Carbonium ion stability

Another type of reaction was seen for dalvastatin (8.151), a prodrug that bears an unsaturated side chain. The hydrolysis of dalvastatin to the active acid competes with epimerization at C(6), the rate of the reaction being independent of pH above pH 2 [192], The mechanism is believed to be one of heterolytic cleavage of the C(6)-0 bond to generate a C-centered carbonium ion stabilized by the extended conjugated system characteristic of this compound. In the pH range 2 - 7, the rate of epimerization was found to be ca. 100 times faster than hydrolysis. Above pH 7, base catalysis accelerates hydrolysis, the rate of which increases ca. 100-fold between pH 7 and 9. These facts serve only to complicate the design of HMG-CoA reductase inhibitors and the interpretation of their pharmacokinetic behavior. 

Fliszar, S., and J. Renard. Quantitative investigation of the ozonolysis reaction. XIV. A simple carbonium ion stabilization approach to the ozone cleavage of un-symmetrical olefins. Can. J. Chem. 48 3002-3018, 1970. 

It is primarily this difference in carbonium ion stability that makes 2-methoxytetrahydropyran 3x10 times more reactive than methyl a-D-glucopyranoside (Dyer et al., 1962). A phenohc leaving group and moderate carbonium ion stability must be present together for general acid catalysis to occur the hydrolysis of 2-ethoxytetrahydro-pyran is specific acid-catalysed (Fife and Jao, 1968). 

The data in Table 7 reveal that leaving-group ability and not carbonium ion stability is the key factor permitting intramolecular... 

This serious limitation of the utility of C-nmr has been recognized (Olah et al., 1970), but dismissed by recourse to the results of extended Hiickel M.O. calculations by Hoffmann (1964). These calculations indicated that the charge on the cationic centre of t-butyl is, in fact, more positive than in the isopropyl ion. Hoffmann noted that his results are at odds with the widely held assumption that a methyl group is a better electron donor than hydrogen but showed that the correct order of carbonium ion stability could be predicted even if a methyl group is electron withdrawing with respect to hydrogen. 

Richards and Hill have recently obtained quantitative evidence of the stabilization of a -metallocenyl carbonium ions (38, 95). They have shown that sol-volyses of methylmetallocenylcarbinyl acetates proceed via a carbonium ion mechanism, and that these acetates solvolyze with rates greater than even tri-phenylmethyl (trityl) acetate. Further, the relative rates of solvolysis and therefore the order of carbonium ion stabilities increas.e, proceeding from the iron to the osmium acetate. A portion of these data is summarized in Table II. 

The reactivity of the organosilanes65 and organostannanes66 towards electrophiles is dependent on the characteristics of the organic ligands. Typically, the alkylsilanes and alkylstannanes are unreactive, which is a consequence of the weakly polarized carbon-silicon and carbon-tin cr-bonds (C8-—Ms+). However, allylsilanes67 and allylstannanes are highly reactive to electrophiles because of extensive ct-tt (C—Si or C—Sn) conjugation in the ally metals and the 0-carbonium ion stabilization effect of the metal center. Consequently, electrophiles add exclusively with allylic transposition. 

This is the reverse sequence to that found for carbonium ion stabilities sequence (5) is explainable in terms of the electron-releasing properties of the various alkyl groups, the greater the electron release ( + 1 character) of the alkyl group the more destabilised is the negative charge on the carbanion. 

Hydride Abstraction from Organic Ligands The removal of a hydride ion from an organic radical is an important method of generating carbonium ions stabilized by metal carbonyl systems. Dauben and Honnen (61) in 1958 were the first to exploit this method by use of the powerful hydride abstractor, triphenyl methyl (or trityl) carbonium ion, which is converted thereby into triphenylmethane. 

G. M. Kramer, C. G. Scouten, The 2-Norbomyl Carbonium Ion Stabilizing Conditions An Assessment of Structural Probes", in Advances in Carbocation Chemistry (X. Creary, Ed.) 1989, 1, JAI Press,... 

