Carbocations nucleophilic reactions with water

By contrast, measurement of pATR = 4.7 for the Fe(CO)3-cooordinated cyclo-hexadienyl cation 44 (Scheme 26) indicates a 107-fold more favorable equilibrium constant for carbocation formation than for the uncoordinated cation.197 However, a more dramatic effect of coordination is to render nucleophilic reaction with water more favorable than loss of a proton. A pXa = 9 can be estimated by computing the energy differences between coordinated and uncoordinated benzene and coordinated cyclohexadiene. This compares with the value of —24.5 for the uncoordinated cyclohexadienyl cation. The large difference must reflect the unfavorable effect of Fe(CO)3 coordination on benzene, an effect analogous to that found by Mayr for Fe (CO)3 coordination on the tropylium ion.196 As expected, both the coordinated cyclohexadienyl and tropylium ions are highly stereoselective toward exo attack by water. 

Reactions of carbocations with water as a base removing a [3-proton to form an alkene or aromatic product have been less studied than nucleophilic reactions with water. Nevertheless, the correlations included in Fig. 1 (p. 43) represent a considerable range of measurements and these can be further extended to include loss of a proton a to a carbonyl group.116 Indeed, if one places these reactions in the wider context of proton transfers, it can be claimed that they constitute the largest of all groups of reactions for which correlations of rate and equilibrium constants have been studied.116,244,245... 

Richard has also shown that intrinsic barriers for carbocation reactions depend not only on the extent of charge delocalization but to what atoms the charge is delocalized. In a case where values of pifR for calculation of A were not available, comparisons of rate constants for attack of water kH2o with equilibrium constants for nucleophilic reaction with azide ion pKAz for 65-67 showed qualitatively that delocalization to an oxygen atom leads to a lower barrier than to an azido group which is in turn lower than to a methoxyphenyl substituent.226... 

When 1-hexyne is treated with a catalytic amount of sulfuric acid in an aqueous solvent, initial reaction with the acid gives the expected secondary vinyl carbocation 103, and the most readily available nucleophile in this reaction is water (from the aqueous solvent). Nucleophilic addition of water to 103 leads to the vinyl oxonium ion 104. Loss of a proton in an acid-base reaction (the water solvent is the base) generates a product (105) where the OH unit is attached to the C=C unit, an enol. Enols are unstable and an internal proton transfer converts enols to a carbonyl derivative, an aldehyde, or a ketone. This process is called keto-enol tautomerization and, in this case, the keto form of 105 is the ketone 2-hexanone (106). (Enols are discussed in more detail in Chapter 18, Section 18.5.) Note that the oxygen of the OH resides on the secondary carbon due to preferential formation of the more stable secondary carbocation followed by reaction with water, and tautomerization places the carbonyl oxygen on that same carbon, so the product is a ketone. When a disubstituted alkyne reacts with water and an acid catalyst, the intermediate secondary vinyl cations are of equal stability and a mixture of isomeric enols is expected each will tautomerize, so a mixture of isomeric ketones will form. 

The reaction begins with an attack on a hydrogen of the electrophile, HaO", by the electrons of the nucleophilic tt bond. Two electrons from the 7T bond form a new a bond between the entering hydrogen and an alkene carbon, as shown by the curved arrow at the top of Figure 7.6. The carbocation intermediate that results is itself an electrophile, which can accept an electron pair from nucleophilic H2O to form a C-0 bond and yield a protonated alcohol addition product. Removal of H" " by acid-base reaction with water then gives the alcohol product and regenerates the acid catalyst. 

Nucleophilic substitution reactions that occur imder conditions of amine diazotization often have significantly different stereochemisby, as compared with that in halide or sulfonate solvolysis. Diazotization generates an alkyl diazonium ion, which rapidly decomposes to a carbocation, molecular nitrogen, and water ... 

The determinations of absolute rate constants with values up to ks = 1010 s-1 for the reaction of carbocations with water and other nucleophilic solvents using either the direct method of laser flash photolysis1 or the indirect azide ion clock method.8 These values of ks (s ) have been combined with rate constants for carbocation formation in the microscopic reverse direction to give values of KR (m) for the equilibrium addition of water to a wide range of benzylic carbocations.9 13... 

