Carbocations reaction with nucleophiles

Calculations of the nucleophilic reactions with MeO" were performed for the carbocations 4H+, 5H+ and 6H+ in order to simulate the crucial step of aza-PAH/adduct formation. These reactions were considered as models for evaluation of the reactivity trend for these carbocations toward nucleophiles. Thus, the thermodynamical tendency of each carbocation to react with the nucleophilic sites of DNA was estimated. 

The extension of equilibrium measurements to normally reactive carbocations in solution followed two experimental developments. One was the stoichiometric generation of cations by flash photolysis or radiolysis under conditions that their subsequent reactions could be monitored by rapid recording spectroscopic techniques.3,4,18 20 The second was the identification of nucleophiles reacting with carbocations under diffusion control, which could be used as clocks for competing reactions in analogy with similar measurements of the lifetimes of radicals.21,22 The combination of rate constants for reactions of carbocations determined by these methods with rate constants for their formation in the reverse solvolytic (or other) reactions furnished the desired equilibrium constants. 

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. 

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... 

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... 

A similar distinction between a system with pre-electrolysis with only one electrode (in this case anodic) process, and a system with simultaneous anodic and cathodic processes (in which anode and cathode are on opposite walls of a microchannel so that each liquid is only in contact with the desired electrode potential, analogous to the fuel cell configurations discussed above) was made by Horii et al. (2008) in their work on the in situ generation of carbocations for nucleophilic reactions. The carbocation is formed at the anode, and the reaction with the nucleophile is either downstream (in the pre-electrolysis case) or after diffusion across the liquid-liquid interface (in the case with both electrodes present at opposite walls). The concept was used for the anodic substitution of cyclic carbamates with allyltrimethylsilane, with moderate to good conversion yields without the need for low-temperature conditions. The advantages of the approach as claimed by the authors are efficient nucleophilic reactions in a single-pass operation, selective oxidation of substrates without oxidation of nucleophile, stabilization of cationic intermediates at ambient temperatures, by the use of ionic liquids as reaction media, and effective trapping of unstable cationic intermediates with a nucleophile. 

The HCl that is produced can add in a regiospecific manner to the isolated double bond, giving a tertiary carbocation. An intramolecular nucleophilic reaction with this cation generates the product. 

Partial but not complete loss of optical activity m S l reactions probably results from the carbocation not being completely free when it is attacked by the nucleophile Ionization of the alkyl halide gives a carbocation-hahde ion pair as depicted m Figure 8 8 The halide ion shields one side of the carbocation and the nucleophile captures the carbocation faster from the opposite side More product of inverted configuration is formed than product of retained configuration In spite of the observation that the products of S l reactions are only partially racemic the fact that these reactions are not stereospecific is more consistent with a carbocation intermediate than a concerted bimolecular mechanism... 

Attack by a nucleophile or the solvent can occur at either of the ion pairs. Nucleophilic attack on the intimate ion pair would be expected to occur with inversion of configuration, since the leaving group would still shield the fiont side of the caibocation. At the solvent-separated ion pair stage, the nucleophile might approach fiom either fece, particularly in the case where solvent is the nucleophile. Reactions through dissociated carbocations should occur with complete lacemization. According to this interpretation, the identity and stereochemistry of the reaction products will be determined by the extent to which reaction occurs on the un-ionized reactant, the intimate ion pair, the solvent-separated ion pair, or the dissociated caibocation. 

Figure 11.11 Ion pairs in an S l reaction. The leaving group shields one side of the carbocation intermediate from reaction with the nucleophile, thereby leading to some inversion ol configuration rather than complete racemization.

The S il reaction occurs when the substrate spontaneously dissociates to a carbocation in a slow rate-limiting step, followed by a rapid reaction with the nucleophile. As a result, SN1 reactions are kinetically first-order and take place with racemization of configuration at the carbon atom. They are most favored for tertiary substrates. Both S l and S 2 reactions occur in biological pathways, although the leaving group is typically a diphosphate ion rather than a halide. 

