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Elimination Reactions of Alkyl Halides Chapter 9 “A pessimist finds difficulty in every opportunity. An optimist finds opportunity in every difficulty.” A. Lincoln Elimination Reactions Elimination Rx can be of two types • E1 mechanism (unimolecular) • E2 mechanism (bimolecular) E2 Eliminations Concerted one step reaction E2 Eliminations • Called “dehydrohalogenations” • Called a / Eliminiation • Called 1-2 Elimination E2 Eliminations Relative reactivities of RX in an E2 reaction: (most reactive) RI > RBr > RCl > RF (least reactive)) F- is a better base than Br- E2 Eliminations Sometimes only one elimination product is possible Sometimes More than one product may result E2 Eliminations Kinetic and Thermodynamic Product (A regioselective reaction !) Zaitsev’s Rule The more highly substituted product is obtained when a proton is removed from the -carbon that is bonded to the fewest hydrogens Reactivity of Alkyl Halides • * Reactivity Considerations • The more substituted product is not always the most rapidly formed… That Conjugated Diene thing just keeps showing up……. Reactivity Considerations • The more substituted product is not always the most rapidly formed… That Pesky Bulky Base – Changes things…… Reactivity Considerations • Steric hindrance may dictate removal of a more accessible H (The most substituted is not formed here.) • * (What does this mean?) Alkyl fluorides • Dehydrohalogenation of R-I, R-Br, R-Cl yield more substituted alkene • Dehydrohalogenation of RF yields the less substituted alkene Elimination of Alkyl fluorides Elimination of Alkyl fluorides • Fluoride is a strong base • Fluoride is a poor leaving group • A partial negative charge develops on the carbon that lost the proton (a carbanion) Carbo - Ions Carbocations are stabilized by alkyl groups Carbanions are destabilized by alkyl groups : R’ - C R 3O < 2O < 1O Increasing stability of Carbanions R” Elimination Considerations • The major product is the more substituted alkene unless… the alkyl halide contains conjugation the base is large the alkyl halide is an alkyl fluoride E1 Mechanism • E1 Mechanism Major product will generally be the more substituted - Zatsev E1 Mechanism Product depends on stability of the carbocation E1 Mechanism • Because a carbocation is formed – rearrangement is possible E1 Mechanism • Because a carbocation is formed – rearrangement is possible Competition E1 vs. E2 RX Elimination comments 1o alkyl halides E2 only Difficulty in forming 1o carbocations 2o alkyl halides E1 and E2 Favored by same as SN2 conditions 3o alkyl halides E1 and E2 Favored by same as SN2 conditions Review of SN Reactions SN1 is Favored By More Substituted Carbocation Weak Nucleophile Polar Protic Solvent SN2 is Favored By Less Substituted Carbocation Strong Nucleophile Polar AProtic Solvent Stereochemistry of E2 • In an E2 reaction, 2 groups are eliminated in one step • The 2 groups MUST be located in the same plane (periplanar) (syn-periplanar) slower (anti-periplanar) faster E2 is regioselective E2 Is Stereoselective • The conformers that have the bulkiest groups on opposite sides will be the major product. Stereochemistry of E2 Note: E isomer is major product because bulky groups, methyl and t-butyl, are anti. Stereochemistry of E2 Important note: use models! E2 for 2-bromo-3-phenylbutane only E isomer (2S, 3S) only Z isomer (2S, 3R) E1 Eliminations – planar, carbocation intermediate – syn and anti elimination can occur bulkiest groups on opposite sides (Major product is the one with bulkiest groups on opposite sides.) Elimination from Cyclics - E2 – In an E2 reaction, both groups must be periplanar and anti to each other. – This is NOT the most stable conformer. Elimination from Cyclics - E2 Elimination from Cyclics - E2 More stable conformer has groups equatorial. Occurs 200 x faster! Elimination from Cyclics - E2 • In an E2 reaction, the H is removed from the most substituted -carbon unless that hydrogen is not in the axial Elimination from Cyclics - E1 • In an E1 reaction, the elimination is not concerted. • Intermediate is a carbocation • Groups do not need to be in the axial position Elimination from Cyclics - E1 • Carbocation intermediates may rearrange. (Zaitsev’s rule is followed, but first watch out for a rearrangement.) Stereochemistry Review mechanism SN1 •E1 •SN2 E2 products Both enantiomers formed (more inverted than retained) Both E and Z formed (more of the stereoisomer with bulkiest groups trans) Only the inverted product is formed Both enantiomers formed (more of the stereoisomer with bulkiest groups trans) comments Racemization w/ some inversion Also C+ intermediate Inversion Using Isotopes In Chemistry • Look at mechanism • Look at research handout • Look at medical questions handout Substitution vs. Elimination • Steps To Deciding • Decide if it favors Sn2/E2 or Sn1/E1 conditions • Decide if it favors Substitution or Elemination …….. That’s all there is to it From Yahoo Images Deciding Between First or Second order • Substrate – 1st order – primary and secondary 2nd order – secondary and tertiary • Nucleophile 1st order – weaker nuclephile 2nd order – strong nucleophile • Solvent 1st order – polar protic solvent 2nd order – polar aprotic or neutral 2 out of three ain’t bad………… or is that just a long lost song Deciding Between Sn2 and E2 • Substrate • Base • Temperature From Yahoo Images Deciding Between Sn2 and E2 • Substrate Sn2 – primary alkyl halide E2 – secondary alkyl halide Deciding Between Sn2 and E2 • Nuclophile Sn2 – Weaker and Smaller E2 – stronger and Bulkier Deciding Between Sn2 and E2 • Temperature Sn2 – Lower Temperature E2 – Higher Temperatue SN1 / E1 Conditions • All alkyl halides have same order of reactivity for SN1 or E1 • Substitution is favored at lower temperatures Practice Activity • Each person create a reaction and conditions • Have your neighbor decide which mechanism it will undergo • Switch and do it again From Yahoo Images Williamson Ether Synthesis • Williamson ether synthesis – Alkyl halide with alkoxide (SN2 reaction) – Alexander Williamson (1850!) – React alcohol with sodium metal or sodium hydride CH3OH + Na NaH CH3O- + Na+ + 1/2 H2 Williamson Ether Synthesis • If you want to prepare n-propyl n-butyl ether, there are two methods. Williamson Ether Synthesis • If you want to prepare ethyl t-butyl ether, there are two methods… HOWEVER, if you use t-butyl halide, you will obtain primarily the elimination product. Alkyne Syntheses • Elimination Reactions involving geminal dihalides (note: use a very strong base NH2 , not OH-, or it stops at vicinyl dihalide!) Synthesis Problems • Synthesize 1,3-cylcohexadiene from cyclohexane. Synthesis Problems • Synthesis Pathway Synthesis Problems • Synthesize trans-1,2-dibromo-1-methylcylcohexane from methylcyclohexane. Synthesis Problems • Synthesis Pathway Synthesis Problems • Synthesize 2-butanone from 1-bromobutane. Synthesis Problems • Retrosynthetic Analysis Synthesis Problems • Synthetic pathway END “A pessimist finds difficulty in every opportunity. An optimist finds opportunity in every difficulty.” A. Lincoln