Ketones electrostatic effects

Lactams from cyclic ketones—Electrostatic effects on the Schmidt reaction s. 13, 379 bicyclic lactams s. R. J. Michaels and H. E. Zaugg, J. Org. Ghem. 25, 637 (1960)... 

Although the nature of the general polar effect suggested by Kamernitzsky and Akhrem " to account for axial attack in unhindered ketones is not clear, several groups have reported electrostatic interactions affect the course of borohydride reductions. Thus the keto acid (5a) is not reduced by boro-hydride but its ester (5b) is reduced rapidly further, the reduction of the ester (6b) takes place much more rapidly than that of the acid (6a). Spectroscopic data eliminate the possibility that in (5a) there is an interaction between the acid and ketone groups (e.g. formation of a lactol). The results have been attributed to a direct repulsion by the carboxylate ion as the borohydride ion approaches. " By contrast, House and co-workers observed no electrostatic effect on the stereochemistry of reduction of the keto acid (7). However, in this compound the acid group may occupy conformations in which it does not shield the ketone. Henbest reported that substituting chlorine... 

In some transitions, the polarity of the chromophore is weaker after absorption of radiation. One case of this is the n — jt absorption due to the carbonyl present in ketones in solution. Before absorption, the C+-0 polarisation stabilises in the presence of a polar solvent whose molecules will be clustered around the solute because of electrostatic effects. Thus, the n —> -rr electronic transition will require more energy and its maximum will be displaced towards a shorter wavelength, contrary to what would be observed in a nonpolar solvent. This is the hypsochromic effect. Because the excited state is readily formed, the solvent shell around the... 

Results of a study of electrostatic acceleration of enolization in cationic ketones have implications for enzymatic catalysis of enolization.136 Rate constants determined for water-, acetate- and hydroxide ion-catalysed enolizations of cationic ketones (79) (pK 11.13) and (80) (pK 11.90) have been compared with those for (81). It has been estimated that the inductive effects of the charged lings lower the p/y,s of (81) and (79) by 4.2 and 1.2 log units, respectively, whereas for (79) the electrostatic effect lowers the pAa by 6.3 log units, and enhances oh by 330-fold relative to a typical methyl ketone. The rate of enolization of (81) is enhanced 2.3 x 104-fold by the through-space electrostatic effect. 

Bernasconi, C. F. Moreira, J. A. Huang, L. L. Kittredge, K. W. Intrinsic rate constants for proton transfer from a monoketone to amine bases and electrostatic effects on the intrinsic rate constants for the deprotonation of cationic ketones by OH". /. Am. Chem. Soc. 1999, 121, 1674-1680. 

Attempts to predict, from precedent, the behaviour of any particular alicyclic epoxide with a Lewis acid are complicated by the great diversity of known reactions. The best that can be done is first to consider the reaction of the epoxide in isolation as likely to lead to a ketone, unless special steric or conformational features interfere with the development of the necessary transition state. Consideration must then be given to inductive or electrostatic effects of any substituents in the vicinity of the epoxide, which may prevent ketone formation. 

Support for an even more remote electrostatic effect on the mechanism is supplied by the studies of Jackson and Fersht (1993). They mutated charged residues on the surface of Subtilisin BPN, that are 13-15A from the active site, to either neutral or oppositely charged residues. The effect of those mutations on the inhibition constant, Ki, of a trifluoromethyl ketone, was compared for wt and mutated subtilisin. The mutations were Asp-36 (located on a surface loop outside the active site cleft and separated from His-64 by about 15-16A) to Gin, and of Asp-99 (about 12-13A from His-64) to Ser and to Lys. The active site of subtilisin includes Ser-221, His-64 and Asp-32. 

The issues that remain under discussion are (1) the relative importance of the acceptor (Felkin-Ahn) or donor (Cieplak) hyperconjugation capacity of a substituents (2) the relative importance of electrostatic effects and (3) the role of reactant pyramidalization in transmitting the substituent effects. Arguments have been offered regarding the importance of electrostatic effects in all the systems we have discussed. Consideration of electrostatic effects appears to be important in the analysis of stereoselective reduction of cyclic ketones. Orbital interactions (hyperconjugation) are also involved, but whether they are primarily ground state (e.g., reactant pyramidalization) or transition state (e.g., orbital stabilization) effects is uncertain. 