There are, however, serious problems that must be overcome in the application of this reaction to synthesis. The product is a new carbocation that can react further. Repetitive addition to alkene molecules leads to polymerization. Indeed, this is the mechanism of acid-catalyzed polymerization of alkenes. There is also the possibility of rearrangement. A key requirement for adapting the reaction of carbocations with alkenes to the synthesis of small molecules is control of the reactivity of the newly formed carbocation intermediate. Synthetically useful carbocation-alkene reactions require a suitable termination step. We have already encountered one successful strategy in the reaction of alkenyl and allylic silanes and stannanes with electrophilic carbon (see Chapter 9). In those reactions, the silyl or stannyl substituent is eliminated and a stable alkene is formed. The increased reactivity of the silyl- and stannyl-substituted alkenes is also favorable to the synthetic utility of carbocation-alkene reactions because the reactants are more nucleophilic than the product alkenes. 

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... 

In summary, there now exists a body of data for the reactions of carbocations where the values of kjkp span a range of > 106-fold (Table 1). This requires that variations in the substituents at a cationic center result in a >8 kcal mol-1 differential stabilization of the transition states for nucleophile addition and proton transfer which have not yet been fully rationalized. We discuss in this review the explanations for the large changes in the rate constant ratio for partitioning of carbocations between reaction with Bronsted and Lewis bases that sometimes result from apparently small changes in carbocation structure. 

Bimetallic activation of acetyl and alkoxyacetyl ligands — through formation of cationic P2 acyl complexes — to reaction with nucleophilic hydride donors was established. Cationic transition metal compounds possessing an accessible coordination site bind a neutral T -acyl ligand on another complex as a cationic P2 acyl system. These i2 3icyl systems activate the acyl ligand to reduction analogous to carbocation activation. Several examples of i2-acyl complexation have been reported previously. 

Aryl(trimethylsiloxy)carbenes. Acylsilanes (153) undergo a photoinduced C —> O silyl shift leading to aryl(trimethylsiloxy)carbenes (154).73,74 The carbenes 154 can be captured by alcohols to form acetals (157) 73 or by pyridine to give transient ylides (Scheme 29).75 LFP of 153 in TFE produced transient absorptions of the carbocations 155 which were characterized by their reactions with nucleophiles.76 The cations 155 are more reactive than ArPhCH+, but only by factors < 10. Comparison of 154 and 155 with Ar(RO)C and Ar(RO)CH+, respectively, would be of interest. Although LFP was applied to generate methoxy(phenyl)carbene and to monitor its reaction with alcohols,77 no attempt was made to detect the analogous carbocation. 

Since these methoxylated and acetoxylated sulfides have an acetal structure, it is expected that Lewis acid catalyzed demethoxylation should generate a carbocation intermediate which is stabilized by the neighboring sulfur atom. In fact, nucleophilic substitution with arenes has been successfully achieved as shown in Scheme 6.7 [43], This procedure is useful for the preparation of trifluoroethyl aromatics. As already mentioned, generation of carbocations bearing an a-trifluoromethyl group is difficult due to the strong electron-withdrawing effect. Therefore, this carbon-carbon bond formation reaction is remarkable from both mechanistic and synthetic aspects. 

In the cationic domino process which is a synonym for an electrophilic reaction a carbocation is formed first, either formally or in reality, which under bond formation reacts with a nucleophile to form a new carbocation. In most of the known... 

Much of our research has involved the use of dicationic electrophiles in reactions with very weak nucleophiles, such as non-activated arenes and alkanes. By comparison to similar monocationic electrophiles, we have been able to show the extent of electrophilic activation by adjacent cationic centers. For example, carbocations show an increased reactivity with a nearby cationic charge (eqs 3-4).9 When 1,1-diphenyletheneis reacted with superacidic CF3SO3H... 

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