Recap
Part 2 of this article discussed two different types of mechanisms. The first of these mechanisms is the neighboring-group mechanism, which may be seen as an extension of the typical nucleophilic substitution reactions because there is still nucleophilic attack, but there is enhancement of the nucleophilic attack because of the higher electrophilicity of the substrate. The neighboring-group mechanism occurs because of the presence of a special substituent, the neighboring group, on the molecule, which is able to attack the electrophilic portion of the molecule faster than that of the nucleophile, leading to an overall different mechanism; as such, mechanisms which are generally expected to be SN1 or SN2 do not display the characteristics that are expected of such reactions. For example, a reaction that is supposedly SN2 does not give Walden inversion, suggesting that a different mechanism takes place instead. There are many notable types of neighboring groups, but perhaps the most interesting case is when alkenes or pi bonds act as neighboring groups (Fig. 1), which results in the formation of nonclassical intermediates. Furthermore, it seems also to be possible for sigma bonds to act as neighboring groups as well, although this is debatable.
Fig. 1: Neighboring-group mechanism with alkenes.
In the previous article, we also discussed another mechanism, the SET (single-electron transfer) mechanism, which, as we noted, is comparable to the free radical substitution mechanism. The mechanism may be identified the same way as the neighboring-group mechanism, in that characteristics typical of SN1 or SN2 reactions are not observed in a reaction, and thus this leads us to the conclusion that a different mechanism applies. Uniquely, since free radicals are involved, there is no inversion and it is typical to yield a racemic mixture (equimolar amounts of enantiomers). However, it is also that inversion may sometimes occur as well. The isolation of intermediates of the SET mechanism has been performed and provides very convincing evidence for the existence of this mechanism. In the SET mechanism, there is first a transfer of a single electron, forming two radicals, one of which is a radical anion. In the second step, there is dissociation of the radical anion, and in the last step, rather synonymous with a termination step in a free radical substitution, the nucleophile and substrate radicals combine to form the stable substitution product. Something similar to the SET mechanism is seen in the Sandmeyer reaction, which has its mechanism outlined in Fig. 2.
Fig. 2: Mechanism of the Sandmeyer reaction.
Intimate Ion Pairs
These are technically not considered separation reactions, because the overall mechanism is still generally the same, however there are a few ‘steps’ in between each of the reactions such that the mechanism may seem different; this is not true. Nevertheless, we will still discuss the intimate ion pair concept. It suggests that there are a few sub-steps involved in the dissociation of a substrate molecule. Firstly, the substrate molecule, facilitated by the solvent, dissociates into an ion pair; this ion pair is known as an intimate ion pair, since the ions still remain close to each other even without a covalent bond. In the next step, the intimate ion pair becomes a loose, solvent-separated ion pair, and in the last step, the dissociated ions form. Where the intimate ion pair recombines is known as internal return. Because the leaving group’s anion is present on one side of the substrate, only the other side can be solvated by solvent molecules, leading to an inversion of configuration.By this concept, SN1 reactions can display either complete racemization or partial inversion. The concept of the intimate ion pair is demonstrated in Fig. 3.
Fig. 3: Intimate ion pair concept.
There is also a relatively large amount of notable evidence of the intimate ion pair concept and the existence of an intimate ion pair. For example, an alkyl brosylate (Fig. 4) was labeled with the 18O isotope of oxygen on one of its sulfone oxygens. After the unreacted brosylate was recovered, it was found that the 18O isotope was detected on all three positions of the sulfone, even though it had only been labeled in one position. This is explained by the intimate ion pair concept. When the intimate ion pair forms, the R+ group remains close to the sulfonate with one of the negatively-charged oxygens; at this point, resonance can occur to bring the negative charge to any of the oxygens. When the internal return occurs, the R group will then form a bond with any of these negatively-charged oxygens, leading to the location of the 18O group being scrambled. Although this seems to provide convincing evidence for the presence of the intimate ion pair, different experiments have been carried out with other compounds that seem to suggest otherwise. Thus, there is no complete proof for the intimate ion pair; yet, it is a useful explanation for the observed inversion and retention of configuration.
Fig. 4: Structure of the brosylate group in blue.
Tetrahedral Mechanisms
The tetrahedral mechanism for nucleophilic substitution is usually synonymous with addition-elimination mechanisms, as it is difficult to distinguish between the two. The tetrahedral mechanism is only generally applied for vinylic carbon. It is difficult to distinguish between the tetrahedral and the addition-elimination mechanism, as both of them involve the same transformations on the first step. Evidence can be discussed for both mechanisms as a whole. Where the reaction follows the tetrahedral or addition-elimination mechanism, the reaction rate increases in the order Br < Cl < F, and this is often attributed to the element effect. For typical SN1 or SN2 reactions, the order would be reversed, since F is the poorest leaving group. However, for the tetrahedral or addition-elimination mechanism, the carbon-halogen bond does not break in the rate-determining step, but at the same time fluorine has the greatest electronegativity, and therefore the carbon it is attached to will be more electrophilic and susceptible to nucleophilic attack, giving the reaction a faster rate.
While many vinylic substrates do not react or react poorly by the tetrahedral or addition-elimination mechanism, there are some types of substrates that greatly enhance the rates of reactions that follow such mechanisms. These substrates typically have an electron-withdrawing group on the β-carbon; when the nucleophile attacks on one of the carbons, the multiple bond would break, making the other carbon a carbanion. The electron-withdrawing group can help to stabilize the negative charge, making the nucleophilic attack more energetically favorable.
In general, it is difficult for vinylic substrates to undergo SN1 reactions. There are a few ways for vinylic substrates to be ‘forced’ to undergo nucleophilic substitution via an SN1 pathway, however. Where stabilizing groups such as cyclopropyl, another double bond and aryls are present on the α-carbon relative to the double bond, there is a possibility of resonance to delocalize the charge formed and thus make the nucleophilic attack more energetically favorable. Another case where the vinylic substrate is particularly susceptible to nucleophilic substitution can occur with excellent leaving groups such as triflate (OSO2CF3), where the energetic favorability of the nucleophilic attack would then come from the favorable departure of the leaving group. This can happen even without stabilization by the former case.
Regardless of the type of vinylic substrate, it has been observed that the stereochemistry of the products is often random; for instance, there is always an equimolar ratio of cis to trans products. One explanation for this is that the vinylic cation is linear, as this would be the only case in which both sides of the carbon are open to nucleophilic attack, and thus equimolar amounts of cis to trans products would be produced. However, it has also been found that the entry of the nucleophile can be affected by the R groups on the sp2 hybridized carbon adjacent to the carbocation. Steric hindrance can hamper the rate of the reaction and even lead to a different mechanism being preferred instead.
Part 2 of this article is here.
Part 4 of this article will be released here on 20 Nov.