If C(6) is substituted with very good carbonium ion stabilizers the transition-state structure [173] becomes more stable than the bicyclo[3.1.0]-hexenyl cation structure. Thus treatment of a series of 5-acyl-1,2,3,4,5-pentamethylcyclopenta-1,3-dienes with AlgCle produced cleanly the corres-... 

A third system, the cymantrenylmethyl carbonium ion, has been briefly examined (46). It appears to possess some carbonium ion-stabilizing ability... 

Enzymes catalyze the formation of carbon-carbon bonds between allylic and homoallylic pyrophosphate species by mechanisms that are very different from those for carbonyl compounds. Here, carbonium ions, stabilized as ion pairs and generated from allylic pyrophosphates, are likely to be the intermediates that add to the TT-electron density of carbon-carbon double bonds to form new carbon-carbon single bonds. Reaction patterns are consistent with model systems and the mechanisms are based on analogies with the models, stereochemical information (which is subject to interpretation), and the structural requirements for inhibitors. Detailed kinetic studies, including isotope effects, which provide probes in the aldolase and Claisen enzymes discussed in Section II, have not yet been performed in these systems. The possibility for surprising discoveries remains and further work is needed to confirm the proposed mechanisms and to generalize them. 

When E+ is a proton, equilibrium C lies to the left and routes A and B are followed. Examples are given in Table 13(a). When R is phenyl, the combination of / -silyl hyperconjugative stabilization and carbonium ion stabilization by the benzene ring are sufficient to drive equilibrium C to the left, and substitution with retention of configuration dominates, as shown in Table 13(b). 

In the 1980s, the successful synthesis of elastomeric polyamides 120 of high molecular weight (d/n =10,000-18,000) was reported from the polycondensation of l,l -bis(/ -aminoethyl)ferrocene with diacid chlorides (Scheme 13). Also, polyureas 121 were prepared from the same ferrocene monomer and diisocyanates, and polyesters and polyurethanes were prepared from l,l -bis(/ -hydroxyethyl)ferrocene. However, the latter materials had much lower molecular weights and were characterized only by scanning electron microscopy. X-ray, and IR analyses. The introduction of ferrocenes in which the functional groups are separated from the cyclopentadienyl ring by at least two methylene units was crucial in order to reduce steric effects and to avoid the instability found previously in polymers of a-functionalized ferrocene due to the a-ferrocenyl carbonium ion stability. 

A number of different types of kinetic evidence have been used to show that the dehydration reactions proceed via carbonium-ion intermediates in an El process. Simple rate studies show that the order of reactivity decreases along the series tertiary alcohol > secondary > primary, the order of decreasing carbonium-ion stability. Skeletal rearrangements typical of carbonium ions have also been observed " On a number of occasions, the rate of olefin formation has been shown to be a slower process than the exchange of the hydroxyl function with the reaction medium " -. This can conveniently be demonstrated by studying the reaction in water enriched with " OH2 or, in the case of an optically active alcohol, by comparing the rates of racemisation and dehydration - . These observations indicate that exchange occurs before (184), and not simultaneously with, elimination. 

There seems little doubt that 7r-complexes do not play a role in the ratedetermining step of acid-catalysed dehydration of 1,2-diphenylethanols and related substrates. However, in simple alkyl structures in which carbonium ion stability is lower, rr-complexes may offer an alternate pathway of lower energy. Certainly rr-complexes appear to account for the greater preference for the formation of c/5-but-2-ene rather than the thermodynamically more stable trans isomer from the dehydration of secondary butanol over solid catalysts ". Of course metal cations with a greater variety of orbitals do not really provide appropriate models for assessing the co-ordination properties of a proton. Considering all the available kinetic evidence the most plausible mechanism for dehydration can be described as (197), with route A for tertiary and secondary alcohols and route B for primary and secondary alcohols, viz. 

DDQ is a powerful oxidizing agent for phenols, and carbonium ion stabilization via the quinone methide makes benzylic oxidation of 4-alkylphenols a highly favored process. With methanol as the solvent it is possible to isolate a-methoxybenzyl derivatives... 

---