TheE1cB elimination reaction is a type ofelimination reaction which occurs under basic conditions, where the hydrogen to be removed is relatively acidic, while theleaving group (such as -OH or -OR) is a relatively poor one. Usually a moderate to strong base is present. E1cB is a two-step process, the first step of which may or may not be reversible. First, abase abstracts the relatively acidic proton to generate a stabilizedanion. The lone pair of electrons on the anion then moves to the neighboring atom, thus expelling the leaving group and forming adouble ortriple bond.[1] The name of the mechanism -E1cB - stands forEliminationUnimolecularconjugateBase.Elimination refers to the fact that the mechanism is anelimination reaction and will lose two substituents.Unimolecular refers to the fact that the rate-determining step of this reaction only involves onemolecular entity. Finally,conjugate base refers to the formation of the carbanionintermediate, which is the conjugate base of the starting material.
E1cB should be thought of as being on one end of a continuous spectrum, which includes the E1 mechanism at the opposite end and the E2 mechanism in the middle. The E1 mechanism usually has the opposite characteristics: the leaving group is a good one (like -OTs or -Br), while the hydrogen is not particularly acidic and a strong base is absent. Thus, in the E1 mechanism, the leaving group leaves first to generate a carbocation. Due to the presence of an empty p orbital after departure of the leaving group, the hydrogen on the neighboring carbon becomes much more acidic, allowing it to then be removed by the weak base in the second step. In an E2 reaction, the presence of a strong base and a good leaving group allows proton abstraction by the base and the departure of the leaving group to occur simultaneously, leading to a concertedtransition state in a one-step process.
There are two main requirements to have a reaction proceed down an E1cB mechanistic pathway. The compound must have anacidic hydrogen on itsβ-carbon and a relatively poorleaving group on theα- carbon. The first step of an E1cB mechanism is the deprotonation of the β-carbon, resulting in the formation of ananionic intermediate, such as a carbanion. The greater the stability of this intermediate, the more the mechanism will favor an E1cB mechanism. This intermediate can be stabilized throughinduction ordelocalization of theelectronlone pair throughresonance. In general it can be claimed that an electron withdrawing group on the substrate, a strong base, a poor leaving group and a polar solvent triggers the E1cB mechanism. An example of an E1cB mechanism that has a stable intermediate can be seen in the degradation ofethiofencarb - acarbamateinsecticide that has a relatively shorthalf-life in Earth's atmosphere. Upon deprotonation of theamine, the resultingamide is relatively stable because it isconjugated with the neighboringcarbonyl. In addition to containing an acidic hydrogen on the β-carbon, a relatively poor leaving group is also necessary. A badleaving group is necessary because a good leaving group will leave before theionization of the molecule. As a result, the compound will likely proceed through anE2 pathway. Some examples of compounds that contain poor leaving groups and can undergo the E1cB mechanism arealcohols andfluoroalkanes.It has also been suggested that the E1cB mechanism is more common amongalkenes eliminating toalkynes than from analkane to alkene.[2] One possible explanation for this is that thesp2 hybridization creates slightly more acidic protons. Although this mechanism is not limited tocarbon-based eliminations. It has been observed with otherheteroatoms, such asnitrogen in the elimination of aphenol derivative fromethiofencarb.[3]
All elimination reactions involve the removal of twosubstituents from a pair of atoms in a compound. Alkene, alkynes, or similar heteroatom variations (such ascarbonyl andcyano) will form. The E1cB mechanism is just one of three types of elimination reaction. The other two elimination reactions are E1 and E2 reactions. Although the mechanisms are similar, they vary in the timing of the deprotonation of the α-carbon and the loss of the leaving group. E1 stands for unimolecular elimination, and E2 stands for bimolecular elimination. In an E1 mechanism, the molecule contains a good leaving group that departs before deprotonation of the α-carbon. This results in the formation of a carbocation intermediate. The carbocation is then deprotonated resulting in the formation of a new pi bond. The molecule involved must also have a very good leaving group such as bromine or chlorine, and it should have a relatively less acidic α-carbon.
