Reactive Intermediate Chemistry

OMe

Scheme 3.10

carbanion that is stabilized by the attached EWGs. With a single nitro group on the methylene (Z ¼ H), both pathways are active and addition at the 9-position is favored by a factor of 4:1 for Y ¼ MeO in MeOH solvent. Attack at the methylene carbon does not lead to a stable addition product, but instead the carbanion eliminates nitrite to complete a vinylic substitution process, another example of a mechanism that incorporates a carbanion intermediate. This pathway becomes available because carbanion 14 has a good leaving group, NO2 , at the b-position and the overall process is exothermic (NO2 is a better leaving group than MeO ). This result again points to the similarities between these carbanion intermediates and those of an E1cB process. In a solvent such as methanol, one expects that the nitro stabilized anion, 13, would be more stable than the fluorenyl anion, 14, because in this type of solvent nitro-substituted carbons have pKa values near 10, whereas fluorenes typically are in the low 20’s. Given this large difference in carbanion stability, one might expect addition to give 13 would be preferred by a much larger factor, but as noted earlier (Section 4.3.4), delocalization of carbanion lone pairs into nitro substituents is not fully realized at the transition states

for their formation and therefore kinetically, nitro groups do not appear to be as stabilizing.140–144,164 In fact, there is a good correlation between the kinetics of

forming stabilized carbanions either via proton transfer (i.e., kinetic acidities) or by alkene additions.163 When Z ¼ NO2, addition occurs exclusively at the

REACTIVITY 103

9-position to give carbanion 13 because the two nitro groups lead to a carbanion that is much more stable than a fluorenyl anion.100 The substitution pathway that appears in Scheme 3.10 is particularly common in reactions of vinylic halides that bear good EWGs on the b-carbon. The reaction in Eq. 16 illustrates the importance of carbanion stability on the reaction rates of these processes.165

Z = Me or NO2; X = Cl or Br

Changing the leaving group from Cl to Br causes a rate increase of only about a factor of 2, whereas changing Z from Me to NO2, increases the rate by roughly a factor of 50. Clearly, stabilization of the carbanion is dominating in this system and leaving group ability only has a minor effect on the transition state for addition.

Alkene addition processes have also been characterized in the gas phase via MS and carbanion intermediates have been identified. For example, Bernasconi et al.166 showed that nucleophiles like acetone enolate readily add to alkenes with good EWGs such as a nitrile (i.e., acrylonitrile). One aspect of the gas-phase work is that localized nucleophiles commonly used in solution such as MeO are strong bases in the gas phase, so proton abstraction competes with addition. In the case of acrylonitrile, MeO gives 100% proton abstraction whereas acetone enolate gives 100% addition (Scheme 3.11). The absence of proton transfer with the enolate is understandable because it is an endothermic process in the gas phase. The preference for proton abstraction with MeO is a result of the process being significantly exothermic ( H ¼ 10 kcal/mol) and entropically much more favorable than the addition process. Deprotonated nitromethane illustrates a third variation in that after the addition process, a subsequent intramolecular substitution process occurs that leads to the formation of a cyclopropane derivative. A related process, the Favorskii rearrangement, is presented in Section 5.3.3.

C N

Scheme 3.11

5.2.2. Nucleophilic Aromatic Substitution. A natural extension of alkene addition processes is aromatic nucleophilic substitution. Again, the ease of the process is highly dependent on the stability of the intermediate carbanion and strong EWGs are needed to facilitate these reactions in solution. The classic example is the

104 CARBANIONS

reaction of a picryl (2,4,6-trinitrophenyl) ether with an alkoxide (Eq. 17). This reaction leads to a stable carbanion complex whose structure was initially confirmed by Meisenheimer, and they have come to be known as Meisenheimer complexes.167

The high stability of the carbanion intermediate in this case is not surprising because it is delocalized (pentadienyl) and bears three strong EWGs. The intermediate carbanion need not be stable and if it is not, a substitution process occurs.

