The functional group of alkyl halides is a carbon-halogen bond, the common halogens being fluorine, chlorine, bromine and iodine. With the exception of iodine, these halogens have electronegativities significantly greater than carbon. Consequently, this functional group is polarized so that the carbon is electrophilic and the halogen is nucleophilic, as shown in the drawing on the right. Two characteristics other than electronegativity also have an important influence on the chemical behavior of these compounds. The first of these is covalent bond strength. The strongest of the carbon-halogen covalent bonds is that to fluorine. Remarkably, this is the strongest common single bond to carbon, being roughly 30 kcal/mole stronger than a carbon-carbon bond and about 15 kcal/mole stronger than a carbon-hydrogen bond. Because of this, alkyl fluorides and fluorocarbons in general are chemically and thermodynamically quite stable, and do not share any of the reactivity patterns shown by the other alkyl halides. The carbon-chlorine covalent bond is slightly weaker than a carbon-carbon bond, and the bonds to the other halogens are weaker still, the bond to iodine being about 33% weaker. The second factor to be considered is the relative stability of the corresponding halide anions, which is likely the form in which these electronegative atoms will be replaced. This stability may be estimated from the relative acidities of the H-X acids, assuming that the strongest acid releases the most stable conjugate base (halide anion). With the exception of HF (pKa = 3.2), all the hydrohalic acids are very strong, small differences being in the direction HCl < HBr < HI.
The characteristics noted above lead us to anticipate certain types of reactions that are likely to occur with alkyl halides. In describing these, it is useful to designate the halogen-bearing carbon as alpha and the carbon atom(s) adjacent to it as beta, as noted in the first four equations shown below. Replacement or substitution of the halogen on the α-carbon (colored maroon) by a nucleophilic reagent is a commonly observed reaction, as shown in equations 1, 2, 5, 6 & 7 below. Also, since the electrophilic character introduced by the halogen extends to the β-carbons, and since nucleophiles are also bases, the possibility of base induced H-X elimination must also be considered, as illustrated by equation 3. Finally, there are some combinations of alkyl halides and nucleophiles that fail to show any reaction over a 24 hour period, such as the example in equation 4. For consistency, alkyl bromides have been used in these examples. Similar reactions occur when alkyl chlorides or iodides are used, but the speed of the reactions and the exact distribution of products will change. It should be emphasized that in all the following examples the carbon bonded to the halogen is sp3 hybridized, as expected for an alkyl halide. Alkenyl and aryl halides (sp2 hybridization) do not normally react in similar ways.
In order to understand why some combinations of alkyl halides and nucleophiles give a substitution reaction, whereas other combinations give elimination, and still others give no observable reaction, we must investigate systematically the way in which changes in reaction variables perturb the course of the reaction. The following general equation summarizes the factors that will be important in such an investigation.
One conclusion, relating the structure of the R-group to possible products, should be immediately obvious. If R- has no beta-hydrogens an elimination reaction is not possible, unless a structural rearrangement occurs first. The first four halides shown on the left below do not give elimination reactions on treatment with base, because they have no β-hydrogens. The two halides on the right do not normally undergo such reactions because the potential elimination products have highly strained double or triple bonds. It is also worth noting that sp2 hybridized C–X compounds, such as the three on the right, do not normally undergo nucleophilic substitution reactions, unless other functional groups perturb the double bond(s).
Using the general reaction shown above as our reference, we can identify the following variables and observables.
R change α-carbon from 1º to 2º to 3º if the α-carbon is a chiral center, set as (R) or (S) X change from Cl to Br to I (F is relatively unreactive) Nu: change from anion to neutral; change basicity; change polarizability Solvent polar vs. non-polar; protic vs. non-protic
Products substitution, elimination, no reaction. Stereospecificity if the α-carbon is a chiral center what happens to its configuration? Reaction Rate measure as a function of reactant concentration.
When several reaction variables may be changed, it is important to isolate the effects of each during the course of study. In other words: only one variable should be changed at a time, the others being held as constant as possible. For example, we can examine the effect of changing the halogen substituent from Cl to Br to I, using ethyl as a common R–group, cyanide anion as a common nucleophile, and ethanol as a common solvent. We would find a common substitution product, C2H5–CN, in all cases, but the speed or rate of the reaction would increase in the order: Cl < Br < I. This reactivity order reflects both the strength of the C–X bond, and the stability of X(–) as a leaving group, and leads to the general conclusion that alkyl iodides are the most reactive members of this functional class.