In an E2-elimination reaction, both the deprotonation of the α-carbon and the loss of the leaving group occur simultaneously in oneconcerted step. Molecules that undergo E2-elimination mechanisms have more acidic α-carbons than those that undergo E1 mechanisms, but their α-carbons are not as acidic as those of molecules that undergo E1cB mechanisms. The key difference between theE2 vs E1cb pathways is a distinctcarbanionintermediate as opposed to one concerted mechanism. Studies have been shown that the pathways differ by using differenthalogenleaving groups. One example useschlorine as a better stabilizinghalogen for theanion thanfluorine,[4] which makesfluorine theleaving group even though chlorine is a much better leaving group.[5] This provides evidence that the carbanion is formed because the products are not possible through the most stable concertedE2 mechanism. The following table summarizes the key differences between the three elimination reactions; however, the best way to identify which mechanism is playing a key role in a particular reaction involves the application ofchemical kinetics.
| E1 | E2 | E1cB |
|---|---|---|
| Stepwise reaction | Concerted reaction | Stepwise reaction |
| Carbocation intermediate | Simultaneous removal of proton, formation of double bond, and loss of leaving group | Carbanion intermediate |
| Strongly acidic media | No preference | Strongly basic media |
| Good leaving groups | Leaving group | Poor leaving groups |
| Less acidic B-H | Acidic B-H | More acidic B-H |
When trying to determine whether or not a reaction follows the E1cB mechanism,chemical kinetics are essential. The best way to identify the E1cB mechanism involves the use ofrate laws and thekinetic isotope effect. These techniques can also help further differentiate between E1cB, E1, and E2-elimination reactions.
When trying to experimentally determine whether or not a reaction follows the E1cB mechanism,chemical kinetics are essential. The best ways to identify the E1cB mechanism involves the use of rate laws and the kinetic isotope effect.
The rate law that governs E1cB mechanisms is relatively simple to determine. Consider the following reaction scheme.
Assuming that there is a steady-state carbanion concentration in the mechanism, the rate law for an E1cB mechanism.
From this equation, it is clear the secondorder kinetics will be exhibited.[6]E1cB mechanisms kinetics can vary slightly based on the rate of each step. As a result, the E1cB mechanism can be broken down into three categories:[7]
Deuterium exchange and a deuteriumkinetic isotope effect can help distinguish amongE1cBrev,E1cBanion, andE1cBirr. If the solvent is protic and containsdeuterium in place of hydrogen (e.g., CH3OD), then the exchange of protons into the starting material can be monitored. If the recovered starting material contains deuterium, then the reaction is most likely undergoing anE1cBrev type mechanism. Recall, in this mechanism protonation of the carbanion (either by the conjugate acid or by solvent) is faster than loss of the leaving group. This means after the carbanion is formed, it will quickly remove a proton from the solvent to form the starting material.
If the reactant contains deuterium at the β position, a primary kinetic isotope effect indicates that deprotonation is rate determining. Of the three E1cB mechanisms, this result is only consistent with theE1cBirr mechanism, since the isotope is already removed inE1cBanion and leaving group departure is rate determining inE1cBrev.
Another way that the kinetic isotope effect can help distinguish E1cB mechanisms involves the use of19F.Fluorine is a relatively poor leaving group, and it is often employed in E1cB mechanisms. Fluorine kinetic isotope effects are also applied in the labeling ofRadiopharmaceuticals and other compounds in medical research. This experiment is very useful in determining whether or not the loss of the leaving group is the rate-determining step in the mechanism and can help distinguish betweenE1cBirr and E2 mechanisms.11C can also be used to probe the nature of the transition state structure. The use of11C can be used to study the formation of the carbanion as well as study its lifetime which can not only show that the reaction is a two-step E1cB mechanism (as opposed to the concerted E2 mechanism), but it can also address the lifetime and stability of the transition state structure which can further distinguish between the three different types of E1cB mechanisms.[8]
The most well known reaction that undergoes E1cB elimination is thealdol condensation reaction under basic conditions. This involves thedeprotonation of a compound containing acarbonyl group that results in the formation of anenolate. The enolate is the very stableconjugate base of the starting material, and is one of the intermediates in the reaction. This enolate then acts as a nucleophile and can attack an electrophilic aldehyde. The Aldol product is then deprotonated forming another enolate followed by the elimination of water in an E1cBdehydration reaction. Aldol reactions are a key reaction in organic chemistry because they provide a means of forming carbon-carbon bonds, allowing for the synthesis of more complex molecules.[9]
A photochemical version of E1cB has been reported by Lukemanet al.[10] In this report, a photochemically induced decarboxylation reaction generates a carbanion intermediate, which subsequently eliminates the leaving group. The reaction is unique from other forms of E1cB since it does not require a base to generate the carbanion. The carbanion formation step is irreversible, and should thus be classified asE1cBirr.
The E1cB-elimination reaction is an important reaction in biology. For example, the penultimate step ofglycolysis involves an E1cB mechanism. This step involves the conversion of2-phosphoglycerate tophosphoenolpyruvate, facilitated by the enzymeenolase.