Andersson and coworkers investigated the role of solvation, dispersion, and steric effects on the enantioselectivity. The authors results agree with the fact that gas-phase B3LYP calculations describe the drop in enantioselectivity of 2,3,4,5,6-pentafluoroacetophenone compared to acetophenone where steric and electrostatic effects are the only major effects, but the approximation is too crude to reproduce quantitatively the extent of enantioselection observed experimentally. In order to extract the isolated contributions of steric effects, the authors correlated the same energetic parameter with respect to an empirical steric parameter called STERIMOL B1 [132]. Their results showed that bulkier alkyl groups tend to decrease the enantioselectivity, which correlates well with the B1 parameter. Based on this observation, it seems that an intrinsic steric factor enhances or depresses the enantioselectivity in the reduction of acetophenone and other n-alkyl aryl ketones. However, a generalized rationalization of this effect is not trivial, and investigation of similar catalysts reveals only a small role for steric effects [105, 109]. 

Cornforth proposed a different explanation for the diastereoselective addition of Grignard reagents to a-chloro aldehydes and ketones. The underlying premise of this model is that electrostatic effects such as dipole-dipole interactions favor a reactant conformation in which the C=0 group and the C —Cl bonds are oriented anti-coplanar. The preferred path for approach of the nucleophile could then be predicted on the basis of the sizes of the other substituents on the a carbon (Figure 9.57). 

In addition to solvolysis and nitrenium ion formation, Af-aLkoxy-A-chloroamides (2) also undergo bimolecular reactions with nucleophiles at nitrogen. Not only is the configuration destabilized by the anomeric effect, it also parallels that of a-halo ketones, where halogen on an sp carbon is activated towards reactions by the adjacent carbonyl. This rate-enhancing effect on 8 /2 processes at carbon is well-known, and has been attributed to conjugation of the p-orbital on carbon with the carbonyl jr-bond in the S 2 transition state stabilization of ionic character at the central carbon as outlined by Pross as weU as electrostatic attraction to the carbonyl carbon. The transition states are also affected by the nature of the nucleophile. ... 

The face-selectivity of hydride reductions of the conformationally-rigid ketone series (100) has been examined for pure axial and equatorial isomers with four different R groups, viz. Me, Cl, OMe, and SMe.162 The reactivities show Taft correlations with the inductive effects of the substituents. Only through-bond and -space electrostatic interactions are used to explain the results neither Cieplak nor Anh antiperiplanar effects are invoked. 

Enolization of cationic ketones is accelerated by electrostatic stabilization of the enolate anion. Rate constants for water-, acetate-, and hydroxide ion-catalysed enolization of 2-acetyl- 1-methylpyridinium ion (94) have been measured13811 and compared with a 2-acetylthiazolium ion (95), a simple analogue of 2-acetylthiamine pyrophosphate.13811 For (94), qh = 1.9 x 102 M-1 s 1, about 1.1 x 106 times that for a typical methyl ketone such as acetone. Thermodynamically, it is >108 times more acidic (pAa values of 11.1 vs 19.3). These increases in kinetic and thermodynamic acidity are derived from through-bond and through-space effects, and the implications for enzymatic catalytic sites with proximal, protonatable nitrogen are discussed. The results for (94) suggest a pAa value of 8.8 for (95), a value that cannot be measured directly due to competing hydrolysis. 

Cholesterol can modify both the hydrophobic attraction between lipid hydrocarbon chains and electrostatic interactions between lipid polar groups. The influence it has on the location of 9HP reflects this dual effect At low temperature, the "spacer" effect of cholesterol allows the ketone to gain access directly to the lipid-water interface. At high temperatures, a more disordered hydrocarbon core favors the solubilization of the guest molecule. 

Bppfoh (9) and bppfa (8) derivatives have been successfully applied for the Rh-catalyzed hydrogenation of functionalized olefins and ketones (Table 15.1). The nature of auxiliary group has a significant effect on the enantioselectivity and often also on activity and is used to tailor the ligand for a particular substrate. These effects could be the result of electrostatic interactions between substrate and catalyst. Rh-bppfa complexes were among the first catalysts able to hydrogenate tetrasubstituted C = C bonds, albeit with rather low activity. 

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