1. Nucleophilicity Recall the definitions of electrophile and nucleophile:
Electrophile: An electron deficient atom, ion or molecule that has an affinity for an electron pair, and will bond to a base or nucleophile. Nucleophile: An atom, ion or molecule that has an electron pair that may be donated in forming a covalent bond to an electrophile (or Lewis acid).
If we use a common alkyl halide, such as methyl bromide, and a common solvent, ethanol, we can examine the rate at which various nucleophiles substitute the methyl carbon. Nucleophilicity is thereby related to the relative rate of substitution reactions at the halogen-bearing carbon atom of the reference alkyl halide. The most reactive nucleophiles are said to be more nucleophilic than less reactive members of the group. The nucleophilicities of some common Nu:(–) reactants vary as shown in the following chart.
The reactivity range encompassed by these reagents is over 5,000 fold, thiolate being the most reactive. Note that by using methyl bromide as the reference substrate, the complication of competing elimination reactions is avoided. The nucleophiles used in this study were all anions, but this is not a necessary requirement for these substitution reactions. Indeed reactions 6 & 7, presented at the beginning of this section, are examples of neutral nucleophiles participating in substitution reactions. The cumulative results of studies of this kind has led to useful empirical rules pertaining to nucleophilicity:
(i) For a given element, negatively charged species are more nucleophilic (and basic) than are equivalent neutral species. (ii) For a given period of the periodic table, nucleophilicity (and basicity) decreases on moving from left to right. (iii) For a given group of the periodic table, nucleophilicity increases from top to bottom (i.e. with increasing size), although there is a solvent dependence due to hydrogen bonding. Basicity varies in the opposite manner.
2. Solvent Effects Solvation of nucleophilic anions markedly influences their reactivity. The nucleophilicities cited above were obtained from reactions in methanol solution. Polar, protic solvents such as water and alcohols solvate anions by hydrogen bonding interactions, as shown in the diagram on the right. These solvated species are more stable and less reactive than the unsolvated "naked" anions. Polar, aprotic solvents such as DMSO (dimethyl sulfoxide), DMF (dimethylformamide) and acetonitrile do not solvate anions nearly as well as methanol, but provide good solvation of the accompanying cations. Consequently, most of the nucleophiles discussed here react more rapidly in solutions prepared from these solvents. These solvent effects are more pronounced for small basic anions than for large weakly basic anions. Thus, for reaction in DMSO solution we observe the following reactivity order:
Note that this order is roughly the order of increasing basicity. For additional information about solvents and solvation effects Click Here.
3. The Alkyl Moiety Some of the most important information concerning nucleophilic substitution and elimination reactions of alkyl halides has come from studies in which the structure of the alkyl group has been varied. As noted earlier, the carbon bonded to the halogen is sp3 hybridized in all the alkyl halides discussed here. If we examine a series of alkyl bromide substitution reactions with the strong nucleophile thiocyanide (SCN–) in ethanol solvent, we find large decreases in the rates of reaction as alkyl substitution of the alpha-carbon increases. Methyl bromide reacts 20 to 30 times faster than simple 1º-alkyl bromides, which in turn react about 20 times faster than simple 2º-alkyl bromides, and 3º-alkyl bromides are essentially unreactive or undergo elimination reactions. Furthermore, β-alkyl substitution also decreases the rate of substitution, as witnessed by the failure of neopentyl bromide, (CH3)3CCH2-Br (a 1º-bromide), to react. Alkyl halides in which the alpha-carbon is a chiral center provide additional information about these nucleophilic substitution reactions. Returning to the examples presented at the beginning of this section, we find that reactions 2, 5 & 6 demonstrate an inversion of configuration when the cyanide nucleophile replaces the bromine. Other investigations have shown this to be generally true for reactions carried out in non-polar organic solvents, the reaction of (S)-2-iodobutane with sodium azide in ethanol being just one example ( in the following equation the alpha-carbon is maroon and the azide nucleophile is blue). Inversion of configuration during nucleophilic substitution has also been confirmed for chiral 1º-halides of the type RCDH-X, where the chirality is due to isotopic substitution.
