Computational studies enolization

A recent paper by Singh et al. summarized the mechanism of the pyrazole formation via the Knorr reaction between diketones and monosubstituted hydrazines. The diketone is in equilibrium with its enolate forms 28a and 28b and NMR studies have shown the carbonyl group to react faster than its enolate forms.Computational studies were done to show that the product distribution ratio depended on the rates of dehydration of the 3,5-dihydroxy pyrazolidine intermediates of the two isomeric pathways for an unsymmetrical diketone 28. The affect of the hydrazine substituent R on the dehydration of the dihydroxy intermediates 19 and 22 was studied using semi-empirical calculations. ... 

The reaction shows a dependence on the E- or Z-stereochemistry of the enolate. Z-enolates favor anti adducts and E-enolates favor syn adducts. These tendencies can be understood in terms of an eight-membered chelated TS.299 The enone in this TS is in an s-cis conformation. The stereochemistry is influenced by the s-cis/s-trans equilibria. Bulky R4 groups favor the s-cis con former and enhance the stereoselectivity of the reaction. A computational study on the reaction also suggested an eight-membered TS.300... 

Magnesium bis(hexamethyldisilazide), Mg(HMDS)2, catalyses the enolization of ketones.287 On addition to propiophenone in toluene at ambient temperature, a ca 3 1 E Z mixture of enolates (103, R=SiMe3) is formed. These enolates, and an initial ketone complex, have been characterized by NMR, X-ray, IR, and UV-visible spectroscopy and computational studies. Kinetics of tautomerization have been measured, with proton transfer confirmed as rate determining ( hAd = 18.9 at 295 K). The significant temperature dependence of the primary isotope effect is indicative of tunnelling. 

Highly coordinated silyl enolates have been studied more than highly coordinated tin enolates and they are reported to accelerate the reactions with both organic halides and carbonyl compounds . Compared to the silyl moiety, the system using highly coordinated tin enolates has unique characteristics which can be applied to obtain chemoselective reactions. Baba and coworkers reported a computational study of the difference between uncoordinated and highly coordinated tin enolates and their reactivities toward organic halides and carbonyl compounds. 

This computational study revealed the mechanism of the reaction between trialkyltin enolates and aldehydes or organic halides, both without and with coordinating ligands. High coordination of trialkyltin enolates causes an increase of their nucleophilicity and decrease of Lewis acidity of the tin center, which control the course of reaction . In the reaction of tin enolates with aldehydes, a noncoordinated tin enolate gives a cyclic TS in sled conformation whereas an acyclic TS leading to deactivation of the process is shown in the case of a highly coordinated enolate. Both theoretical and experimental results of... 

Bernard , A., Capelli, A. M., Comotti, A., Gennari, C., Gardner, M., Goodman, J. M., Paterson, I. Origins of stereoselectivity in chiral boron enolate aldol reactions a computational study using transition state modeling. Tetrahedron 1991, 47, 3471-3484. 

Bemardi, A., Gennari, C., Raimondi, L., Villa, M. B. Computational studies on the aldol-type addition of boron enolates to imines an ab-initio approach. Tetrahedron 997, 53, 7705-7714. 

Besides being aq clic, another confounding factor with this substrate is that it is secondary, so the product still contains an active proton such that racemiza-tion and dialkylation are concerns. However, neither of these potential obstacles were problems in this chemistry since the monoalkylated product is 4 pKa units less acidic than the starting active methylene compound [23]. A further complication of the acyclic enolate is that both Z- and -enolates can be formed, and these are likely to complex differently with the catalyst. A computational study suggested that the Z-enolate complexes to the cinchoninium catalyst more strongly than the -enolate, and this enolate fits into a groove of the catalyst rather than directly in a face-to-face orientation. However, calculations could not determine any trends or patterns to explain the enantioselectivity [18]. 

DHFR catalyzes the reduction of 7,8-dihydrofolate (H2F) to 5,6,7,8-tetrahydrofolate (H4F) using nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor (Fig. 17.1). Specifically, the pro-R hydride of NADPH is transferred stereospecifi-cally to the C6 of the pterin nucleus with concurrent protonation at the N5 position [1]. Structural studies of DHFR bound with substrates or substrate analogs have revealed the location and orientation of H2F, NADPH and the mechanistically important side chains [2]. Proper alignment of H2F and NADPH is crucial in enhancing the rate of the chemical step (hydride transfer). Ab initio, mixed quantum mechanical/molecular mechanical (QM/MM), and molecular dynamics computational studies have modeled the hydride transfer process and have deduced optimal geometries for the reaction [3-6]. The optimal C-C distance between the C4 of NADPH and C6 of H2F was calculated to be 2.7A [5, 6], which is significantly smaller than the initial distance of 3.34 A inferred from X-ray crystallography [2]. One proposed chemical mechanism involves a keto-enol tautomerization (Fig. 

Computational studies predict that the geometry (chair, half-chair, boat, etc) depends on the nature of Ri, R2, and M. Theory also predicts that Z-enolates prefer a closed chair, but that -enolates may prefer a boat [54-56]. For an empirical rule for predicting aldol topicity, see ref. [57]. For an investigation into the effect of metal and solvent on transition structures, see ref. [58]. 

On the other hand, a computational study [159] of the Michael addition of propionaldehyde lithium enolate adding to E-crotonaldehyde indicates an anticlinal conformation around the forming bond (i.e. A eclipsing R2 in the ul topicity and A eclipsing H in the Ik topicity of Figure 5.9). 

The two plausible mechanisms for the DAAA are either via inner-sphere or outer-sphere attack of the allyl group (Scheme 4.25). As mentioned previously the different selectivity observed by Trost between the Li-enolate and the enol carbonate is suggestive of an inner-sphere mechanism via a Pd-enolate rather than an outer-sphere mechanism as is typically seen in other 7i-allyl alkylations [48]. The limited enolate scrambling observed in the DAAA would be consistent with an inner-sphere mechanism. A series of computational studies were carried out by Stoltz which suggest that the inner-sphere mechanism is lower in energy that the... 

Computational studies and experimental observations led to the discovery that the enol tautomer coordinates to the catalyst through hydrogen-bond interactions with the catalyst s hydroxyl group and tertiary amine. In this chiral nucleophile, the quinoline ring is effectively blocking the (-face of the enol, thus giving rise to a highly selective reaction (Fig. 5.2). 

Scheme 3.15 Initial formation of complex 11 from cinchona alkaloid QD-4 and enole form of dimethyl malonate 8a suggested in the computational study. (Data from Jiang, H. et al., Int. J. Quant. Chem., 114,642-651,2014.)...

Further, computational study of the possible binding modes between 14 and enolic form of 11 revealed the most facile route for the proton transfer (Scheme 3.23). Initial formation of the adduct 16 is followed by a barrierless proton transfer resulting in the ion pair 16 in which all three NH protons are involved in multiple intramolecular hydrogen bonds. 

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