E2 Reactions

E2: Elimination, Bimolecular An E2 reaction takes place in a single step The B–H s bond and the C=C p bond form at the same time the H–C s bond and the C–L s bond break. http://www.masterorganicchemistry.com/2012/09/27/the-e2-mechanism/

E2: Elimination, Bimolecular The base in an E2 step is the electron-rich species, but the hydrogen atom that the base attacks is not particularly electron poor; instead, the electron-poor atom is the carbon atom bonded to the leaving group. Thus, the movement of electrons from the electron-rich site to the electron-poor site is depicted with two curved arrows originating from the strong base (B:-)

Four-way Rate Competition SN1 SN2 E1 E2

E2: Elimination, Bimolecular The E2 is concerted and takes place in a single step The B–H s bond and the C=C p bond form at the same time the H–C s bond and the C–L s bond break The attacking species is a Brønsted base which abstracts a b-H to LG

E2: Elimination, Bimolecular E2 free energy diagram - maps DE as reaction progresses Single ‡ EA from the only and rate limiting step Can be slightly endothermic or exothermic

Factor 1: Structure of R-X/LG Empirical data for E2 reactions: Substrate Type of Carbon 1o 2o 3o Relative E2 rate 1 4.76 40.5 http://www.masterorganicchemistry.com/2012/09/27/the-e2-mechanism/

The Hammond Postulate Applied to E2 E2 is concerted and neither strongly endothermic or exothermic The increase in reaction rate with increasing alkyl substitution can be rationalized in terms of ‡ stability. In the ‡, the double bond is partially formed The more stable the alkene this will lead to, the more stable the ‡

Alkene Stability Alkene stability comes from hyperconjugation The greater the number of adjacent sp3 orbitals, the greater the electron interaction, which lowers the energy of the structure

Alkene Stability The greater the alkyl substitution, the greater the hyperconjugation Within the same substitution pattern, trans is more stable than cis.

Factor 1: Structure of R-X/LG

E2 Rate Determining Step Like an SN2 reaction, an E2 reaction consists of a single step that must be rate determining. Both the base and carbon substrate are involved in the rate limiting step, thus a bimolecular rate law Rate (E2) = kE2[Base][C-LG]

Factor 2: Strength of the Base: Remember nucleophilicity and basicity are interrelated, but fundamentally different. Basicity is a measure of how stable a species becomes after it has accepted a proton It is a thermodynamic property characterized by an equilibrium constant, KA Nucleophilicity is a measure of how rapidly an atom donates its electron pair to other atoms to form bonds. It is a kinetic property characterized by a rate constant, k For elimination reactions to compete with substitution, the attacking species must act as a base rather than a nucleophile

Factor 2: Strength of the Base: Hammond Postulate and E2 : A stronger Base: is closer in energy to the ‡, which lowers the EA giving a faster E2 reaction. A weaker Base: is farther in energy to the ‡, which raises the EA giving a slower E2 reaction. ‡ closer to raised energy of reactants Lower EA Stronger Base: Weaker Base:

Factor 2: Strength of the Base: Strong bases fall into two categories: Big, bulky bases – these are sterically encumbered and never act as nucleophiles unless the substrate is methyl (CH3-LG)

Factor 2: Strength of the Base: Strong bases fall into two categories: Strong, small bases – these can act as both nucleophiles and bases

Factor 2: Strength of the Base: Some species appear basic, but only act as nucleophiles They are either polarizable ions or resonance stabilized species that are not strong enough Brønsted bases for E2: Polarizable ions: Resonance stabilized ions: Too weak for E2 reactions

Factor 3: Leaving Group Ability A leaving group must leave in the rate-determining step of an SN2, SN1, E2, or E1 reaction. The identity of the leaving group has an effect on the rate of each reaction. A good leaving group is necessary for the reaction to be exothermic (and spontaneous) via a –DH Leaving group ability strongly affects E2 reactions

Factor 3: Leaving Group Ability Overall, E2 is similar to SN2 and SN1 with regard to leaving group ability: Are never LGs!

