DFT analysis of a key step in the cinchona-mediated organocatalytic Michael-addition of nitromethane to 1,3-diphenylpropenone

Károlyi, Benedek Imre; Fábián, Attila; Kovács, Zoltán; Varga, Szilárd; Drahos, László; Sohar, P.; Csámpai, Antal

doi:10.1016/j.comptc.2012.07.022

Cited by 9 publications

(9 citation statements)

References 38 publications

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“…Through πstacking, the replacement of the widely used trifluoromethyl groups by nitro groups allows the interacting rings to get closer lowering the activation barrier of the C−C bond formation step. 45 Zhu et al performed an experimental (NMR) and theoretical (B3LYP/6-311++G(d,p)//B3LYP6-31G(d) in chloroform (CPCM)) study and described a new dual activation pathway for the Michael reaction of α,β-unsaturated γ-butyrolactam (Nu) and chalcone (EI) catalyzed by bifunctional CA-thiourea organocatalyst (Cat). 46 The key feature of the new dual activation mechanism is the simultaneous activation of the nucleophile (Nu) by the thiourea moiety and the protonated catalyst amine.…”

Section: Asymmetric Michael Additionsmentioning

confidence: 99%

“…Besides the interaction of the substrates with the urea and the quinuclidine moiety, the importance of π-stacking and H-bonding interactions between the electrophilic component and the catalyst was also highlighted. Through π-stacking, the replacement of the widely used trifluoromethyl groups by nitro groups allows the interacting rings to get closer lowering the activation barrier of the C–C bond formation step …”

Section: Computational Studies On Cinchona Alkaloid Catalyzed Reactionsmentioning

confidence: 99%

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Computational Studies on Cinchona Alkaloid-Catalyzed Asymmetric Organic Reactions

et al. 2016

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Remarkable progress in the area of asymmetric organocatalysis has been achieved in the last decades. Cinchona alkaloids and their derivatives have emerged as powerful organocatalysts owing to their reactivities leading to high enantioselectivities. The widespread usage of cinchona alkaloids has been attributed to their nontoxicity, ease of use, stability, cost effectiveness, recyclability, and practical utilization in industry. The presence of tunable functional groups enables cinchona alkaloids to catalyze a broad range of reactions. Excellent experimental studies have extensively contributed to this field, and highly selective reactions were catalyzed by cinchona alkaloids and their derivatives. Computational modeling has helped elucidate the mechanistic aspects of cinchona alkaloid catalyzed reactions as well as the origins of the selectivity they induce. These studies have complemented experimental work for the design of more efficient catalysts. This Account presents recent computational studies on cinchona alkaloid catalyzed organic reactions and the theoretical rationalizations behind their effectiveness and ability to induce selectivity. Valuable efforts to investigate the mechanisms of reactions catalyzed by cinchona alkaloids and the key aspects of the catalytic activity of cinchona alkaloids in reactions ranging from pharmaceutical to industrial applications are summarized. Quantum mechanics, particularly density functional theory (DFT), and molecular mechanics, including ONIOM, were used to rationalize experimental findings by providing mechanistic insights into reaction mechanisms. B3LYP with modest basis sets has been used in most of the studies; nonetheless, the energetics have been corrected with higher basis sets as well as functionals parametrized to include dispersion M05-2X, M06-2X, and M06-L and functionals with dispersion corrections. Since cinchona alkaloids catalyze reactions by forming complexes with substrates via hydrogen bonds and long-range interactions, the use of split valence triple-ζ basis sets including diffuse and polarization functions on heavy atoms and polarization functions on hydrogens are recommended. Most of the studies have used the continuum-based models to mimic the condensed phase in which organocatalysts function; in some cases, explicit solvation was shown to yield better quantitative agreement with experimental findings. The conformational behavior of cinchona alkaloids is also highlighted as it is expected to shed light on the origin of selectivity and pave the way to a comprehensive understanding of the catalytic mechanism. The ultimate goal of this Account is to provide an up-to-date overlook on cinchona alkaloid catalyzed chemistry and provide insight for future studies in both experimental and theoretical fields.

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Section: Asymmetric Michael Additionsmentioning

confidence: 99%

Section: Computational Studies On Cinchona Alkaloid Catalyzed Reactionsmentioning

confidence: 99%

Computational Studies on Cinchona Alkaloid-Catalyzed Asymmetric Organic Reactions

et al. 2016

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“…where R is the ideal gas constant of 8.314 J K −1 mol −1 and T is the temperature in K. The apparent activation energy was found to be 65 kJ mol −1 , which falls within the 19–76 kJ mol −1 range reported for the same Michael Addition catalyzed by cinchona‐urea‐based organocatalysts . The obtained kinetic parameters can be used for process modelling toward automation.…”

Section: Resultsmentioning

confidence: 99%

Nanofiltration‐Enabled In Situ Solvent and Reagent Recycle for Sustainable Continuous‐Flow Synthesis

et al. 2017

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Solvent usage in the pharmaceutical sector accounts for as much as 90 % of the overall mass during manufacturing processes. Consequently, solvent consumption poses significant costs and environmental burdens. Continuous processing, in particular continuous‐flow reactors, have great potential for the sustainable production of pharmaceuticals but subsequent downstream processing remains challenging. Separation processes for concentrating and purifying chemicals can account for as much as 80 % of the total manufacturing costs. In this work, a nanofiltration unit was coupled to a continuous‐flow rector for in situ solvent and reagent recycling. The nanofiltration unit is straightforward to implement and simple to control during continuous operation. The hybrid process operated continuously over six weeks, recycling about 90 % of the solvent and reagent. Consequently, the E‐factor and the carbon footprint were reduced by 91 % and 19 %, respectively. Moreover, the nanofiltration unit led to a solution of the product eleven times more concentrated than the reaction mixture and increased the purity from 52.4 % to 91.5 %. The boundaries for process conditions were investigated to facilitate implementation of the methodology by the pharmaceutical sector.

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“…A variety of new chiral compounds have been synthesized as organocatalysts and showed high efficiency, excellent selectivity and great universality . Among these catalysts, the bifunctional systems [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41], which mimic the natural enzymes, can bind with the substrates on two sites, so are usually more effective. Lately cinchona alkaloid based aminothiourea catalysts, one kind of bifunctional catalysts, are applied in a series of asymmetric reactions and exhibit excellent stereoselectivity [42][43][44][45][46][47][48][49].…”

Section: Introductionmentioning

confidence: 99%

Understanding the mechanism of procedure-controlled enantioselectivity switch in cinchona alkaloid thiourea catalyzed [3+2] cycloaddition: H-bonds controlled enantioselectivity

Huang

Sun

et al. 2015

Computational and Theoretical Chemistry

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DFT analysis of a key step in the cinchona-mediated organocatalytic Michael-addition of nitromethane to 1,3-diphenylpropenone

Cited by 9 publications

References 38 publications

Computational Studies on Cinchona Alkaloid-Catalyzed Asymmetric Organic Reactions

Computational Studies on Cinchona Alkaloid-Catalyzed Asymmetric Organic Reactions

Nanofiltration‐Enabled In Situ Solvent and Reagent Recycle for Sustainable Continuous‐Flow Synthesis

Understanding the mechanism of procedure-controlled enantioselectivity switch in cinchona alkaloid thiourea catalyzed [3+2] cycloaddition: H-bonds controlled enantioselectivity

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