In Eq. 18, this is illustrated for the gas-phase reaction of MeO with fluorobenzene.168

Localized anions such as methoxide are very strong bases in the gas phase, so the addition to give the pentadienyl carbanion intermediate is favorable under these circumstances. This outcome can be rationalized in the following way. The proton affinity of methoxide is 382 kcal/mol in the gas phase, whereas the proton affinity of the pentadienyl anion is only 369 kcal/mol. Of course, the carbanion intermediate will have an even lower proton affinity because it is stabilized by the presence of a pair of EWGs, the fluoro and methoxy groups. The conversion to a much weaker base as well as the formation of a new, strong C O bond can overcome the disadvantage of the loss of aromaticity in forming the Meisenheimer complex in this case. In solution, species like methoxide are much weaker bases, so EWGs are needed to make the Meisenheimer complex a viable intermediate. In the gas-phase reaction (Eq. 18), the overall process can be completed by an SN2 reaction between the departing fluoride and the anisole. Again, this can be understood in terms of proton affinities. In the product complex, fluoride with a proton affinity of 371 kcal/mol is a stronger base than phenoxide, whose proton affinity is 350 kcal/ mol, and therefore, an exothermic SN2 reaction is possible before the products separate. The mechanisms of nucleophilic aromatic substitution have been widely studied and the results point to a delicate balance with variations in the rate-determining step depending on the nature of the nucelophile, leaving

group, and solvent. Descriptions of these studies have appeared in various reviews.169–171

5.3. Carbanion Intermediates in Rearrangements

Carbanions also appear as intermediates in rearrangement processes. In some cases, this involves the rearrangement from one carbanion to another, but in other cases,

REACTIVITY 105

carbanions are involved in the conversion to a heteroatom-centered anion such as an alkoxide.

5.3.1. Wittig Rearrangement. There is a continuing controversy over the role of carbanion intermediates in this process. The reaction involves the formation of a carbanion at the a-carbon of an ether leading to a rearrangement that produces an alkoxide (Eq. 19).172

It is formally a 1,2 migration of the alkyl group, R2, from oxygen to carbon and in solution, generally requires a strong base such as an alkyllithium salt to form the initial carbanion. The issue is the nature of the intermediate, which could either be a carbanion– carbonyl or radical anion–radical complex pair (Eq. 19). The real question is whether the transferring alkyl group or the carbonyl has a higher effective electron affinity in the intermediate complex. Both carbonyl compounds and simple alkyl groups are known to have low electron affinities, so the question is not straightforward to answer. Often R1 is an aromatic group that helps to stabilize the initial carbanion and would also stabilize a potential carbonyl radical anion. On the other hand, the dipole of the carbonyl in the complex would electrostatically stabilize a carbanion intermediate and increase the apparent electron affinity of the transferring alkyl group. Data in solution are not conclusive, but suggest a radical anion mechanism. For example, the migratory aptitude of the alkyl groups (e.g., R2 ¼ benzyl > methyl, ethyl > phenyl) parallels radical stability more closely than the expected carbanion stability.173 In addition, Garst and Smith174 showed that when the migrating alkyl group was 5-hexenyl, it undergoes, to some extent, a cyclization process well known for the 5-hexenyl radical (Eq. 20). However, the reaction has also been shown to produce intermolecular products that are most consistent with a true carbonyl intermediate that escapes the complex with the transferring carbanion. For example, the reaction of dibenzyl ether with methyllithium produces varying yields of 1-phenylethanol, the condensation product of benzaldehyde and methyllithium (Eq. 21) suggesting that the aldehyde escaped from the benzyl anion in the initial complex and was trapped by excess methyllithium rather than the benzyl anion.175

106 CARBANIONS

Gas-phase Wittig rearrangements are also known and similar migratory propensities have been observed, but the data have been interpreted in terms of a carbanion intermediate mechanism.176 Computational modeling offers an explanation for the seemingly conflicting results on this mechanism.177 For a bare carbanion (i.e., gas phase), high-level calculations favor a heterolytic cleavage of the C O bond to give a carbonyl– carbanion pair. In contrast, complexation of a lithium cation to the system preferentially stabilizes the carbonyl radical anion via a strong O /Liþ electrostatic interaction and favors a pathway involving radical migration. When solvation is included in the computational model, the effect of the lithium is weakened and leads to a situation where competition between the mechanisms might occur.