Fig. 5 Logarithmic plots of rate-equilibrium data for the formation and reaction of ring-substituted 1-phenylethyl carbocations X-[6+] in 50/50 (v/v) trifluoroethanol/water at 25°C (data from Table 2). Correlation of first-order rate constants hoh for the addition of water to X-[6+] (Y) and second-order rate constants ( h)so1v for the microscopic reverse specific-acid-catalyzed cleavage of X-[6]-OH to form X-[6+] ( ) with the equilibrium constants KR for nucleophilic addition of water to X-[6+]. Correlation of first-order rate constants kp for deprotonation of X-[6+] ( ) and second-order rate constants ( hW for the microscopic reverse protonation of X-[7] by hydronium ion ( ) with the equilibrium constants Xaik for deprotonation of X-[6+]. The points at which equal rate constants are observed for reaction in the forward and reverse directions (log ATeq = 0) are indicated by arrows.

The nucleophilic site (-Q-) of ROH then bonds to the C" of the carbocation, forming an onium ion of the ether, which loses a proton to the solvent alcohol (ROH) and becomes the ether product. Aqueous acid reverses the reaction of (a), reforming the same intermediate carbocation. This loses a proton to give the C==C, rather than reacting with water to give the very unstable alcohol-analog of the ether. 

Surprisingly, the kinetic measurements now available for the nucleophilic trapping of carbocations with water are not always matched by measurements of rate constants for formation of the carbocation from the corresponding alcohol required to evaluate the equilibrium constant AR. Although carbocations are reactive intermediates in the acid-catalyzed dehydration of alcohols to form alkenes,85,86 the equilibrium in this reaction usually favors the alcohol and the carbocation forming step is not rate-determining. Rate constants may... 

The value of kp obtained in this way for the phenanthreneonium ion is not far from the limit set by the rotational relaxation of water. For such fast reactions, Richard has pointed out that azide trapping could be influenced by preassociation.6 Preassociation has been well characterized in a number of nucleophilic reactions of reactive carbocations with water6 but its impact on deprotonation has not been fully clarified.5,6 In so far as preassociation... 

The starting point for most discussions of reactivity is a correlation of rate and equilibrium constants. One such correlation is shown in Fig. 1 of this chapter. It applies not to reactions of the carbocation with water as a nucleophile but to water acting as base, that is, the removal of a [3-proton from the carbocation to form an alkene or aromatic product. We will consider this reaction below, but here note that for most of the carbocations in Fig. 1 values of kH2o> the rate constants for reaction of the carbocation with water as a nucleophile are also available.25... 

A notable difference between reactions of carbocations with water as a nucleophile and a base is the significantly higher intrinsic barrier for the latter. This difference has been demonstrated most explicitly by Richard, Williams, and Amyes22,246 for reaction of the a-methoxyphenethyl cation 68 with methanol (rather than water) acting as the base and nucleophile. The two reactions and the intrinsic barriers calculated from their rate and equilibrium constants are shown in Scheme 32. Values of A = 6.8 and 13.8 kcal mol 1 are found for the substitution and elimination, respectively. 

Fig. 6 A plot of log (kp/ku2o) for reactions of secondary (O) and tertiary ( ) carbocations with water as a nucleophile and base against pA H,o for hydration of the 7i-bond of the deprotonation product (points close to or above the dashed line correspond to reactions for which deprotonation leads to an aromatic product).

We will deal more briefly with reactions of carbocations with nucleophiles other than water, and then consider correlations in which the nucleophile rather than (as hitherto) the carbocation is varied. Fig. 7 shows a plot of... 

Far from confirming a dependence of nucleophilic selectivity on the reactivity of the carbocations, Ritchie observed that selectivities were unchanged over a 106-fold change in reactivity.15 He enshrined this result in an equation (29) analogous to that of Swain and Scott, but with the nucleophilic parameter n modified to N+ to indicate its reference (initially) to reactions of cations, and with the selectivity parameter s taken as 1.0, that is, with no dependence of the selectivity of the cation on its reactivity (as measured by the rate constant for the reference nucleophile, kn2o for water). 

