Unraveling the Origin of Solvent Induced Enantioselectivity in the Henry Reaction with Cinchona Thiourea as Catalyst

Heshmat, Mojgan

doi:10.1021/acs.jpca.8b04589

Cited by 7 publications

(6 citation statements)

References 47 publications

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“…In a recent computational study by Baldauf and co-workers, it was predicted that Schreiner’s catalyst (TUR-H; Scheme ) prefers the syn–syn conformation in dichloromethane and switches to the syn–anti conformation upon hydrogen bonding to a ketone substrate. Similarly, the active form of the asymmetrically substituted cinchona thiourea catalyzing the Henry reaction in DMF was found to be the syn–anti rather than the anti–anti conformer . In a comprehensive study of the Cambridge Structural Database, it was found that >98.8% of the 1953 crystal structures of diaryl ureas displayed the anti–anti conformation.…”

Section: Introductionsupporting

confidence: 79%

“…Similarly, the active form of the asymmetrically substituted cinchona thiourea catalyzing the Henry reaction in DMF was found to be the syn−anti rather than the anti−anti conformer. 19 In a comprehensive study of the Cambridge Structural Database, 20 it was found that >98.8% of the 1953 crystal structures of diaryl ureas displayed the anti−anti conformation. The diaryl thiourea structures (190 in total) displayed a broader range of conformers: anti−anti (38%), syn−anti (60%), and syn−syn (2%) conformations.…”

Section: ■ Introductionmentioning

confidence: 99%

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Anion Binding Affinity: Acidity versus Conformational Effects

et al. 2020

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High-level quantum chemical calculations were used to elucidate the gas-and solution-phase conformational equilibria for a series of symmetrically substituted (thio)ureas, (thio)squaramides, and croconamides. Gas-phase calculations predict that the thermodynamic conformer of many of these anion receptors is not the dual-hydrogenbond-facilitating anti−anti conformer as is commonly assumed. For N,N′-diaryl thiosquaramides and croconamides, the syn−syn conformer is typically the predominant conformer. Solution-phase calculations show that the anti−anti conformer is increasingly stabilized as the polarity of the solvent increases. However, the syn− syn conformer remains the lowest energy conformation for croconamides. These predictions are used to explain the acidity versus chloride binding affinity correlations recently reported for some of these compounds. The chloride binding constants for thioureas and croconamides are significantly lower than expected on the basis of their pK a values, and this may be due in part to the need for these receptors to reorganize into the anti−anti conformer. Experimental NMR nuclear Overhauser effect (NOE) measurements of an asymmetrically substituted squaramide and its thio analogue are consistent with the syn−syn conformation being predominant at 298 K. The conformational equilibria should therefore be an important consideration for the design and development of future anion receptors and organocatalysts.

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Section: Introductionsupporting

confidence: 79%

Section: ■ Introductionmentioning

confidence: 99%

Anion Binding Affinity: Acidity versus Conformational Effects

et al. 2020

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“…[6a] To explain the enantioselectivity of an asymmetric Henry reaction, Heshmat proposed cinchonathiourea catalyst substrate activation via the syn-anti conformer. [8] Experimental data suggest a similar trend. In an extensive study of crystal structures of urea and thiourea derivatives, Luchini et al [9] showed that around 60% of all thiourea motifs crystallize in a syn-syn or syn-anti fashion.…”

Section: Introductionmentioning

confidence: 79%

“…Consequently, diphenylthiourea populates the syn – anti and syn – syn conformers, thereby lowering its anion binding affinity [6a] . To explain the enantioselectivity of an asymmetric Henry reaction, Heshmat proposed cinchona‐thiourea catalyst substrate activation via the syn – anti conformer [8] . Experimental data suggest a similar trend.…”

Section: Introductionmentioning

confidence: 99%

London Dispersion Favors Sterically Hindered Diarylthiourea Conformers in Solution

et al. 2022

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We present an experimental and computational study on the conformers of N,N′‐diphenylthiourea substituted with different dispersion energy donor (DED) groups. While the unfolded anti–anti conformer is the most relevant for thiourea catalysis, intramolecular noncovalent interactions counterintuitively favor the folded syn–syn conformer, as evident from a combination of low‐temperature nuclear magnetic resonance measurements and computations. In order to quantify the noncovalent interactions, we utilized local energy decomposition analysis and symmetry‐adapted perturbation theory at the DLPNO‐CCSD(T)/def2‐TZVPP and sSAPT0/6‐311G(d,p) levels of theory. Additionally, we applied a double‐mutant cycle to experimentally study the effects of bulky substituents on the equilibria. We determined London dispersion as the key interaction that shifts the equilibria towards the syn–syn conformers. This preference is likely a factor why such thiourea derivatives can be poor catalysts.

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“…According to this bound state conformational preference, highly differentiated complexation shifts were detected for the two NH protons, that is, very low (0.05–0.09 ppm) for NH(2) and remarkably high (0.59–0.82 ppm) for NH(3) interacting with the enantiomeric substrates (Table S8 in Supporting Information). Even though unexpected, the interaction of thiourea receptors in their syn – anti conformation is already reported in the literature. ,− …”

Section: Resultsmentioning

confidence: 99%

Bis-Thiourea Chiral Sensor for the NMR Enantiodiscrimination of N-Acetyl and N-Trifluoroacetyl Amino Acid Derivatives

et al. 2022

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A C2-symmetrical bis-thiourea chiral solvating agent (CSA), TFTDA , for NMR spectroscopy has been obtained by reacting (1 R ,2 R )-1,2-bis(2-hydroxyphenyl)ethylenediamine and 3,5-bis(trifluoromethyl)phenyl isothiocyanate. TFTDA shows remarkable propensity to enantiodiscriminate N -trifluoroacetyl ( N -TFA) and N -acetyl ( N -Ac) derivatives of amino acids with free carboxyl functions, with the co-presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) as the third achiral additive, which is needed for substrate solubilization. TFTDA shows enhanced enantiodiscriminating efficiency in comparison with the corresponding monomeric counterpart, TFTMA , pointing out cooperativity between its two symmetrical entities. A wide range of amino acid derivatives have been efficiently enantiodiscriminated in CDCl 3 , with high enantioresolution quotients, which guarantee high quality in applications devoted to the quantification of enantiomers. High enantiodiscriminating efficiency is maintained also in diluted 5 mM conditions or in the presence of sub-stoichiometric amounts of CSA (0.3 equiv). The role of phenolic hydroxyls in the DABCO-mediated interaction mechanism between TFTDA and the two enantiomeric substrates has been pointed out by means of diffusion-ordered spectroscopy (DOSY) and rotating frame Overhauser effect spectroscopy (ROESY) experiments. A conformational model for both the CSA and its diastereomeric solvates formed with the two enantiomers of N -acetyl leucine has also been conceived on the basis of ROE data in order to give a chiral discrimination rationale.

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Unraveling the Origin of Solvent Induced Enantioselectivity in the Henry Reaction with Cinchona Thiourea as Catalyst

Cited by 7 publications

References 47 publications

Anion Binding Affinity: Acidity versus Conformational Effects

Anion Binding Affinity: Acidity versus Conformational Effects

London Dispersion Favors Sterically Hindered Diarylthiourea Conformers in Solution

Bis-Thiourea Chiral Sensor for the NMR Enantiodiscrimination of N-Acetyl and N-Trifluoroacetyl Amino Acid Derivatives

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