Nucleophilic substitution carbocation intermediates

This chapter deals with silyl-substituted carbocations. In Section II results of quantum chemical ab initio calculations of energies and structures of silyl-substituted carbocations are summarized1. Throughout the whole chapter results of ab initio calculations which relate directly to the experimental observation of silyl-substituted carbocations and their reactions are reviewed. Section m reports on gas phase studies and Section IV on solvolytic investigations of reactions which involve silyl-substituted carbocation intermediates and transition states. Section V summarizes the structure elucidation studies on stable silyl-substituted carbocations. It includes ultra-fast optical spectroscopic methods for the detection of transient intermediates in solution, NMR spectroscopic investigations of silyl-substituted carbocations in superacids and non-nucleophilic solvents, concomitant computational studies of model cation and X-ray crystallography of some silyl-substituted carbocations which can be prepared as crystals of salts. 

Additional evidence for carbocation intermediates in certain nucleophilic substitutions comes from observing rearrangements of the kind normally associated with such species For example hydrolysis of the secondary alkyl bromide 2 bromo 3 methylbutane yields the rearranged tertiary alcohol 2 methyl 2 butanol as the only substitution product... 

The sp hybridized carbon of an acyl chloride is less sterically hindered than the sp hybridized carbon of an alkyl chloride making an acyl chloride more open toward nude ophilic attack Also unlike the 8 2 transition state or a carbocation intermediate m an Stvfl reaction the tetrahedral intermediate m nucleophilic acyl substitution has a stable arrangement of bonds and can be formed via a lower energy transition state... 

Secondary isotope effects at the position have been especially thoroughly studied in nucleophilic substitution reactions. When carbocations are involved as intermediates, substantial /9-isotope effects are observed. This is because the hyperconjugative stabliliza-... 

Because carbocations are key intermediates in many nucleophilic substitution reactions, it is important to develop a grasp of their structural properties and the effect substituents have on stability. The critical step in the ionization mechanism of nucleophilic substitution is the generation of the tricoordinate carbocation intermediate. For this mechanism to operate, it is essential that this species not be prohibitively high in energy. Carbocations are inherently high-energy species. The ionization of r-butyl chloride is endothermic by 153kcal/mol in the gas phase. ... 

Substitution reactions by the ionization mechanism proceed very slowly on a-halo derivatives of ketones, aldehydes, acids, esters, nitriles, and related compounds. As discussed on p. 284, such substituents destabilize a carbocation intermediate. Substitution by the direct displacement mechanism, however, proceed especially readily in these systems. Table S.IS indicates some representative relative rate accelerations. Steric effects be responsible for part of the observed acceleration, since an sfp- caibon, such as in a carbonyl group, will provide less steric resistance to tiie incoming nucleophile than an alkyl group. The major effect is believed to be electronic. The adjacent n-LUMO of the carbonyl group can interact with the electnai density that is built up at the pentacoordinate carbon. This can be described in resonance terminology as a contribution flom an enolate-like stmeture to tiie transition state. In MO terminology,.the low-lying LUMO has a... 

This mechanism explains the observed formation of the more highly substituted alcohol from unsymmetrical alkenes (Markownikoff s rule). A number of other points must be considered in order to provide a more complete picture of the mechanism. Is the protonation step reversible Is there a discrete carbocation intermediate, or does the nucleophile become involved before proton transfer is complete Can other reactions of the carbocation, such as rearrangement, compete with capture by water ... 

FIGURE 8.7 Formation of a racemic product by nucleophilic substitution via a carbocation intermediate. 

Aikene chemistry is dominated by electrophilic addition reactions. When HX reacts with an unsymmetrically substituted aikene, Markovnikov s rule predicts that the H will add to the carbon having fewer alky) substituents and the X group will add to the carbon having more alkyl substituents. Electrophilic additions to alkenes take place through carbocation intermediates formed by reaction of the nucleophilic aikene tt bond with electrophilic H+. Carbocation stability follows the order... 

Before seeing how electrophilic aromatic substitutions occur, let s briefly recall what we said in Chapler 6 about electrophilic alkene additions. When a reagent such as HCl adds to an alkene, the electrophilic hydrogen approaches the p orbitals of the double bond and forms a bond to one carbon, leaving a positive charge at the other carbon. This carbocation intermediate then reacts with the nucleophilic Cl- ion to yield the addition product. 

The mechanistic aspects of nucleophilic substitution reactions were treated in detail in Chapter 4 of Part A. That mechanistic understanding has contributed to the development of nucleophilic substitution reactions as important synthetic processes. Owing to its stereospecificity and avoidance of carbocation intermediates, the Sw2 mechanism is advantageous from a synthetic point of view. In this section we discuss... 

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. 

It was expected that values of ks/kp for partitioning of [1+] could be obtained from the yields of the products of acid-catalyzed reactions of [l]-OH and [2]. However, significantly different relative yields of these products are obtained from the perchloric acid-catalyzed reactions of [l]-OH and [2] in several mixed alcohol/water solvents.21 This demonstrates that the nucleophilic substitution and elimination reactions of these two substrates do not proceed through identical tertiary carbocation intermediates (Scheme 4). The observed... 

The results of studies of the acid-catalyzed hydration of oxygen-, sulfur-, seleno-and nitrogen-substituted alkenes and the relevance of this work to partitioning of the corresponding carbocation intermediates (Chart 1) between deprotonation and nucleophile addition was reviewed in 1986.70. We present here a brief summary of this earlier review, along with additional discussion of recent literature. 

Different rate-determining steps are observed for the acid-catalyzed hydration of vinyl ethers (alkene protonation, ks kp) and hydration of enamines (addition of solvent to an iminium ion intermediate, ks increasing stabilization of a-CH substituted carbocations by 71-electron donation from an adjacent electronegative atom results in a larger decrease in ks for nucleophile addition of solvent than in kp for deprotonation of the carbocation by solvent. 

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. 

Azide ion is a modest leaving group in An + Dn nucleophilic substitution reactions, and at the same time a potent nucleophile for addition to the carbocation reaction intermediate. Consequently, ring-substituted benzaldehyde g m-diazides (X-2-N3) undergo solvolysis in water in reactions that are subject to strong common-ion inhibition by added azide ion from reversible trapping of an o -azido carbocation intermediate (X-2 ) by diffusion controlled addition of azide anion (Scheme... 

The prominent role of alkyl halides in formation of carbon-carbon bonds by nucleophilic substitution was evident in Chapter 1. The most common precursors for alkyl halides are the corresponding alcohols, and a variety of procedures have been developed for this transformation. The choice of an appropriate reagent is usually dictated by the sensitivity of the alcohol and any other functional groups present in the molecule. Unsubstituted primary alcohols can be converted to bromides with hot concentrated hydrobromic acid.4 Alkyl chlorides can be prepared by reaction of primary alcohols with hydrochloric acid-zinc chloride.5 These reactions proceed by an SN2 mechanism, and elimination and rearrangements are not a problem for primary alcohols. Reactions with tertiary alcohols proceed by an SN1 mechanism so these reactions are preparatively useful only when the carbocation intermediate is unlikely to give rise to rearranged product.6 Because of the harsh conditions, these procedures are only applicable to very acid-stable molecules. 

The benzylic substrates X-l-Y and X-2-Y have provided a useful platform for examining the changes in reaction mechanism for nucleophilic substitution that occur as the lifetime of the carbocation intermediate is decreased systematically by varying the meta- and para- aromatic ring substituents. When X is strongly resonance electron-donating, X-l-Y and X-2-Y react by a stepwise mechan-... 

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