Chemical carbocation-nucleophile addition

The more favorable partitioning of [1+ ] to form [l]-OH than to form [2] must be due, at least in part, to the 4.0 kcal mol-1 larger thermodynamic driving force for the former reaction (Kadd = 900 for conversion of [2] to [l]-OH, Table 1). However, thermodynamics alone cannot account for the relative values of ks and kp for reactions of [1+] that are limited by the rate of chemical bond formation, which may be as large as 600. A ratio of kjkp = 600 would correspond to a 3.8 kcal mol-1 difference in the activation barriers for ks and kp, which is almost as large as the 4.0 kcal mol 1 difference in the stability of [1]-OH and [2]. However, only a small fraction of this difference should be expressed at the relatively early transition states for the reactions of [1+], because these reactions are strongly favored thermodynamically. These results are consistent with the conclusion that nucleophile addition to [1+] is an inherently easier reaction than deprotonation of this carbocation, and therefore that nucleophile addition has a smaller Marcus intrinsic barrier. However, they do not allow for a rigorous estimate of the relative intrinsic barriers As — Ap for these reactions. 

The observed value of kjkp for partitioning of the simple tertiary carbocation [1+] is smaller than that expected if the nucleophilic addition of solvent were to occur by rate-determining chemical bond formation. This is probably because solvent addition is limited by the rate constant for reorganization of the solvation shell that surrounds the carbocation. 

Compounds with a low HOMO and LUMO (Figure 5.5b) tend to be stable to selfreaction but are chemically reactive as Lewis acids and electrophiles. The lower the LUMO, the more reactive. Carbocations, with LUMO near a, are the most powerful acids and electrophiles, followed by boranes and some metal cations. Where the LUMO is the a of an H—X bond, the compound will be a Lowry-Bronsted acid (proton donor). A Lowry-Bronsted acid is a special case of a Lewis acid. Where the LUMO is the cr of a C—X bond, the compound will tend to be subject to nucleophilic substitution. Alkyl halides and other carbon compounds with good leaving groups are examples of this group. Where the LUMO is the n of a C=X bond, the compound will tend to be subject to nucleophilic addition. Carbonyls, imines, and nitriles exemplify this group. 

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. 

In all the bimolecular reactions considered thus far the surfactant has been chemically inert, but a functionalized surfactant will generate a micelle in which reactant is covalently bonded (Scheme 3). The functional groups are basic or nucleophilic, and include amino, imidazole, oximate, hydroxamate, thiolate or hydroxyl [3-6,97-108]. In some cases comicelles of a functional and an inert surfactant have also been used. The reactions studied include deacylation, dephosphorylation, nucleophilic aromatic substitution, and nucleophilic addition to preformed carbocations, and some examples are shown in Scheme 7. 

An important question is whether nucleophilic substitution at tertiary carbon proceeds though a carbocation intermediate that shows a significant chemical barrier to the addition of solvent and other nucleophiles. The yield of the azide ion substitution product from the reaction of 5-Cl is similar to that observed for the reactions of X-2-Y when this product forms exclusively by conversion of the preassociation complex to product. Therefore the carbocation 5 is too unstable to escape from an aqueous solvation shell and undergo diffusion-controlled trapping by azide ion. This result sets a lower limit of w fcj > -d 1.6 x 10 ° s (Scheme 2.4) " for addition of solvent to the ion pair intermediate 5" C1 . 

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. 

Generally speaking, liquid-phase fluorination catalysts are located in groups 4 (Ti [2], etc.), 5 (Nb, Ta [3], etc.), 6 (Mo, etc.), 14 (Sn [4], etc.) and 15 (Bi, As, Sb [5], etc.) columns of the Periodic Table of the chemical elements. Among all these compounds, SbClj and more specifically the Sb(V)Cl F entities which were first synthesized by Swarts in 1895 [6], are the most active catalysts. From a mechanistic point of view, Sb(V)Cl Fj, in the presence of HF form superacidic species such as SbCl F +i H. Cl/F exchange reaction can be concerted or can proceed via a carbocation followed by addition of F [7], while the addition of HF to a double bond could proceed via two types of attack, nucleophilic (F ) or electrophilic (H ) [8]. 

It is clear that atoms other than hydrogen can be electron deficient and function as electron pair acceptors. Can a carbon atom function as a Lewis acid The answer is yes, if the definition is modified somewhat. Various reactions generate carbocation intermediates (see 55 and 58) and a Lewis base can certainly donate electrons to that positive carbon. A species that donates electrons to carbon is called a nucleophile (see Section 6.7), so an electron donor that reacts with 55 or with 58 is a nucleophile. In addition to carbocations, which are charged species, the carbon atom in a polarized bond is electron deficient, and a nucleophile could donate electrons to the 6+ carbon. This is the basis of many organic reactions to be discussed, particularly in Chapter 11. The fundamental concept of a species donating electrons to a carbon is introduced in this section, with the goal of relating this chemical reactivity to the Lewis acid-Lewis base definitions used in previous sections. 

One way to look at this process is to say that the elements H and Cl added to the 7t-bond, so it can be called an addition reaction. In reality, the alkene reacts as a Brpnsted-Lowry base with the strong acid to form the C-H bond and a carbocation intermediate. In a second chemical step, the chloride cormter-ion is a nucleophile that attacks the electropositive carbon of the carbocation to form a C-Cl bond. The conversion of cyclopentene to 2 and then to 3 constitutes the mechanism of this reaction, which is the step-by-step chemical sequence of reactions that transforms cyclopentene to chlorocyclopentene. The mechanism of this reaction, as described in Chapter 7 (Section 7.8), is a two-step process in which cyclopentene reacts with HCl to give carbocation 2, which reacts with chloride ion in a second chemical step to give 3. 

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