Alkoxycarbenium ions

When alcohols are added to the reaction mixture, unsymmetrical ether products may be obtained. Starting with a mixture of aldehydes can also give rise to the formation of unsymmetrical ethers. These ether products are formed under conditions different from those used in the formation of ethers directly from alcohols. Thus, it is postulated that the reaction sequence that leads from the carbonyl substrate to the ether involves the intermediate formation of hemiacetals, acetals, or their protonated forms and alkoxycarbenium ions, which are intercepted and reduced to the final ether products by the organosilicon hydrides present in the reaction mix. The probable mechanistic scheme that is followed when Brpnsted acids are present is outlined in Scheme 2.311-327 328... 

Focusing on the synthetic/preparative aspects, in Chapter 10 by J-i. Yoshida, novel approaches to generation of N-acyliminium and alkoxycarbenium ions are presented and their synthetic applications are discussed. 

We focused on two types of organic cations, W-acyliminium ions and alkoxycarbenium ions,2 because they are very popular in organic synthesis. A number of reactions involving such onium ions have been developed and widely utilized for the construction of organic molecules. 

Alkoxycarbenium ions are important reactive intermediates in modem organic synthesis.28 It should be noted that other names such as oxonium ions, oxocarbenium ions, and carboxonium ions have also been used for carbocations stabilized by an adjacent oxygen atom and that we often draw structures having a carbon-oxygen double bond for this type of cations.2 Alkoxycarbenium ions are often generated from the corresponding acetals by treatment with Lewis acids in the presence of carbon nucleophiles. This type of reaction serves as efficient methods for carbon-carbon bond formation. 

Lewis acid-acetal complexes in NMR studies, but never detected alkoxycarbenium ions.29 The absence of alkoxycarbenium ions in the spectra, however, does not necessarily rule out their intermediacy in the reactions with nucleophiles. Therefore, it was imperative to accomplish the reactions of spectroscopically characterized, nonstabilized alkoxycarbenium ions with carbon nucleophiles. The cation pool method made it possible and opened a new chapter in the chemistry of alkoxycarbenium ions. 

If we consider the generation of alkoxycarbenium ions by C-H bond dissociation, ethers should be of our first choice as precursors of alkoxycarbenium ions by analogy to carbamates. The oxidation potentials of ethers, especially aliphatic ethers, however, are very positive, and therefore, it is rather difficult to oxidize ethers selectively under usual conditions. The regioselectivity is also a problem. Usually a mixture of two regioisomers of products is obtained because two regioisomeric alkoxycarbenium ions are generated. 

The concept of electroauxiiiaiy is quite powerful to solve these problems. The pre-introduction of a silyl group as an electroauxiliary decreases the oxidation potential of dialkyl ethers by virtue of the orbital interaction. As a matter of fact, we demonstrated that the anodic oxidation of a-silyl ether took place smoothly in methanol.30 Selective dissociation of the C-Si bond occured and the methoxy group was introduced on the carbon to which the silyl group was attached. Therefore, a-silyl ethers seemed to serve as suitable precursors for alkoxycarbenium ions in the cation pool method. 

Alkoxycarbenium ion pool 26 was allowed to react with allyltrimethylsilane as a carbon nucleophile to give the corresponding allylated product 27. The success of the nucleophilic reaction also indicated the presence of the alkoxycarbenium ion in relatively high concentration in the solution. 

The thermal stability of the alkoxycarbenium ion is noteworthy. When the electrolysis was complete, the cation pool of 26 was allowed to warm up to a second temperature. After being kept there for 30 min, the cation was allowed to react with allyltrimethylsilane. The yield of allylated product 27 was plotted against the temperature. It can be seen from Fig. 7 that alkoxycarbenium ion 26 is stable at temperatures approximately below -50 °C. Above this temperature, the yield of 27 decreased significantly. Intramolecular coordination of ether functionality seems to be effective for the stabilization of alkoxycarbenium ions.33... 

The alkoxycarbenium ions generated by the cation pool method react with various carbon nucleophiles such as substituted allylsilanes and enol silyl ethers to give the corresponding coupling products in good yields. It should be noted that the reactions of alkoxycarbenium ion pools with such nucleophiles are much faster than the Lewis acid promoted reactions of acetals with similar nucleophiles. A higher concentration of the cationic species in the cation pool method seems to be responsible. 

Generation of Alkoxycarbenium Ion Pools by Oxidative C-S Bond Cleavage... 

The a-phenylthioether 28 was oxidized in the absence of a nucleophile by low temperature electrolysis (Scheme 15). The corresponding alkoxycarbenium ion pool 26 was formed, which exhibited a single set of signals in H and l3C NMR spectroscopy. The chemical shifts were quite similar to those obtained by the oxidative C-Si bond dissociation described in the previous section. Subsequently, the cation pool was allowed to react with allyltrimethylsilane to obtain the allylated product 27. 