With allylic alcohols, there is the possibility of a [2,3] variant of the Wittig rearrangement that can compete with the [1,2] rearrangement described above (Eq. 22, the indicated electron flow is for the [2,3] rearrangement).178 The reaction is expected to be a one-step, pericyclic process without a distinct carbanion intermediate. This rearrangement has proven to be useful synthetically because its concerted nature can lead to high stereoselectivity.179

5.3.2. 1,2 Phenyl Migrations. Phenyl migrations of carbanion intermediates are an intramolecular example of nucleophilic aromatic substitution. They often occur without the need of an activating group and are facilitated by an entropically favorable transition state because the nucleophile and phenyl ring are always in close proximity. A classic example is provided by Zimmerman and Zweig180 who found that 2,2-diphenyl-1-propyllithium derivatives rearrange to give more stable 1,2-diphenyl-2-propyllithiums (Eq. 23).

The spirocyclic species, 15, on the reaction path could either be an intermediate or a transition state, but low-temperature NMR studies have identified a closely related species as a stable compound and proven its structure via reaction chemistry.181 However, there is evidence that this type of reaction could also proceed via a dissociative mechanism where a carbanion is eliminated to form an alkene inter-

108 CARBANIONS

of the ring and the production of a localized carbanion that is trapped by solvent. The driving force for forming the highly basic carbanion is undoubtedly the release of ring strain. In acyclic ketones, the process results in the formation of an ester with the transfer of one of the ketone’s alkyl groups to the a position of the opposing alkyl group. In cyclic ketones, a ring contraction occurs (e.g., see Eq. 24). Support for the mechanism in Scheme 3.13 comes from the fact that when the

cyclopropanone intermediate, 16, is prepared independently and treated with MeO , a similar mixture of esters results.185,186 As is the case in many of these

carbanion systems, other pathways are possible and the mechanism can shift to alternative routes with variations in the substituent patterns. For example, Bordwell and Carlson187 showed that in some cases, the addition of methyl substituents on the halogen-bearing carbon can alter the rate-determining step and lead to substitution rather than rearrangement products (i.e., the halogen undergoes a solvolysis reaction). In addition, computational work suggests that in the reaction of 2-chlor- ocyclobutanone with hydroxide, the Favorskii rearrangement involves direct addition of the nucleophile at the carbonyl followed by ring-opening–ring-closing to give the expected ring contraction product (Eq. 24).188 Apparently the high strain of a bicyclobutanone inhibits the conventional pathway (i.e., analogous to that in Scheme 3.13), so addition at the carbonyl becomes the more favorable process.

ð24Þ

5.4. Carbanion Reactions in the Gas Phase

As noted in Section 4.2.1, the gas phase has proven to be a useful medium for probing the physical properties of carbanions, specifically, their basicity. In addition, the gas phase allows chemists to study organic reaction mechanisms in the absence of solvation and ion-pairing effects. This environment provides valuable data on the intrinsic, or baseline, reactivity of these systems and gives useful clues as to the roles that solvent and counterions play in the mechanisms. Although a variety of carbanion reactions have been explored in the gas phase,189 two will be considered here (1) SN2 substitutions and (2) nucleophilic acyl substitutions. Both of these reactions highlight some of the characteristic features of gas-phase carbanion chemistry.

