Insight into the Solvation and Isomerization of 3‐Halo‐1‐azaallylic Anions from Ab Initio Metadynamics Calculations and NMR Experiments

Declerck, Reinout; Sterck, Bart De; Verstraelen, Toon; Verniest, Guido; Mangelinckx, Sven; Jacobs, Jan; Kimpe, Norbert De; Waroquier, Michel; Speybroeck, Véronique Van

doi:10.1002/chem.200800948

Cited by 9 publications

(16 citation statements)

References 75 publications

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“…Even more ambitious have been the efforts brought to bear the effect of the environment in atomistic detail. These included studies on small solvated amino acids,79 polyoxometalates,80 beta‐ d ‐xylose condensation reactions,81 ester82 and formamide hydrolysis,83 and solvation84 and isomerization in water 85. The area of reaction at surfaces has also been explored to study chemical vapor deposition,86 heterogeneous reactions on carbon surfaces,87,88 and on anatase 89.…”

Section: Chemical Reactionsmentioning

confidence: 99%

Metadynamics

Barducci

Bonomi

Parrinello

2011

WIREs Comput Mol Sci

1,170

1,296

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Metadynamics is a powerful technique for enhancing sampling in molecular dynamics simulations and reconstructing the free-energy surface as a function of few selected degrees of freedom, often referred to as collective variables (CVs). In metadynamics, sampling is accelerated by a history-dependent bias potential, which is adaptively constructed in the space of the CVs. Since its first appearance, significant improvements have been made to the original algorithm, leading to an efficient, flexible, and accurate method that has found many successful applications in several domains of science. Here, we discuss first the theory underlying metadynamics and its recent developments. In particular, we focus on the crucial issue of choosing an appropriate set of CVs and on the possible strategies to alleviate this difficulty. Later in the second part, we present a few recent representative applications, which we have classified into three main classes: solid-state physics, chemical reactions, and biomolecules.

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Section: Chemical Reactionsmentioning

confidence: 99%

Metadynamics

Barducci

Bonomi

Parrinello

2011

WIREs Comput Mol Sci

1,170

1,296

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“…To account for the flexibility of the system and its interactions with the aqueous environment, we also used molecular dynamics (MD). MD considers the solvated system at a finite temperature and accurately describes the structural fluctuations during a small time period 3841 In this respect, it can provide a superior insight in the specific solvation of a molecular system.…”

Section: Introductionmentioning

confidence: 99%

Investigating the Halochromic Properties of Azo Dyes in an Aqueous Environment by Using a Combined Experimental and Theoretical Approach

Meyer

Hemelsoet

Schueren

et al. 2012

Chemistry A European J

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The halochromism in solution of a prototypical example of an azo dye, ethyl orange, was investigated by using a combined theoretical and experimental approach. Experimental UV/Vis and Raman spectroscopy pointed towards a structural change of the azo dye with changing pH value (in the range pH 5-3). The pH-sensitive behavior was modeled through a series of ab initio computations on the neutral and various singly and doubly protonated structures. For this purpose, contemporary DFT functionals (B3LYP, CAM-B3LYP, and M06) were used in combination with implicit modeling of the water solvent environment. Static calculations were successful in assigning the most-probable protonation site. However, to fully understand the origin of the main absorption peaks, a molecular dynamics simulation study in a water molecular environment was used in combination with time-dependent DFT (TD-DFT) calculations to deduce average UV/Vis spectra that take into account the flexibility of the dye and the explicit interactions with the surrounding water molecules. This procedure allowed us to achieve a remarkable agreement between the theoretical and experimental UV/Vis spectrum and enabled us to fully unravel the pH-sensitive behavior of ethyl orange in aqueous environment.

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“…8 In previous computational research, the 3-chloro-3-methyl-1-azaallylic anion 1 (R 3 = Me) was chosen as a model compound to obtain deeper insight into the structural features of 3-halo-1-azaallylic anions and a better understanding of the factors that control the stereochemical outcome of the reactions involving these anions. 9,10 Herein, the use of 3-chloro-3-methyl-1-azaallylic anions 1 (R 3 = Me) in aldol reactions with aromatic aldehydes is reported, 11,12 en route to the stereoselective synthesis of new azetidines 3 (R 3 = Me) with a chlorinated quaternary stereocenter at the 3-position and tertiary stereocenters at the 2-and 4-positions. To the best of our knowledge, the only report on the synthesis of such type of 3-haloazetidines with carbon-centered substituents at the 1-, 2-, 3-, and 4-positions involves the reaction of 1,2,2,3-tetrasubstituted aziridines or substituted 4-oxazolines, via the corresponding intermediate azomethine ylides, with sulfur ylides.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Previous reported theoretical calculations demonstrated that the lithiated 3-chloro-3-methyl-1-azaallylic anion 1a (M = Li, R 1 = iPr, R 2 = C 6 H 5 , R 3 = Me) is present in a monosolvated monomeric Z-isomer form and should readily undergo transmetalation to the zincated Zisomer 1b (M = ZnCl, R 1 = iPr, R 2 = C 6 H 5 , R 3 = Me). 9,10 In order the verify these calculations and to use these new fundamental insights in stereoselective organic synthesis, anions 1a and 1b, derived from the N-isopropylimine 4a of α-chloropropiophenone, were reacted with aromatic aldehydes 5 (Table 1, Scheme 2). N-Isopropyl-α-chloro imine 4a was prepared by condensation of α-chloropropiophenone with isopropylamine in the presence of titanium(IV) chloride.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In our previous work, 9,10 it was shown that transmetalation of lithiated azaallylic anions 1a to zincated anions 1b takes place with ease. Subsequently, azaallylic anions 1b are present as monomers and bear a ZnCl + cation; however, free lithium cations are also expected to interact with the benzaldehyde oxygen to which the negative charge will be transferred after the addition reaction.…”