We can now piece together a plausible picture of how nucleophilic substitution reactions of 1º and 2º-alkyl halides take place. The nucleophile must approach the electrophilic alpha-carbon atom from the side opposite the halogen. As a covalent bond begins to form between the nucleophile and the carbon, the carbon halogen bond weakens and stretches, the halogen atom eventually leaving as an anion. The diagram on the right shows this process for an anionic nucleophile. We call this pathway the SN2 mechanism, where S stands for Substitution, N stands for Nucleophilic and 2 stands for bimolecular (defined below). In the SN2 transition state the alpha-carbon is hybridized sp2 with the partial bonds to the nucleophile and the halogen having largely p-character. Both the nucleophile and the halogen bear a partial negative charge, the full charge being transferred to the halogen in the products. The consequence of rear-side bonding by the nucleophile is an inversion of configuration about the alpha-carbon. Neutral nucleophiles react by a similar mechanism, but the charge distribution in the transition state is very different. This mechanistic model explains many aspects of the reaction. First, it accounts for the fact that different nucleophilic reagents react at very different rates, even with the same alkyl halide. Since the transition state has a partial bond from the alpha-carbon to the nucleophile, variations in these bond strengths will clearly affect the activation energy, ΔE‡, of the reaction and therefore its rate. Second, the rear-side approach of the nucleophile to the alpha-carbon will be subject to hindrance by neighboring alkyl substituents, both on the alpha and the beta-carbons. For a model illustrating this "steric hindrance" effect Click Here. To see an animated model of the SN2 reaction Click Here
4. Molecularity If a chemical reaction proceeds by more than one step or stage, its overall velocity or rate is limited by the slowest step, the rate-determining step. This "bottleneck concept" has analogies in everyday life. For example, if a crowd is leaving a theater through a single exit door, the time it takes to empty the building is a function of the number of people who can move through the door per second. Once a group gathers at the door, the speed at which other people leave their seats and move along the aisles has no influence on the overall exit rate. When we describe the mechanism of a chemical reaction, it is important to identify the rate-determining step and to determine its "molecularity". The molecularity of a reaction is defined as the number of molecules or ions that participate in the rate determinining step. A mechanism in which two reacting species combine in the transition state of the rate-determining step is called bimolecular. If a single species makes up the transition state, the reaction would be called unimolecular. The relatively improbable case of three independent species coming together in the transition state would be called termolecular.
5. Kinetics One way of investigating the molecularity of a given reaction is to measure changes in the rate at which products are formed or reactants are lost, as reactant concentrations are varied in a systematic fashion. This sort of study is called kinetics, and the goal is to write an equation that correlates the observed results. Such an equation is termed a kinetic expression, and for a reaction of the type: A + B –––> C + D it takes the form: Reaction Rate = k[A] n[B] m, where the rate constant k is a proportionality constant that reflects the nature of the reaction, [A] is the concentration of reactant A, [B] is the concentration of reactant B, and n & m are exponential numbers used to fit the rate equation to the experimental data. Chemists refer to the sum n + m as the kinetic order of a reaction. In a simple bimolecular reaction n & m would both be 1, and the reaction would be termed second order, supporting a mechanism in which a molecule of reactant A and one of B are incorporated in the transition state of the rate-determining step. A bimolecular reaction in which two molecules of reactant A (and no B) are present in the transition state would be expected to give a kinetic equation in which n=2 and m=0 (also second order). The kinetic expressions found for the reactions shown at the beginning of this section are written in blue in the following equations. Each different reaction has its own distinct rate constant, k#. All the reactions save 7 display second order kinetics, reaction 7 is first order.
It should be recognized and remembered that the molecularity of a reaction is a theoretical term referring to a specific mechanism. On the other hand, the kinetic order of a reaction is an experimentally derived number. In ideal situations these two should be the same, and in most of the above reactions this is so. Reaction 7 above is clearly different from the other cases reported here. It not only shows first order kinetics (only the alkyl halide concentration influences the rate), but the chiral 3º-alkyl bromide reactant undergoes substitution by the modest nucleophile water with extensive racemization. Note that the acetonitrile cosolvent does not function as a nucleophile. It serves only to provide a homogeneous solution, since the alkyl halide is relatively insoluble in pure water. One of the challenges faced by early workers in this field was to explain these and other differences in a rational manner.
