Reactive Intermediate Chemistry

Cl

Me Me

kobsd Products

X

Me Me

ks

Products

X

Scheme 2.5

2. This linear correlation was then assumed to hold for the formation and re-

the tert-butyl carbocation, respectively, were estimated from the values of

kobsd for reaction of the corresponding tertiary aliphatic chlorides using Eq. 2.42

The value of ks 1012 s 1 estimated for capture of the tert-butyl carbocation and 5þ by water/trifluoroethanol is larger than both the rate constant for their diffusional encounter with external nucleophilic reagents and that for reorganization

of the carbocation solvation shell by the dielectric relaxation of solvent (kreorg 1011 s 1).47,48 This result suggests that the ion pair or ion molecule intermediates of the solvolysis of precursors to these carbocations undergo direct reac-

tion with a molecule of solvent that is present within the solvation shell at the time of carbocation formation, with ks0 ks ¼ kreorg 1011 s 1.42

The fleeting lifetimes of tertiary carbocations, and the difficulties in describing the energy profiles for their formation and reaction, are highlighted by the results of attempts to determine rate constant ratios for the partitioning of 5þ and the tertbutyl carbocation between capture by nucleophilic solvents and deprotonation that are independent of the pathway for formation of the carbocation.42,49 A telling result is the observation of different yields of the trisubstituted alkene 8 and the nucleophilic substitution products 5-OTFE and 5-OMe from the acid-catalyzed reactions of 5-OH and the disubstituted alkene 7 in 50:45:5 (v/v/v) water/trifluoroethanol/methanol (Scheme 2.6).42 The data require either that the carbocation intermediates of these two acid-catalyzed reactions are too short lived to come to equilibrium with respect to their respective solvation shells, or that the formation of these intermediates is avoided in concerted reactions in which there is minimal coupling of cleavage of the bond to leaving group and formation of the bond to nucleophile/and or proton loss.42

62 CROSSING THE BORDERLINE BETWEEN SN1 AND SN2 NUCLEOPHILIC SUBSTITUTION

3.2. Nucleophilic Solvent Participation and Nucleophilic Solvation

There is an ongoing controversy about whether there is any stabilization of the transition state for nucleophilic substitution at tertiary aliphatic carbon from interaction with nucleophilic solvent.41,50 This controversy has developed with the increasing sophistication of experiments to characterize solvent effects on the rate constants for solvolysis reactions. Grunwald and Winstein51 determined rate constants for solvolysis of tert-butyl chloride in a wide variety of solvents and used these data to define the solvent ionizing parameter Y (Eq. 3). They next found that rate constants for solvolysis of primary and secondary aliphatic carbon show a smaller sensitivity (m) to changes in Y than those for the parent solvolysis reaction of tert-butyl chloride (for which m ¼ 1 by definition).52 A second term was added (‘N) to account for the effect of changes in solvent nucleophilicity on kobsd that result

from transition state stabilization by a nucleophilic interaction between solvent and substrate.52,53 It was first assumed that there is no significant stabilization of

the transition state for solvolysis of tert-butyl chloride from such a nucleophilic interaction. However, a close examination of extensive rate data revealed, in some cases, a correlation between rate constants for solvolysis of tert-butyl derivatives and solvent nucleophicity.54–56

Many other solvent parameters have been defined in an attempt to model as thoroughly as possible solvent effects on the rate constants for solvolysis. These include: (a) Several scales of solvent ionizing power YX developed for different substrates R X that are thought to undergo limiting stepwise solvolysis.57 (b) Several different scales of solvent nucleophilicity developed for substrates of different charge type that undergo concerted bimolecular substitution by solvent.53 (c) An

aromatic ring parameter (I), which was added to account for differences in the interactions of solvent with aromatic rings in the ground and transition states for solvolysis of ring-substituted benzyl and benzhydryl derivatives.58

The development of these various solvent parameters and scales has been accompanied by the realization that there are uncertainties in the physical property of the solvent that is correlated by a particular parameter in cases where systematic changes in solvent structure affect several solvent properties. Consider a reaction that shows no rate dependence on the basicity of hydroxylic solvents, and a second reaction that proceeds through a transition state in which there is a small transition state stabilization from a nucleophilic interaction with the hydroxyl group. The rate constants for the latter reaction will increase more sharply with changing solvent nucleophilicity than those for the former, and they should show a correlation with some solvent nucleophilicity parameter. This trend was observed in a comparison of the effects of solvent on the rate constants for solvolysis of 1-adamantyl and tert-butyl halides, and is consistent with a greater stabilization of the transition state for reaction of the latter by interaction with nucleophilic solvents.59,60

The problems with this interpretation are (a) There is a strong correlation between the nucleophilicity of hydroxylic solvents and the acidity of their hydroxylic proton; and, (b) The transition state for solvolysis is stabilized by an electrophilic (hydrogen-bonding) interaction between this acidic proton and the leaving group anion. Therefore, a greater electrophilic stabilization of the transition state for solvolysis of a 1-adamantyl halide than for the corresponding tert-butyl halide would result in a relative decrease in the rate constant for reaction of the former with decreasing solvent acidity (increasing nucleophilicity), which is not easily distinguished from a relative increase in the rate constant for solvolysis of the tert-butyl halide due to a nucleophilic interaction.41,61

Results such as these have led to recurring discussions about the extent of stabilization of the transition state for heterolytic cleavage at tertiary carbon by ‘‘nucleophilic assistance’’ from solvent. The difficulty lies in reconciling studies that suggest that there is a small dependence of kobsd (s 1) for solvolysis of tertbutyl chloride,59,60 and some cumyl derivatives,62,63 on solvent nucleophilicity with other work that shows there is no detectable stabilization of the transition state for these reactions by interaction with the strongly nucleophilic azide and hydroxide ions, and the strong neutral nucleophile propanethiol.42

