Organic Chemistry, Second Edition Janice Gorzynski Smith University of Hawai i Chapter 8 Alkyl Halides and Elimination Reactions Prepared by Rabi Ann Musah State University of New York at Albany Copyright The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 1 8.1 General Features of Elimination Elimination reactions involve the loss of elements from the starting material to form a new π bond in the product. 2 1
Equations [1] and [2] illustrate examples of elimination reactions. In both reactions a base removes the elements of an acid, HX, from the organic starting material. 3 Removal of the elements HX is called dehydrohalogenation. Dehydrohalogenation is an example of β elimination. The curved arrow formalism shown below illustrates how four bonds are broken or formed in the process. 4 2
The most common bases used in elimination reactions are negatively charged oxygen compounds, such as HO and its alkyl derivatives, RO, called alkoxides. 5 To draw any product of dehydrohalogenation Find the α carbon. Identify all β carbons with H atoms. Remove the elements of H and X from the α and β carbons and form a π bond. 6 3
8.2 Alkenes The Products of Elimination Recall that the double bond of an alkene consists of a σ bond and a π bond. 7 Alkenes are classified according to the number of carbon atoms bonded to the carbons of the double bond. Figure 8.1 Classifying alkenes by the number of R groups bonded to the double bond 8 4
Recall that rotation about double bonds is restricted. Figure 8.2 9 Because of restricted rotation, two stereoisomers of 2-butene are possible. cis-2-butene and trans-2-butene are diastereomers, because they are stereoisomers that are not mirror images of each other. 10 5
Whenever the two groups on each end of a carbon-carbon double bond are different from each other, two diastereomers are possible. 11 In general, trans alkenes are more stable than cis alkenes because the groups bonded to the double bond carbons are further apart, reducing steric interactions. 12 6
The stability of an alkene increases as the number of R groups bonded to the double bond carbons increases. The higher the percent s-character, the more readily an atom accepts electron density. Thus, sp 2 carbons are more able to accept electron density and sp 3 carbons are more able to donate electron density. Consequently, increasing the number of electron donating groups on a carbon atom able to accept electron density makes the alkene more stable. 13 trans-2-butene (a disubstituted alkene) is more stable than cis-2-butene (another disubstituted alkene), but both are more stable than 1-butene (a monosubstituted alkene). 14 7
8.3 Mechanisms of Elimination There are two mechanisms of elimination E2 and E1, just as there are two mechanisms of substitution, S N 2 and S N 1. E2 mechanism bimolecular elimination E1 mechanism unimolecular elimination The E2 and E1 mechanisms differ in the timing of bond cleavage and bond formation, analogous to the S N 2 and S N 1 mechanisms. E2 and S N 2 reactions have some features in common, as do E1 and S N 1 reactions. 15 8.4 Mechanisms of Elimination E2 The most common mechanism for dehydrohalogenation is the E2 mechanism. It exhibits second-order kinetics, and both the alkyl halide and the base appear in the rate equation, i.e., rate = k[(ch 3 ) 3 CBr][ OH] The reaction is concerted all bonds are broken and formed in a single step. 16 8
17 Figure 8.3 An energy diagram for an E2 reaction: 18 9
There are close parallels between E2 and S N 2 mechanisms in how the identity of the base, the leaving group and the solvent affect the rate. The base appears in the rate equation, so the rate of the E2 reaction increases as the strength of the base increases. E2 reactions are generally run with strong, negatively charged bases like OH and OR. Two strong sterically hindered nitrogen bases called DBN and DBU are also sometimes used. 19 Figure 8.4 An E2 elimination with DBN used as the base 20 10
21 The S N 2 and E2 mechanisms differ in how the R group affects the reaction rate. 22 11
The increase in E2 reaction rate with increasing alkyl substitution can be rationalized in terms of transition state stability. In the transition state, the double bond is partially formed. Thus, increasing the stability of the double bond with alkyl substituents stabilizes the transition state (i.e., lowers E a, which increases the rate of the reaction. 23 Increasing the number of R groups on the carbon with the leaving group forms more highly substituted, more stable alkenes in E2 reactions. In the reactions below, since the disubstituted alkene is more stable, the 3 alkyl halide reacts faster than the 1 0 alkyl halide. 24 12
Table 8.2 summarizes the characteristics of the E2 mechanism. 25 Figure 8.5 Two examples of the E2 reaction used in organic synthesis 26 13
8.5 The Zaitsev (Saytzeff) Rule Recall that when alkyl halides have two or more different β carbons, more than one alkene product is formed. When this happens, one of the products usually predominates. The major product is the more stable product the one with the more substituted double bond. This phenomenon is called the Zaitsev rule. 27 The Zaitsev rule: the major product in β elimination has the more substituted double bond. A reaction is regioselective when it yields predominantly or exclusively one constitutional isomer when more than one is possible. Thus, the E2 reaction is regioselective. 28 14