1. The SN2 Mechanism As noted in the previous section, a majority of the reactions thus far described appear to proceed by a common single-step mechanism, the SN2 mechanism (where S stands for Substitution, N stands for Nucleophilic and 2 stands for bimolecular). Other features of the SN2 mechanism are inversion at the alpha-carbon, increased reactivity with increasing nucleophilicity of the nucleophilic reagent and steric hindrance to rear-side bonding, especially in tertiary and neopentyl halides. Although reaction 3 above exhibits second order kinetics, it is an elimination reaction and must therefore proceed by a very different mechanism, which will be described later. Furthermore, the SN2 mechanism applies only to alkyl halides, i.e. compounds in which the carbon bonded to the halogen is sp3 hybridized. Alkenyl and aryl halides (sp2 hybridization) often are unreactive, and follow different mechanisms when pushed. On the other hand, allylic and benzylic halides exhibit enhanced SN2 reactivity thanks to conjugation of the newly formed and breaking bonds with the adjacent π-electron system. This is shown below for the benzyl halide case.
The stereoselectivity of SN2 reactions is in large part due to a stereoelectronic effect. To learn more about this important factor Click Here.
2. The SN1 Mechanism Reaction 7, shown at the bottom of the previous table, is clearly different from the other cases we have examined. It not only shows first order kinetics, but the chiral 3º-alkyl bromide reactant undergoes substitution by the modest nucleophile water with extensive racemization. In all of these features this reaction fails to meet the characteristics of the SN2 mechanism. A similar example is found in the hydrolysis of tert-butyl chloride, shown below. Note that the initial substitution product in this reaction is actually a hydronium ion, which rapidly transfers a proton to the chloride anion. This second acid-base proton transfer is often omitted in writing the overall equation, as in the case of reaction 7 above.
Although the hydrolysis of tert-butyl chloride, as shown above, might be interpreted as an SN2 reaction in which the high and constant concentration of solvent water does not show up in the rate equation, there is good evidence this is not the case. First, the equivalent hydrolysis of ethyl bromide is over a thousand times slower, whereas authentic SN2 reactions clearly show a large rate increase for 1º-alkyl halides. Second, a modest increase of hydroxide anion concentration has no effect on the rate of hydrolysis of tert-butyl chloride, despite the much greater nucleophilicity of hydroxide anion compared with water. The first order kinetics of these reactions suggests a two-step mechanism in which the rate-determining step consists of the ionization of the alkyl halide, as shown in the diagram on the right. In this mechanism, a carbocation is formed as a high-energy intermediate, and this species bonds immediately to nearby nucleophiles. If the nucleophile is a neutral molecule, the initial product is an "onium" cation, as drawn above for t-butyl chloride, and presumed in the energy diagram. In evaluating this mechanism, we may infer several outcomes from its function. First, the only reactant that is undergoing change in the first (rate-determining) step is the alkyl halide, so we expect such reactions would be unimolecular and follow a first-order rate equation. Hence the name SN1 is applied to this mechanism. Second, since nucleophiles only participate in the fast second step, their relative molar concentrations rather than their nucleophilicities should be the primary product-determining factor. If a nucleophilic solvent such as water is used, its high concentration will assure that alcohols are the major product. Recombination of the halide anion with the carbocation intermediate simply reforms the starting compound. Note that SN1 reactions in which the nucleophile is also the solvent are commonly called solvolysis reactions. The hydrolysis of t-butyl chloride is an example. Third, the Hammond postulate suggests thst the activation energy of the rate-determining first step will be inversely proportional to the stability of the carbocation intermediate. The stability of carbocations was discussed earlier, and a qualitative relationship is given below.
