Bredt's Rule should not be applied blindly to all bridged ring systems. If large rings are present their conformational flexibility may permit good overlap of the p-orbitals of a double bond at a bridgehead. This is similar to recognizing that trans-cycloalkenes cannot be prepared if the ring is small (3 to 7-membered), but can be isolated for larger ring systems. The anti-tumor agent taxol has such a bridgehead double bond (colored red), as shown in the following illustration. The bicyclo[3.3.1]octane ring system is the smallest in which bridgehead double bonds have been observed. The drawing to the right of taxol shows this system. The bridgehead double bond (red) has a cis-orientation in the six-membered ring (colored blue), but a trans-orientation in the larger eight-membered ring.

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 S_N2 mechanism. In this drawing the ? and ? carbon atoms are undergoing a rehybridization from sp³ to sp² and the developing ?-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 should 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.

 

Just as there were two mechanisms for nucleophilic substitution, there are two elimination mechanisms. The E1 mechanism is nearly identical to the S_N1 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 S_N1 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 S_N1 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.

To summarize, when carbocation intermediates are formed one can expect them to react further by one or more of the following modes:

Since the S_N1 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 S_N2 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).

summary of Factors Influencing Alkyl Halide Reactions

 

Formation of Organometallic Compounds by Reductive Substitution of Alkyl Halides