Enolization substituent effects

Table 9.5 Counterion and substituent effect on enolization selectivity. ...

Introduction of 3,5-dimethyl and 4-substituent on the Phebox skeleton revealed a weak substituent effect on the degree of asymmetric induction (Scheme 15) [28,29]. When trimethylsilyl acrylate was used as enolate source, the (3-hydroxy carboxylic acid was obtained directly upon mild acid hydrolysis. In the production of carboxylic acid 49, an enantiomeric excess of 96% ee was attained using the NC -substituted Phebox-Rh catalyst. 

KSIEs for the reaction of aromatic olefins, 1,1-diphenylethylene and a-methylstyrene (Table 21) are significantly smaller they can be related to transition states earlier than those in the aliphatic series. Unfortunately, for the reactions of highly reactive aromatic olefins or enol ethers, whose low sensitivity to solvent and substituent effects indicates very early transition states, there are not enough KSIE data to confirm this conclusion. 

This result, associated with those on substituent effects, supports previous conclusions to the effect that the position of the transition state depends on the reactivity in agreement with RSP. In particular, stabilization of the intermediate as a result of conjugation, such as that in the reaction of enol ethers, makes the transition state very early. The few available KSIEs also suggest that the transition states for aromatic series are earlier than those for alkenes. 

Aldol reactions have continued to attract attention.28-39 hi order to determine the mechanism of addition of lithium pinacolone enolate [CH2=C(OLi)C(Me)3] to benzaldehyde the carbonyl-carbon KIE (xlk/nk = 1.019) and the substituent effects (p = 1.16 0.31) have been compared with those for other lithium reagents.28,29 The small positive KIE, which is larger than the equilibrium IE (nK/nK = 1.006) determined by ab initio MO calculations (HF/6—31 + G ), is in contrast with nk/l4k = 1.000 for MeLi addition which proceeds by the rate-determining ET mechanism, characterized by a much smaller p value. Since probe experiments showed no evidence of single electron transfer, it has been concluded that the significant isotope effect for reaction of lithium pinacolone enolate is indicative of rate-determining polar attack (PL) rather than radical coupling (RC) (Scheme 2). 

It is also possible to examine the effect of oxygen substituents on the stability of arenonium ions. Wirz has studied keto-enol equilibria for phenol,151 naphthol (Wirz J, Personal communication), and anthrol.152,153 The tautomeric constants may be combined with p/y,s for protonation of the keto tautomer and ionization of the phenol to provide pifas f°r protonation of the aromatic ring of phenol and the phenoxide ion. As illustrated in Scheme 18 the unstable keto tautomer of phenol 22 was produced by photolysis of the bicyclooctene dione 21. Except in the case of the anthrone a pA a for protonation of the keto tautomer has not been measured directly. However, values can be estimated from the pfor protonation of the 4,4-dimethylated analog136 with a correction for the substituent effect of the methyl groups. 

The bottom line complements Figure 12.1 by adding the >Ky values of representative ketones. The comparison of E G reveals the same substituent effects that are familiar from the analogous aldehydes A-C the enol content is increased by alkyl substituents in the on-position, and even more so by aryl substituents in the a-position. The ketone H in Figure 12.1, the nonexistent isophenol has by far the highest propensity to enolization of all the carbonyl compounds shown. The reason, of course, is that the tautomeric enol, phenol, is favored because of its aromaticity and thus particularly efficient C=C double bond stabilization. 

Tab. 12.1 Substituent Effects on the Enol Content of Active-Methylene Compounds (for the enol content of monocarboxyl and monocarbonyl compounds cf. Figure 12.2)...

The acidifying effect of the remaining acceptor substituents of Table 10.1 decreases in the order —C(=0)—H > —C(=0)—alkyl > —C(=0)—O-alkyl, and the amide group —C(=0)—NR2 is even less effective. This ordering essentially reflects substituent effects on the stability of the C=0 double bond in the respective C,H-acidic compound. The resonance stabilization of these C=0 double bonds drastically increases in the order R—C(=0)—H < R—C(=0)—alkyl < R—C(=0)—0—alkyl < R—C(=0)— NR2 (cf. Table 6.1 see Section 7.2.1 for a comparison between the C=0 double bonds in aldehydes and ketones).This resonance stabilization is lost completely once the a-H-atom has been removed by way of deprotonation and the respective enolate has formed. 