5.4.1. SN 2 Reactions. Given its central role in the development of modern physical organic chemistry, it is no surprise that the SN2 substitution reaction is the most widely studied of all gas-phase anionic processes. In a classic study, Olmstead and Brauman190 used an ion cyclotron resonance (ICR) spectrometer to obtain

Energy

Reaction Coordinate

Figure 3.5. Diagram of a double-well potential energy surface for an SN2 reaction.190

data on gas-phase SN2 reactions and suggested that these reactions involve a double-well potential energy surface (Fig. 3.5). The reactions, although exothermic, do not occur at the collision controlled rate so a barrier must exist on the surface. On the other hand, there is always a long-range attractive potential between an ion and a neutral molecule (i.e., either ion–dipole or ion–induced-dipole), so the initial part of the surface must be attractive. The simplest way to account for both of these effects is a double-well potential where the initial attraction leads to a minimum on the surface for a loosely bound ion–molecule complex. From the complex, the energy rises as the system passes through the SN2 transition state and finally drops as an ion–molecule complex is formed between the products. Given the low pressures generally employed in mass spectrometers, no collisions occur during the reaction process so the system retains all its energy (i.e., it is still at the energy level of the separated reactants) and the final complex possesses enough energy to dissociate to give the separated products. This type of surface is not unique to SN2 reactions and is observed in many ionic gas-phase reactions.

In Table 3.8, rate constants are given for the reactions of several carbanions with methyl chloride. Most of the data was obtained in a flowing-after glow instrument.

TABLE 3.8. Rate Constants for Reactions with

Methyl Chloridea

110 CARBANIONS

In this method, the reactant ions are entrained in a fast flow of helium containing a small amount of a reagent gas. Reactions occur in the flowing helium on a time scale of 10 ms and the products are detected at the end of the flow tube by a mass analyzer, usually a quadrupole. The data indicate that the SN2 reactivity of a carbanion is closely related to its basicity, but not perfectly. Specifically, the benzyl anion is more basic than acetylide, but reacts nearly 10 times slower. Benzyl also has a lower rate constant than CF3 , another less basic carbanion. However, a low SN2 rate constant for the benzyl anion is not unexpected. This carbanion derives much of its stability from its ability to delocalize charge into the benzene ring. It is logical that with reduced charge density at the benzylic carbon, the carbanion is less nucleophilic than a highly localized carbanion such as acetylide. Similar effects were noted in Section 4.3.4 when Brønsted correlations were discussed with respect to proton-transfer rates involving delocalized carbanions.

When a ketone or aldehyde enolate is allowed to react with an alkyl halide, there are two possible modes of attack because the anion can act as a carbon or oxygen nucleophile. Determining the site of alkylation has proven to be a challenging task in gas-phase studies because mass spectrometers are only able to identify charged products, but the characteristic ones in this case are neutral. The most direct evidence comes from a very difficult experiment involving the collection of the neutral products in a flowing afterglow mass spectrometer. In this way, Ellison and co-workers114 showed that for the reaction of cyclohexanone enolate with MeBr, the sole product is the result of oxygen alkylation (Scheme 3.14). Of course, alkylation at carbon would be more exothermic, but the greater charge density on the

oxygen makes it the more nucleophilic site. This type of behavior has also been seen in condensed-phase reactions of enolates.113,115

Scheme 3.14

5.4.2. Nucleophilic Acyl Substitution. Studies of nucleophilic acyl substitution have also been completed in the gas phase. As in the condensed phase, esters offer a range of reactivity with strong bases. Two modes of attack are common:

(1) the nucleophile can attack the carbonyl carbon in a nucleophilic acyl substitution process or (2) it can act as a base and deprotonate the ester at the a-carbon. In addition, the nucleophile can attack the alkyl group of the ester in either an SN2 substitution or E2 elimination process. An interesting comparison can be made between the reactivity of CF3 and N CCH2 in their reactions with methyl acetate. The latter ion undergoes a Claissen-type reaction with the ester to produce a stabilized enolate (Scheme 3.15).191 After the nucleophilic acyl substitution process is complete, the methoxide is left in an ion–molecule complex with cyanoacetone, and a proton transfer occurs before the complex separates giving the enolate. The tetrahedral addition species is shown as an intermediate in this case (i.e., it is a