We chose to study the generation of alkoxycarbenium ion 26 from thioacetal 28. The electrochemically generated ArS(ArSSAr)+, 37 which was well characterized by CSI-MS, was found to be quite effective for the generation of alkoxycarbenium ions, presumably because of its high thiophilicity (Scheme 17). The conversion of 28 to 26 requires 5 min at -78 °C. The alkoxycarbenium ion pool 26 thus obtained exhibited similar stability and reactivity to that obtained with the direct electrochemical method. The indirect cation pool method serves a powerful tool not only for mechanistic studies on highly reactive cations but also for rapid parallel synthesis. 

Alkoxycarbenium ion pools can also be generated by oxidative C-C bond dissociation. Oxidative C-C bond dissociation is well known in the literature.38 Thus, the electrochemical oxidation of l,2-dimethoxy-l,2-diphenylethane 32... 

Ip. Begue, D. Bonnet-Delpon, F. Benayoud, T.T. Tidwell, R.A. Cox, A. Allen, Comparison of the formation energy of fluorinated alkoxycarbenium ions, Gazz. Chim. Ital. 125 (1995) 399 02. 

The presence of fluorine strongly destabihzes a carbocation centered on the jS carbon because only the inductive effect takes place. " The effect on solvolysis or protonation reaction of double bonds can be very important. The destabilization of carbenium and alkoxycarbenium ions plays an importantrole in the design of enzyme inhibitors (cf Chapter 7) and in the hydrolytic metabolism of active molecules (cf. Chapter 3). 

Some irreversible inhibitors of the glycosyltransferases have been designed on the basis of the destabilization by a fluorinated substituent of the alkoxycarbenium ion intermediate. The presence of fluorine atoms renders the formation of the incipient alkoxycarbenium ion too difficult from an energetic point of view. As a consequence, the elimination of the leaving group, which normally provides this alkoxycarbenium ion, becomes difficult (cf. Chapter 7)7 ... 

The X-ray structure of a number of alkoxycarbenium ions has been determined.66 An interesting example is 2-methoxy-l,7,7,-trimethylbicyclo[2.2.1]hept-2-ylium tetrafluroborate 326.630 It is a substituted 2-norbomyl cation and, indeed, the C(2)-C(l)-C(6) bond angle (98.8°) and the C(l)-C(6) bond distance (1.603 A) indicate G-bond charge delocalization, that is, the contribution of the 326b resonance form. 

Ether groups in the side-chain were found to stabilize primary alkoxycarbenium ions via neighbouring group participation (Scheme ll).92 This allowed these intermediates to react with carbon nucleophiles in Sn reactions, giving alkylated products in moderate to good yields. The second step of these reactions was rate determining. Since the five- and six-membered ring intermediates were the most stable, they reacted slowest with the carbon nucleophile. 

On the other hand, in view of important analogies in kinetic behaviour between enol ketonisation and enol ether hydrolysis, the HA [HA,] terms cannot correspond to a concerted mechanism. Lienhard and Wang (1969) and this author (Dubois and Toullec, 1969b Toullec and Dubois, 1974) have pointed out that the rate-limiting step of enol ketonisation is closely similar to that of enol ether hydrolysis if the two-step mechanism for acid-catalysed enolisation is valid. The two reactions occur by rate-limiting proton transfer to the double bond with formation of either a hydroxycarbenium ion (19) or an alkoxycarbenium ion (20). However, in the latter reaction, in contrast to the... 

Kinetic data on acetal formation and cleavage in alcohols are scarce although kinetic and thermodynamic data in the same experimental conditions are of great interest (Davis et al., 1975). It should be noted that under these conditions inequality (53) is inverted and that, therefore, the rate-limiting step corresponds to water addition to an alkoxycarbenium ion (Step 3) or hemiacetal cleavage (Step 4). Recent data by El-Alaoui (1979) on forward and reverse rates are in agreement with those expected the acetal formation rate is independent of water concentration for a series of substituted acetophenones. 

In alcohols, rate-limiting proton addition to the enol ether double-bond yields an alkoxycarbenium ion which can react with alcohol and with the small amounts of water contained in alcohols (59). For simple alcohols, since alcohol and water have comparable reactivities, acetal is formed predominantly as the kinetic product. Subsequent equilibration with the carbonyl compound usually occurs more slowly (El-Alaoui, 1979). 

Recently, a new effective method for electrophilic activation of carbonyl compounds was proposed in order to enable the latter to react with weak nucleophiles such as nitriles102. This method involves the conversion of aldehydes and ketones into highly active acyloxycarbenium ions 163. This new type of carboxonium ions is related to the hydroxycarbenium and alkoxycarbenium ions 105, whose high stability is well known76. 

---