Chapter 8 Substitution and Elimination Reactions of Alkyl Halides Paula Yurkanis Bruice University of California, Santa Barbara

Contents of Chapter 8 Reactivity Considerations The SN2 Reaction Stereochemistry of SN2 and SN1 Reactions Benzylic, Allylic, Vinylic & Aryl Halides Competition between SN2 and SN1 Reactions The E2 Reaction The E1 Reaction Substitution and Elimination Reactions in Synthesis No Biological Methylating Reagents Chapter 9

Substitution and Elimination A compound with an sp3 hybridized carbon bonded to a halogen can undergo two types of reactions Two different mechanisms for substitution are SN1 and SN2 mechanisms These result in diff prods under diff conditions Chapter 9

SN2 Mechanism SN2 mechanism: C–X bond weakens as nucleophile approaches all in one step Chapter 9

SN1 Mechanism SN1 mechanism: C–X bond breaks first without any help from nucleophile slow step fast step This is a two-step process Chapter 9

Substitution Reactions Both mechanisms are called nucleophilic substitutions Which one takes place depends on the structure of the alkyl halide the reactivity and structure of the nucleophile the concentration of the nucleophile, and the solvent in which reaction is carried out Chapter 9

The SN2 Reaction Bimolecular nucleophilic substitution rate = k [alkyl halide][nucleophile] Chapter 9

The SN2 Reaction The inversion of configuration resembles the way an umbrella turns inside out in the wind If a single chiral enantiomer reacts a single chiral product (inverted) results. Chapter 9

Steric Accessibility in the SN2 Reaction Chapter 9

The SN2 Reaction: Nucleophile Bulkiness Nucleophilicity is affected by steric effects A bulky nucleophile has difficulty getting near the back side of a sp3 carbon ethoxide ion tert-butoxide ion better nucleophile stronger base Chapter 9

The SN1 Reaction The more stable the C+ the lower the DG‡, and the faster the rxn Chapter 9

The SN1 Reaction Chapter 9

The SN1 Reaction The SN1 reaction leads to a mixture of stereoisomers Chapter 9

Stereochemistry of SN2 and SN1 Reactions inversion both enantiomers Chapter 9

Competition Between SN2 and SN1 Reactions Chapter 9

Competition Between SN2 and SN1 Reactions TABLE 9.6 Summary of the Reactivity of Alkyl Halides in Nucleophilic Substitution Reactions methyl & 1o alkyl halides SN2 only 2o alkyl halides SN2 & SN1 3o alkyl halides SN1 only vinylic & aryl halides neither SN2 nor SN1 benzylic & allylic halides SN2 & SN1 3o benzylic & allylic halides SN1 only Chapter 9

Elimination Reactions A compound with an electronegative atom bonded to an sp3 carbon, when approached by a nucleophile/base can undergo either a substitution reaction OR an elimination reaction In this chapter we start with elimination rxns then work subst/elim competition Chapter 9

The E2 Reaction Chapter 9

The E2 Reaction: Regioselectivity 2-bromobutane has two structurally different -carbons from which to abstract a hydrogen E2 rxns give more stable alkene if possible Chapter 9

The E2 Reaction: Regioselectivity Zaitsev’s rule: The more substituted alkene will be formed in elimination reactions Chapter 9

The E1 Reaction “E1” stands for “Elimination unimolecular” The E1 reaction is a two-step reaction The first step is rate-determining Chapter 9

The E1 Reaction Relative reactivities of alkyl halides in an E1 reaction are similar to the relative stabilities of carbocations 3o benzylic > 3o allylic > 2o benzylic > 2o allylic > 3o > 1o benzylic > 1o allylic  2o > 1o > vinyl Increasing reactivity and C+ stability Chapter 9

Competition Between E2 and E1 Reactions Summary of the Reactivity of Alkyl Halides in Elimination Reactions primary alkyl halide E2 only secondary alkyl halide E1 and E2 tertiary alkyl halide E1 and E2 Chapter 9

Competition Between E2 and E1 Reactions E2 reaction is favored by the same factors that favor SN2 reactions over SN1 primary alkyl halide electrophiles a high concentration of a strong base (e.g. HO– or –NH2) in 1°, 2°, or 3° electrophiles an aprotic polar solvent in 1°, 2°, or 3° electrophiles An E1 reaction is favored by a weak base (e.g. a neutral solvent) a polar protic solvent (e.g. H2O or ROH) Chapter 9

The E1 Reaction: Stereochemistry With C+ both syn and anti elimination can occur, so E1 reaction forms both E and Z products regardless of whether b-carbon is bonded to one or two H’s Product stability leads to stereoselectivity but not stereospecificity Chapter 9

Williamson Ether Synthesis If you want to synthesize butyl propyl ether you have a choice of starting materials Other ethers should be made by choosing least-hindered electrophile if possible Ethers usually best made by SN2 rxn Chapter 9

Williamson Ether Synthesis ethyl bromide tert-butoxide tert-butyl ethyl ethene ion ether If you want to prepare tert-butyl ethyl ether the starting materials must be an ethyl halide and tert-butoxide ion When ethoxide ion and tert-butyl bromide are used, only elimination product is produced Chapter 9