo‐Lithium Amide Reagent? DOSY NMR Spectroscopic Evidence

“LiZn(TMP)₃”, a Zincate or a Turbo‐Lithium Amide Reagent? DOSY NMR Spectroscopic Evidence