Consequently, we expect that 3º-alkyl halides will be more reactive than their 2º and 1º-counterparts in reactions that follow a SN1 mechanism. This is opposite to the reactivity order observed for the SN2 mechanism. Allylic and benzylic halides are exceptionally reactive by either mechanism. Fourth, in order to facilitate the charge separation of an ionization reaction, as required by the first step, a good ionizing solvent will be needed. Two solvent characteristics will be particularly important in this respect. The first is the ability of solvent molecules to orient themselves between ions so as to attenuate the electrostatic force one ion exerts on the other. This characteristic is related to the dielectric constant, ε, of the solvent. Solvents having high dielectric constants, such as water (ε=81), formic acid (ε=58), dimethyl sulfoxide (ε=45) & acetonitrile (ε=39) are generally considered better ionizing solvents than are some common organic solvents such as ethanol (ε=25), acetone (ε=21), methylene chloride (ε=9) & ether (ε=4). The second factor is solvation, which refers to the solvent's ability to stabilize ions by encasing them in a sheath of weakly bonded solvent molecules. Anions are solvated by hydrogen-bonding solvents, as noted earlier. Cations are often best solvated by nucleophilic sites on a solvent molecule (e.g. oxygen & nitrogen atoms), but in the case of carbocations these nucleophiles may form strong covalent bonds to carbon, thus converting the intermediate to a substitution product. This is what happens in the hydrolysis reactions described above. Fifth, the stereospecificity of these reactions may vary. The positively-charged carbon atom of a carbocation has a trigonal (flat) configuration (it prefers to be sp2 hybridized), and can bond to a nucleophile equally well from either face. If the intermediate from a chiral alkyl halide survives long enough to encounter a random environment, the products are expected to be racemic (a 50:50 mixture of enantiomers). On the other hand, if the departing halide anion temporarily blocks the front side, or if a nucleophile is oriented selectively at one or the other face, then the substitution might occur with predominant inversion or even retention of configuration. To see an animated model of the SN1 ionization step in which a chiral alkyl halide generates a trigonal carbocation Click Here
If you understand the factors and principles that influence the course of nucleophilic substitution reactions, try your hand at the following exercises. For each case the possibility of a substitution versus no reaction must be considered. If a substitution is predicted will it take place by a SN1 or a SN2 mechanism? If chiral centers are present will the configuration change?
1. The E2 Reaction We have not yet considered the factors that influence elimination reactions, such as example 3 in the group of reactions shown earlier, and redrawn below.
We know that t-butyl bromide is not expected to react by a SN2 mechanism. Furthermore, the ethanol solvent is not sufficiently polar to facilitate a SN1 reaction. The other reactant, cyanide anion, is a good nucleophile; and it is also a decent base, being about ten times weaker than bicarbonate. Consequently, a base-induced elimination seems to be the only plausible reaction remaining for this combination of reactants. To get a clearer picture of the interplay of these factors consider the reaction of a 2º-alkyl halide, isopropyl bromide, with two different nucleophiles.
In the methanol solvent used here, methanethiolate has greater nucleophilicity than methoxide by a factor of 100. Methoxide, on the other hand is roughly 106 times more basic than methanethiolate. As a result, we see a clearcut difference in the reaction products, which reflects nucleophilicity (bonding to an electrophilic carbon) versus basicity (bonding to a proton). Kinetic studies of these reactions show that they are both second order (first order in R–Br and first order in Nu:(–)), suggesting a bimolecular mechanism for each. The substitution reaction is clearly SN2. The corresponding designation for the elimination reaction is E2. An energy diagram for the single-step bimolecular E2 mechanism is shown on the right. We should be aware that the E2 transition state is less well defined than is that of SN2 reactions. More bonds are being broken and formed, with the possibility of a continuum of states in which the extent of C–H and C–X bond-breaking and C=C bond-making varies. For example, if the R–groups on the beta-carbon enhance the acidity of that hydrogen, then substantial breaking of C–H may occur before the other bonds begin to be affected. Similarly, groups that favor ionization of the halogen may generate a transition state with substantial positive charge on the alpha-carbon and only a small degree of C–H breaking. For most simple alkyl halides, however, it is reasonable to envision a balanced transition state, in which there has been an equal and synchronous change in all the bonds. Such a model helps to explain an important regioselectivity displayed by these elimination reactions.
2. The Zaitsev Rule If two or more structurally distinct groups of beta-hydrogens are present in a given reactant, then several constitutionally isomeric alkenes may be formed by an E2 elimination. This situation is illustrated by the 2-bromobutane and 2-bromo-2,3-dimethylbutane elimination examples given below.
By using the strongly basic hydroxide nucleophile, we direct these reactions toward elimination. In both cases there are two different sets of beta-hydrogens available to the elimination reaction (these are colored red and magenta and the alpha carbon is blue). If the rate of each possible elimination was the same, we might expect the amounts of the isomeric elimination products to reflect the number of hydrogens that could participate in that reaction. For example, since there are three 1º-hydrogens (red) and two 2º-hydrogens (magenta) on beta-carbons in 2-bromobutane, statistics would suggest a 3:2 ratio of 1-butene and 2-butene in the products. This is not observed, and the latter predominates by 4:1. This departure from statistical expectation is even more pronounced in the second example, where there are six 1º-beta-hydrogens compared with one 3º-hydrogen. These results point to a strong regioselectivity favoring the more highly substituted product double bond, an empirical statement generally called the Zaitsev Rule.