Nearly all the data of Sect. II was gathered from NMR spectra. In this section we turn our attention to the hydrogen bonding proton of the ds enol tautomer, looking firstly at the more usual properties of < (OHO), line width, and coupling constants. The second part will cover the substituent effects on the and 13C NMR chemical shift. The third part will deal with the isotopic shift Ad H, 2H). 

In the alternative, equatorial, sulfoxide conformation 20, one face of the enolate is effectively shielded by the bulk of the dithiane ring, the other face being exposed unless a very large 2-alkyl substituent is present. Stereoselectivity is therefore expected to become poorer as the relative size of the (equatorial) 2-alkyl substituent is increased, an effect which can be observed in the results outlined in Table 4 on moving from R = Me to R = Ph. 

In a more complex scenario, the /J-substituents were also found to participate in partially matched or mismatched reactions577. Examples of double induction pave the route of polypropionate and polyketide synthesis and it was emphasized that the relative influence of the enolate or aldehyde component may be enhanced, depending on the coordinating metal employed in the double stereodifferentiating aldol reaction. Thus, it was found that, in spite of their modest synlanti selectivity, lithium enolates are effective in double stereodifferentiating aldol reaction578. In the matched and partially matched cases, lithium enolate face selectivity is opposite to that which is found for their boron or titanium counterparts. This is perfectly illustrated in a recent work by Roush and coworkers reporting a partial synthesis of Bafilomycin Aj (Scheme 122)579. 

The proximity of the diffusion limit also inhibits a detailed discussion of the data in Table 7, but a significant difference to the substituent effects discussed in Section III.D.4 is obvious. Whereas the reactivities of terminal alkenes, dienes, and styrenes toward AnPhCH correlate with the stabilities of the new carbenium ions and not with the ionization potentials of the 7r-nucleophiles [69], the situation is different for the reactions of enol ethers with (p-ClC6H4)2CH+ [136]. In this reaction series, methyl groups at the position of electrophilic attack activate the enol ether double bonds more than methyl groups at the new carbocationic center, i.e., the relative activation free enthalpies are not controlled any longer by the stabilities of the intermediate carbocations but by the ionization potentials of the enol ethers (Fig. 20). An interpretation of the correlation in Fig. 20 has not yet been given, but one can alternatively discuss early transition states which are controlled by frontier orbital interactions or the involvement of outer sphere electron transfer processes [220]. 

Similarly, the reversal of the thermochemical stability order upon one-electron oxidation has been demonstrated theoretically and experimentally for several heteroatom substituted carbonyl/enol pairs, e.g. esters [52,53] and acids [54,55]. A recent detailed evaluation of the substituent effect by Heinrich, Frenking and Schwarz using ab initio molecular orbital calculations [56] is summarized in Table 3. Both a- and 7t-donors X stabilize the two cationic tautomeric forms, but with Ji-donating groups (X F, OH, NHj) the enol radical cations are much more stable than the corresponding keto ions. On the other hand, with c-donor/rt-withdrawing substituents this thermochemical preference is less pronounced and in the case X BeH the order of relative stabilities of ionic keto/enol pairs is even reverted. 

Bertolasi, V., Ferretti, V., Gilli, P., etcd. (2008) Substituent effects on keto-enol tautomerization of fS-diketones from X-ray structural data and DFT calculations. New Journal of Chemistry, 32, 694-704. 

The carbonyl-carbon kinetic isotope effect (KIE) and the substituent effects for the reaction of lithium pinacolone enolate (112) with benzaldehyde (equation 31) were analyzed by Yamataka, Mishima and coworkers ° and the results were compared with those for other lithium reagents such as MeLi, PhLi and AllLi. Ab initio (HF/6-31-I-G ) calculations were carried out to estimate the equilibrium isotope effect (EIE) on the addition to benzaldehyde. In general, a carbonyl addition reaction (equation 32) proceeds by way of either a direct one-step polar nucleophilic attack (PL) or a two-step process involving electron transfer (ET) and a radical ion intermediate. The carbonyl-carbon KIE was of primary nature for the PL or the radical coupling (RC) rate-determining ET mechanism, while it was considered to be less important for the ET rate-determining mechanism. The reaction of 112 with benzaldehyde gave a small positive KIE = 1.019),... 

Aldol reactions have continued to attract attention. In order to determine the mechanism of addition of lithium pinacolone enolate [CH2=C(OLi)C(Me)3] to benzaldehyde the carbonyl-carbon KIE 1.019) and the substituent effects... 

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