During my early years as an assistant professor at the University of Kentucky, I demonstrated the synthesis of a simple quinone methide as the product of the nucleophilic aromatic substitution reaction of water at a highly destabilized 4-methoxybenzyl carbocation. I was struck by the notion that the distinctive chemical reactivity of quinone methides is related to the striking combination of neutral nonaromatic and zwitterionic aromatic valence bond resonance structures that contribute to their hybrid resonance structures. This served as the starting point for the interpretation of the results of our studies on nucleophile addition to quinone methides. At the same time, many other talented chemists have worked to develop methods for the generation of quinone methides and applications for these compounds in organic syntheses and chemical biology. The chapter coauthored with Maria Toteva presents an overview of this work. 

First, the oxygen is protonated to make it a better leaving group. Then water leaves to produce the ferf-butyl cation. This step is very fast, even at -60°C, so the carbocation is the only product that can be detected as soon as the alcohol is added to the superacid medium. Because there is no nucleophile for the carbocation to react with (the H,0 generated in the reaction is protonated by the strong acid to form HjO+), its lifetime under these conditions is quite long, and it can be studied by a variety of techniques. 

The mercurinium ion reacts with water in the same manner as the bromonium ion. The nucleophile attaches to the more highly substituted carbon from the side opposite the leaving mercury. Because a free carbocation is not involved in the mechanism, the reaction is not prone to reairangement. 

The reaction of a carbocation with a neutral nucleophile such as water gives a protonated alcohol. Tertiary butyl carbocation, for example, reacts with water (neutral nucleophile) to give protonated tert-butyl alcohol, which eliminates a proton to give tert-butyl alcohol (Scheme 2.5). 

Terpene synthases, also known as terpene cyclases because most of their products are cyclic, utilize a carbocationic reaction mechanism very similar to that employed by the prenyltransferases. Numerous experiments with inhibitors, substrate analogues and chemical model systems (Croteau, 1987 Cane, 1990, 1998) have revealed that the reaction usually begins with the divalent metal ion-assisted cleavage of the diphosphate moiety (Fig. 5.6). The resulting allylic carbocation may then cyclize by addition of the resonance-stabilized cationic centre to one of the other carbon-carbon double bonds in the substrate. The cyclization is followed by a series of rearrangements that may include hydride shifts, alkyl shifts, deprotonation, reprotonation and additional cyclizations, all mediated through enzyme-bound carbocationic intermed iates. The reaction cascade terminates by deprotonation of the cation to an olefin or capture by a nucleophile, such as water. Since the native substrates of terpene synthases are all configured with trans (E) double bonds, they are unable to cyclize directly to many of the carbon skeletons found in nature. In such cases, the cyclization process is preceded by isomerization of the initial carbocation to an intermediate capable of cyclization. 

Carbocyclic compounds can be formed by the nucleophilic intramolecular capture of a seleniranium intermediate of an olefinic bond. The carbonium ion which is formed as intermediate can react with another nucleophile or with the solvent. The first examples of these carbocyclization reactions were observed with dienes. Clive [105] reported that the reaction of the diene 203 with phenyl-selenyl chloride in acetic acid afforded the intermediate 204 which reacted with the solvent to give the bicyclic compound 205 (Scheme 31). Carbocyclization reactions were efficiently promoted by phenylselenyl iodide produced by diphenyl diselenide and iodine. As indicated in Scheme 31,Toshimitsu reported that the reaction of 1,5-hexadiene 206, in acetonitrile and water, afforded the acetamido cyclohexane derivative 209, derived from the cyclization of the seleniranium intermediate 207 followed by the reaction of the carbocation 208 with acetonitrile [106]. In several cases, carbocyclization reactions can be more conveniently effected by independently generating the seleniranium intermediates. A simple procedure consists of the reaction of trifluoromethane-sulfonic acid with j9-hydroxyselenides, which can be easily obtained from the... 

Addition of electrophiles is a reaction typical of aliphatic tt bonds (see Example 4.3). Such additions involve two major steps (1) addition of the electrophile to the nucleophilic tt bond to give an intermediate carbocation, and (2) reaction of the carbocation with a nucleophile. Typical electrophiles are bromine, chlorine, a proton supplied by HCl, HBr, HI, H2SO4, or H3PO4, Lewis acids, and carbocations. The nucleophile in step 2 is often the anion associated with the electrophile, e.g., bromide, chloride, iodide, etc., or a nucleophilic solvent like water or acetic acid. 

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