The main factor contributing to Zaitsev Rule behavior is the stability of the alkene. We noted earlier that carbon-carbon double bonds are stabilized (thermodynamically) by alkyl substituents, and that this stabilization could be evaluated by appropriate heat of hydrogenation measurements. Since the E2 transition state has significant carbon-carbon double bond character, alkene stability differences will be reflected in the transition states of elimination reactions, and therefore in the activation energy of the rate-determining steps. From this consideration we anticipate that if two or more alkenes may be generated by an E2 elimination, the more stable alkene will be formed more rapidly and will therefore be the predominant product. This is illustrated for 2-bromobutane by the energy diagram on the right. The propensity of E2 eliminations to give the more stable alkene product also influences the distribution of product stereoisomers. In the elimination of 2-bromobutane, for example, we find that trans-2-butene is produced in a 6:1 ratio with its cis-isomer. The Zaitsev Rule is a good predictor for simple elimination reactions of alkyl chlorides, bromides and iodides as long as relatively small strong bases are used. Thus hydroxide, methoxide and ethoxide bases give comparable results. Bulky bases such as tert-butoxide tend to give higher yields of the less substituted double bond isomers, a characteristic that has been attributed to steric hindrance. In the case of 2-bromo-2,3-dimethylbutane, described above, tert-butoxide gave a 4:1 ratio of 2,3-dimethyl-1-butene to 2,3-dimethyl-2-butene ( essentially the opposite result to that obtained with hydroxide or methoxide). This point will be discussed further once we know more about the the structure of the E2 transition state.
Bridged ring structures may exert geometric restrictions on the position of double bonds, described by a principle called Bredt's Rule. For more information on this subject Click Here.
3. Stereochemistry of the E2 Reaction E2 elimination reactions of certain isomeric cycloalkyl halides show unusual rates and regioselectivity that are not explained by the principles thus far discussed. For example, trans-2-methyl-1-chlorocyclohexane reacts with alcoholic KOH at a much slower rate than does its cis-isomer. Furthermore, the product from elimination of the trans-isomer is 3-methylcyclohexene (not predicted by the Zaitsev rule), whereas the cis-isomer gives the predicted 1-methylcyclohexene as the chief product. These differences are described by the first two equations in the following diagram. Unlike open chain structures, cyclic compounds generally restrict the spatial orientation of ring substituents to relatively few arrangements. Consequently, reactions conducted on such substrates often provide us with information about the preferred orientation of reactant species in the transition state. Stereoisomers are particularly suitable in this respect, so the results shown here contain important information about the E2 transition state.
The most sensible interpretation of the elimination reactions of 2- and 4-substituted halocyclohexanes is that this reaction prefers an anti orientation of the halogen and the beta-hydrogen which is attacked by the base. These anti orientations are colored in red in the above equations. The compounds used here all have six-membered rings, so the anti orientation of groups requires that they assume a diaxial conformation. The observed differences in rate are the result of a steric preference for equatorial orientation of large substituents, which reduces the effective concentration of conformers having an axial halogen. In the case of the 1-bromo-4-tert-butylcyclohexane isomers, the tert-butyl group is so large that it will always assume an equatorial orientation, leaving the bromine to be axial in the cis-isomer and equatorial in the trans. Because of symmetry, the two axial beta-hydrogens in the cis-isomer react equally with base, resulting in rapid elimination to the same alkene (actually a racemic mixture). This reflects the fixed anti orientation of these hydrogens to the chlorine atom. To assume a conformation having an axial bromine the trans-isomer must tolerate serious crowding distortions. Such conformers are therefore present in extremely low concentration, and the rate of elimination is very slow. Indeed, substitution by hydroxide anion predominates. A similar analysis of the 1-chloro-2-methylcyclohexane isomers explains both the rate and regioselectivity differences. Both the chlorine and methyl groups may assume an equatorial orientation in a chair conformation of the trans-isomer, as shown in the top equation. The axial chlorine needed for the E2 elimination is present only in the less stable alternative chair conformer, but this structure has only one axial beta-hydrogen (colored red), and the resulting elimination gives 3-methylcyclohexene. In the cis-isomer the smaller chlorine atom assumes an axial position in the more stable chair conformation, and here there are two axial beta hydrogens. The more stable 1-methylcyclohexene is therefore the predominant product, and the overall rate of elimination is relatively fast. An orbital drawing of the anti-transition state is shown on the right. Note that the base attacks the alkyl halide from the side opposite the halogen, just as in the SN2 mechanism. In this drawing the α and β carbon atoms are undergoing a rehybridization from sp3 to sp2 and the developing π-bond is drawn as dashed light blue lines. The symbol R represents an alkyl group or hydrogen. Since both the base and the alkyl halide are present in this transition state, the reaction is bimolecular and should exhibit second order kinetics. We note in passing that a syn-transition state would also provide good orbital overlap for elimination, and in some cases where an anti-orientation is prohibited by structural constraints syn-elimination has been observed. It is also worth noting that anti-transition states were preferred in several addition reactions to alkenes, so there is an intriguing symmetry to these inverse structural transformations. To see an animated display of the E2 elimination Click Here. To examine Jmol models of the E2 elimination of 2-bromobutane by ethoxide base Click Here.