Experiments to estimate directly the difference in the free energy of solvation of the transition states for solvolysis of tertiary derivatives in the nucleophilic solvent ethanol and the non-nucleophilic solvent hexafluoroisopropanol suggest that any controversy about the role of solvent in transition state stabilization may be resolved by careful use of the term ‘‘solvation’’. There is good linear correlation, with slope < 1, between the difference in activation barriers for solvolysis of 1-adamantyl chloride and a series of caged and bridgehead tertiary alkyl chlorides

RCl [ Gz ¼ ð GzÞAdCl ð GzÞRCl] and the relative Gibbs free energy change for transfer of chloride ion between RCl and the 1-adamantyl carbocation in the gas

phase ( G , Scheme 2.7). This correlation is observed for solvolysis in both the weakly nucleophilic solvent 97% HFIP/H2O (HFIP ¼ hexafluoroisopropanol) and

good nucleophiles such as propanethiol and azide ion effectively exclude this possibility.50

In summary, controversy concerning the mechanism for solvolysis at tertiary carbon is semantic and can be avoided by making a clear distinction between

(a) nucleophilic solvation, which is stabilization of the transition state for stepwise solvolysis through carbocation or ion pair intermediates by charge–dipole interactions with nucleophilic solvents (Scheme 2.8A); and, (b) nucleophilic solvent participation, which is stabilization of the transition state for concerted solvolysis by formation of a partial covalent bond to the solvent nucleophile (Scheme 2.8B).

4. CONCLUSION AND OUTLOOK

Generally, only a single stepwise or concerted pathway for aliphatic nucleophilic substitution is detected by experiment because of the very different activation barriers for formation of the respective reaction transition states for these reactions. The description of the borderline between stepwise and concerted nucleophilic substitution reactions presented in this chapter has been obtained through a search for those rare substrates that show comparable barriers to these two reactions; and through the characterization of the barrier for nucleophile addition to the putative carbocation intermediate of the stepwise reaction in the region of this change in mechanism.

No break to a fully concerted reaction mechanism is observed for nucleophilic substitution of azide ion at the tertiary benzylic substrates X-2-Y, even as the energy well for the tertiary carbocation is transformed into a ‘‘flat plateau.’’ Removal of a single a-methyl group from X-2-Y to give X-1-Y reduces the barrier to concerted bimolecular substitution of azide ion relative to that for the stepwise solvolysis, and similar barriers are observed for these reactions of the secondary substrates X-1-Cl at the point where the energy well for the intermediate is transformed into a ‘‘flat plateau.’’ There is minimal steric hindrance to concerted bimolecular nucleophilic substitution at the primary benzylic substrates (4-MeO,X)-3-Y, and concerted bimolecular substitution by azide ion is observed even when there is a substantial barrier for addition of solvent to the carbocation intermediate of the stepwise reaction. The simple conclusion from these results is that the advantage to the coupling of bond formation and bond cleavage in concerted nucleophilic substitution at benzylic carbon is relatively small, but that the advantage changes significantly and systematically with changing structure of the nucleophile, electrophilic carbon, and leaving group.

The description of the borderline between stepwise and ‘‘concerted’’ nucleophilic substitution remains murky in cases where there is no significant stabilization of the transition state for the concerted reaction through the coupling of bond cleavage and formation. The reason is that there are no simple experimental protocols to detect the point at which the energy well for the carbocation intermediate of the stepwise reaction in the upper right hand corner of Figure 2.3 is transformed into

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1. INTRODUCTION

Carbanions provide a rich chemistry and have been the subject of intense study over the past 100 years, partly because of their central role in important synthetic reaction schemes. Given the low electronegativity of carbon, it is not surprising that carbon-centered anions can be highly reactive and appear as transient intermediates in reaction mechanisms; however, when certain conditions are met, they can be prepared and studied as stable species. For example, the addition of multiple electronwithdrawing substituents can lead to a carbanion that is stable in aqueous solution [e.g., C(CN)3] or bonding with a cation can render a carbanion that is stable in a weakly acidic solvent such as diethyl ether (e.g., MeMgBr). As both of these examples suggest, the stability of a carbanion is intimately associated with its basicity, which in turn, is generally measured by the acidity (i.e., pKa) of the parent carbon acid.

This chapter will begin with a brief overview of the development of carbanion chemistry followed by a section devoted to the structure and stability of carbanions. Methods of measuring carbon acidity and systematic trends in carbanion stability will be key elements in this chapter. Next, processes in which carbanions appear as transient, reactive intermediates will be presented and typical carbanion mechanisms will be outlined. Finally, some new developments in the field will be described. Although the synthetic utility of carbanions will be alluded to many times in this chapter, specific uses of carbanion-like reagents in synthesis will not be explored. This topic is exceptionally broad and well beyond the scope of this chapter.

2. DEVELOPMENT OF CARBANION CHEMISTRY

The origins of carbanion chemistry are deeply rooted in synthesis given the great utility of these species in forming new carbon–carbon bonds. Carbanions are highly nucleophilic and rarely undergo rearrangement reactions so they are very attractive reactive intermediates from a synthetic point of view. As a result, metal salts of carbanions have been widely used in synthesis for >100 years.1–8 Certainly the best known example is the Grignard reagent9,10 where bonding of magnesium to a carbanion center leads to a species that is relatively easy to prepare and handle. However, the initial evidence of organomagnesium compounds actually predates Grignard and goes back to the middle of the nineteenth century.11,12 Organolithium compounds were investigated later13 and are more difficult to handle because the