Factor 4: Solvent Effects Basicity, like nucleophilicity can be affected by the nature of the solvent! If the solvent stabilizes the B: too strongly, its energy will be reduced and by the Hammond postulate the reaction will slow Stronger Base: Weaker Base:

Factor 4: Solvent Effects Since it is the base that matters in E2, solvents that do not stabilize negative charge give faster reactions. Like SN2 reactions, E2 reactions proceed at much higher rates in polar aprotic solvents In a polar protic solvent the base is stabilized, as the solvent makes partial bonds to it In a polar aprotic solvent the base is not stabilized and is fully active for E2

Factor 5: Heat When substitution and elimination reactions are both favored under a specific set of conditions, it is often possible to influence the outcome by changing the temperature under which the reactions take place. All of these reactions have an EA that needs to be surmounted. Heat will accelerate the rate of all reactions; the object is not to overheat to allow higher EA reaction pathways to compete E2 reactions are more strongly accelerated by heat than substitution

Factor 5: Heat

Factor 5: Heat This temperature effect is due to entropy. ∆S °rxn is more positive for an elimination reaction than for a substitution reaction.

Factor 6a: Regioselectivity of E2 Many reactions lead to product mixtures of constitutional isomers from the same ‡. Reactions that favor one or more isomers over others are called regioselective. E2 reactions are both regioselective and stereoselective

Factor 6a: Regioselectivity of E2 Consider the E2 reaction of 2-iodohexane; there are two b-Hs that can be abstracted in the mechanism: Product is 1-hexene Product is 2-hexene

Factor 6a: Regioselectivity of E2 Remember, the more substituted an alkene, the more stable it is. The ‡ leading to a lower energy product has a lower EA. More of the lower energy product will be formed.

Factor 6a: Regioselectivity of E2 A mixture still results, but a major product dominates: E2 is regioselective The observation that elimination reactions favor the most stable (substituted) alkenes is called the Zaitsev’s Rule (Saytzeff’s)

Factor 6b: Stereoselectivity of E2 The E2 reaction consists of a single concerted step. In the E2 ‡, the geometry of the base, abstracted hydrogen and leaving group are in the plane of the p-bond being formed:

Factor 6b: Stereoselectivity of E2 Note that the position of groups 1, 2, 3 and 4 are the same before and after the reaction:

Factor 6b: Stereoselectivity of E2 E2 can occur from any conformer where a H and LG are anti-periplanar

Factor 6b: Stereoselectivity of E2 Example:

Factor 6b: Stereoselectivity of E2 Example:

Factor 6b: Stereospecificity of E2 The conformation in which the H and the leaving group are anti to each other is referred to as anti- coplanar or anti-periplanar.

Factor 6b: Stereospecificity of E2 If there are two H atoms that can be eliminated from the same C atom, then a mixture of diastereomers can form in an E2 reaction.

Factor 6b: Stereospecificity of E2

Factor 6b: Stereospecificity of E2 The requirement of anti-periplanar geometry in an E2 reaction has important consequences for compounds containing six-membered rings. Chlorocyclohexane exists as two chair conformations. Conformation A is preferred since the bulkier Cl group is in the equatorial position

Factor 6b: Stereospecificity of E2 For E2 elimination, the C-Cl bond must be anti periplanar to the C-H bond on a  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.

Factor 6b: Stereospecificity of E2 Consider the E2 dehydrohalogenation of cis- and trans-1-chloro-2-methylcyclohexane.

Factor 6b: Stereospecificity of E2 The cis isomer exists as two conformations, A and B, each of which has one group axial and one group equatorial. E2 reaction must occur from conformation B, which contains an axial Cl atom.

Factor 6b: Stereospecificity of E2 Because conformation B has two different axial  hydrogens, labeled Ha and Hb, E2 reaction occurs in two different directions to afford two alkenes. The major product contains the more stable tri-substituted double bond, as predicted by the Zaitsev rule.

Factor 6b: Stereospecificity of E2 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.

Factor 6b: Stereospecificity of E2 Because conformer D has only one axial  H, the E2 reaction occurs only in one direction to afford a single product. The most substituted, “Zaitsev” alkene is not the major product in this case.

Summary E2 SN1 SN2 E1 E2 Optimize SN2 rate: Factor 1: CH3>1o>2o; never 3o Factor 2: Strong, small Nu: Factor 3: Good LG-weak CB Factor 4: Polar aprotic solvent Factor 5: DS = 0 Factor 6: Stereospecific Optimize SN1 rate: Factor 1: 3o >2o; never 1o, CH3 Factor 2: Any Nu: Factor 3: Good LG-weak CB Factor 4: Polar protic solvent Factor 5: DS = 0 Factor 6: Non-stereospecific SN2 SN1 E1 E2 Optimize E2 rate: Factor 1: 3o >2o>>1o Factor 2: Strong Base: Factor 3: Good LG-weak CB Factor 4: Polar aprotic solvent Factor 5: +DS, T increase rate Factor 6: Stereospecific and regiospecific