Having arrived at a useful and plausible model of the E2 transition state, we can understand why a bulky base might shift the regioselectivity of the reaction away from the most highly substituted double bond isomer. Steric hindrance to base attack at a highly substituted beta-hydrogen site would result in preferred attack at a less substituted site. To see the effect of steric hindrance at a beta carbon on the E2 transition state Click Here.
The preferred anti-orientation of E2 transition states is in large part due to a stereoelectronic effect. This aspect of these reactions may be explored by clicking here.
4. The E1 Reaction Just as there were two mechanisms for nucleophilic substitution, there are two elimination mechanisms. The E1 mechanism is nearly identical to the SN1 mechanism, differing only in the course of reaction taken by the carbocation intermediate. As shown by the following equations, a carbocation bearing beta-hydrogens may function either as a Lewis acid (electrophile), as it does in the SN1 reaction, or a Brønsted acid, as in the E1 reaction.
Thus, hydrolysis of tert-butyl chloride in a mixed solvent of water and acetonitrile gives a mixture of 2-methyl-2-propanol (60%) and 2-methylpropene (40%) at a rate independent of the water concentration. The alcohol is the product of an SN1 reaction and the alkene is the product of the E1 reaction. The characteristics of these two reaction mechanisms are similar, as expected. They both show first order kinetics; neither is much influenced by a change in the nucleophile/base; and both are relatively non-stereospecific.
(CH3)3C–Cl + H2O ——> [ (CH3)3C(+) ] + Cl(–) + H2O ——> (CH3)3C–OH + (CH3)2C=CH2 + HCl + H2O
To summarize, when carbocation intermediates are formed one can expect them to react further by one or more of the following modes:
1. The cation may bond to a nucleophile to give a substitution product. 2. The cation may transfer a beta-proton to a base, giving an alkene product. 3. The cation may rearrange to a more stable carbocation, and then react by mode #1 or #2.
Since the SN1 and E1 reactions proceed via the same carbocation intermediate, the product ratios are difficult to control and both substitution and elimination usually take place.
Having discussed the many factors that influence nucleophilic substitution and elimination reactions of alkyl halides, we must now consider the practical problem of predicting the most likely outcome when a given alkyl halide is reacted with a given nucleophile. As we noted earlier, several variables must be considered, the most important being the structure of the alkyl group and the nature of the nucleophilic reactant. The nature of the halogen substituent on the alkyl halide is usually not very significant if it is Cl, Br or I. In cases where both SN2 and E2 reactions compete, chlorides generally give more elimination than do iodides, since the greater electronegativity of chlorine increases the acidity of beta-hydrogens. Indeed, although alkyl fluorides are relatively unreactive, when reactions with basic nucleophiles are forced, elimination occurs (note the high electronegativity of fluorine). The potential usefulness of acetylide anions in the synthesis of larger alkynes was noted earlier. Because terminal alkyne bases, such as RC≡C:(–) Na(+), are very strong bases (roughly a billion times stronger than NaOH) as well as good nucleophiles, their use as in SN2 reactions is limited to 1º-alkyl halides, as shown below. Reaction with 2º and 3º-alkyl halides proceeds by E2 elimination.