When a mixture of stereoisomers is possible from a dehydrohalogenation, the major product is the more stable stereoisomer. A reaction is stereoselective when it forms predominantly or exclusively one stereoisomer when two or more are possible. The E2 reaction is stereoselective because one stereoisomer is formed preferentially. 29 8.6 Mechanisms of Elimination E1 The dehydrohalogenation of (CH 3 ) 3 CCI with H 2 O to form (CH 3 ) 2 C=CH 2 can be used to illustrate the second general mechanism of elimination, the E1 mechanism. An E1 reaction exhibits first-order kinetics: rate = k[(ch 3 ) 3 CCI] The E1 reaction proceeds via a two-step mechanism: the bond to the leaving group breaks first before the π bond is formed. The slow step is unimolecular, involving only the alkyl halide. The E1 and E2 mechanisms both involve the same number of bonds broken and formed. The only difference is timing. In an E1, the leaving group comes off before the β proton is removed, and the reaction occurs in two steps. In an E2 reaction, the leaving group comes off as the β proton is removed, and the reaction occurs in one step. 30 15
31 Figure 8.6 Energy diagram for an E1 reaction: 32 16
The rate of an E1 reaction increases as the number of R groups on the carbon with the leaving group increases. The strength of the base usually determines whether a reaction follows the E1 or E2 mechanism. Strong bases like OH and OR favor E2 reactions, whereas weaker bases like H 2 O and ROH favor E1 reactions. 33 E1 reactions are regioselective, favoring formation of the more substituted, more stable alkene. Zaitsev s rule applies to E1 reactions also. 34 17
Table 8.3 summarizes the characteristics of the E1 mechanism. 35 8.7 S N 1 and E1 Reactions S N 1 and E1 reactions have exactly the same first step formation of a carbocation. They differ in what happens to the carbocation. Because E1 reactions often occur with a competing S N 1 reaction, E1 reactions of alkyl halides are much less useful than E2 reactions. 36 18
8.8 Stereochemistry of the E2 Reaction The transition state of an E2 reaction consists of four atoms from an alkyl halide one hydrogen atom, two carbon atoms, and the leaving group (X) all aligned in a plane. There are two ways for the C H and C X bonds to be coplanar. E2 elimination occurs most often in the anti periplanar geometry. This arrangement allows the molecule to react in the lower energy staggered conformation, and allows the incoming base and leaving group to be further 37 away from each other. Figure 8.7 Two possible geometries for the E2 reaction 38 19
The stereochemical requirement of an anti periplanar geometry in an E2 reaction has important consequences for compounds containing sixmembered rings. Consider chlorocyclohexane which exists as two chair conformations. Conformation A is preferred since the bulkier Cl group is in the equatorial position. For E2 elimination, the C-Cl bond must be anti periplanar to the C H bond on a β carbon, and this occurs only when the H and Cl atoms are both in the axial position. The requirement for trans diaxial geometry means that elimination must occur from the less stable conformer, B. 39 Figure 8.8 The trans diaxial geometry for the E2 elimination in chlorocyclohexane 40 20
Now consider the E2 dehydrohalogenation of cis- and trans-1-chloro-2- methylcyclohexane. This cis isomer exists as two conformations, A and B, each of which as one group axial and one group equatorial. E2 reaction must occur from conformation B, which contains an axial Cl atom. 41 Because conformation B has two different axial β hydrogens, labeled H a and H b, E2 reaction occurs in two different directions to afford two alkenes. The major product contains the more stable trisubstituted double bond, as predicted by the Zaitsev rule. 42 21
The trans isomer of 1-chloro-2-methylcyclohexane exists as two conformers: C, having two equatorial substituents, and D, having two axial substituents. E2 reaction must occur from D, since it contains an axial Cl atom. 43 Because conformer D has only one axial β H, the E2 reaction occurs only in one direction to afford a single product. This is not predicted by the Zaitsev rule. 44 22
8.9 When is the Mechanism E1 or E2? The strength of the base is the most important factor in determining the mechanism for elimination. Strong bases favor the E2 mechanism. Weak bases favor the E1 mechanism. 45 8.10 E2 Reactions and Alkyne Synthesis A single elimination reaction produces a π bond of an alkene. Two consecutive elimination reactions produce two π bonds of an alkyne. 46 23
Two elimination reactions are needed to remove two moles of HX from a dihalide substrate. Two different starting materials can be used a vicinal dihalide or a geminal dihalide. 47 Stronger bases are needed to synthesize alkynes by dehydrohalogenation than are needed to synthesize alkenes. The typical base used is NH 2 (amide), used as the sodium salt of NaNH 2. KOC(CH 3 ) 3 can also be used with DMSO as solvent. 48 24
The reason that stronger bases are needed for this dehydrohalogenation is that the transition state for the second elimination reaction includes partial cleavage of the C H bond. In this case however, the carbon atom is sp 2 hybridized and sp 2 hybridized C H bonds are stronger than sp 3 hybridized C H bonds. As a result, a stronger base is needed to cleave this bond. 49 Figure 8.9 Example of Dehydrohalogenation of dihalides to afford alkynes 50 25
8.11 When Is the Reaction S N 1, S N 2, E1 or E2. Good nucleophiles that are weak bases favor substitution over elimination Certain anions generally give products of substitution because they are good nucleophiles but weak bases. These include I, Br, HS, CN, and CH 3 COO. 51 Bulky nonnucleophilic bases favor elimination over substitution KOC(CH 3 ) 3, DBU, and DBN are too sterically hindered to attack tetravalent carbon, but are able to remove a small proton, favoring elimination over substitution. 52 26
Figure 8.10 Determining whether an alkyl halide reacts by an S N 1, S N 2, E1, or E2 mechanism 53 Figure 8.10 continued 54 27
Figure 8.10 continued 55 28