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confidence: 96%

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Diastereoselective Aldol Reaction of Zincated 3-Chloro-3-methyl-1-azaallylic Anions as Key Step in the Synthesis of 1,2,3,4-Tetrasubstituted 3-Chloroazetidines

et al. 2012

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Zincated 3-chloro-3-methyl-1-azaallylic anions undergo a stereoselective aldol addition across aromatic aldehydes and subsequent mesylation to produce syn α-chloro-β-mesyloxyketimines, which were isolated in 80−84% yield and high diastereomeric excess (dr > 97/3) after purification via flash chromatography. The syn α-chloro-β-mesyloxyketimines were further stereoselectively reduced to give stereochemically defined 3-aminopropyl mesylates, which were cyclized to 1,2,3,4-tetrasubstituted 3-chloroazetidines containing three contiguous stereogenic centers. DFT calculations on the key aldol addition revealed the presence of a highly ordered bimetallic six-membered twist-boat-like transition state structure with a tetra-coordinated metal cyclic structure. DFT calculations revealed that chelation of both zinc and lithium cations in the transition state structure leads to the experimentally observed high syn diastereoselectivity of aldol reactions. ■ INTRODUCTIONThe stereoselective synthesis of azetidines, particularly of highly substituted derivatives, represents an underdeveloped research area, despite their importance as a class of strained azaheterocyclic compounds, which occur in a wide range of natural products and with application in medicinal chemistry for the synthesis of bioactive compound libraries.1 3-Haloazetidines, in particular, form an important subclass of functionalized four-membered azaheterocycles due to their potential physiological activities and their use as synthons in the synthesis of 3-substituted azetidine derivatives.2 Only very recently, our group reported the first asymmetric synthesis of trans-2-aryl-3-chloroazetidines via cyclization of optically pure β-chloro-γ-sulfonylamino alcohols under Mitsunobu conditions. 3 The latter result, together with a variety of other examples, 1h,4 demonstrated that the cyclization of a preformed aminopropyl chain via nucleophilic substitution of a leaving group, such as a chloride, bromide, or an activated hydroxyl group, in the γ-position, forms a general method to prepare azetidines. The applicability of this method for the stereoselective synthesis of highly substituted 3-haloazetidines 3 depends, naturally, on the efficient synthetic accessibility of the corresponding stereochemically defined aminopropyl precursors 2 (Scheme 1). Metalated 3-chloro-1-azaallylic anions 1 5 have proven to be suitable building blocks in organic synthesis by reaction with electrophiles and elaboration of the resulting functionalized α-chloroketimines.6 More specifically, the aldol reaction of 3,3-dichloro-1-azaallylic anions 1 (R 3 = Cl) with aromatic aldehydes, followed by mesylation to the corresponding β-mesyloxyketimines, 7 and reduction afforded amines 2 (R 3 = Cl) as precursors of stereochemically defined 2,4-diaryl-3,3-dichloroazetidines 3 (R 3 = Cl). 8 In previous computational research, the 3-chloro-3-methyl-1-azaallylic anion 1 (R 3 = Me) was chosen as a model compound to obtain deeper insight into the structural features of 3-halo-1-azaallylic anions a...

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Insight into the Solvation and Isomerization of 3‐Halo‐1‐azaallylic Anions from Ab Initio Metadynamics Calculations and NMR Experiments

Cited by 9 publications

References 75 publications

Metadynamics

Metadynamics

Investigating the Halochromic Properties of Azo Dyes in an Aqueous Environment by Using a Combined Experimental and Theoretical Approach

Diastereoselective Aldol Reaction of Zincated 3-Chloro-3-methyl-1-azaallylic Anions as Key Step in the Synthesis of 1,2,3,4-Tetrasubstituted 3-Chloroazetidines

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