Elimination Rxn Predict the reaction pathway (main products) for E2 and E1 Draw reaction mechanism for E1 Design synthetic pathway based on mechanism

Introduction to Elimination Definition: A molecule loses H-X (H and X atom/group from vinyl carbon) to form alkene Elimination is the opposite of Addition, typically requiring high temperature, driven by alkaline (basic) environment. Two main ingredients for an elimination: A BASE (to remove H as H+) an electrophile with a Leaving Group

Nucleophile vs. Base Consider –OH, which can act as a base or a nucleophile Attack at the α Carbon ALKENE β or 1,2 Reaction at the β Hydrogen

Two mechanisms for Elimination All elimination reactions involve both loss of a leaving group and proton transfer The mechanism may be a concerted (one step) process or a step-wise process.

E1: Elimination with 1st order kinetics E1 elimination represents the 1st order rate law The rate law for E1 rxn appears: r = k[substrate] Reaction rate for E1 rxn depends only on [substrate] A change in [Base] will NOT affect the rate of E1 rxn. Mechanism involves a slow first step followed by fast second step.

E2: Elimination with 2nd order kinetics The rate law for E2 rxn appears as 2nd order rxn: r = k[substrate][Base] Both change in [base] or [substrate] will affect the E2 reaction rate. Mechanism: single step reaction

Structure of Substrate a-/b-position in reaction center

3° Substrate is preferred in E2 3° substrates are more reactive toward E2 than are 1° substrates even though 1° substrates are less hindered The 3° substrate should proceed through a more stable transition state (kinetically favored) and a more stable product (thermodynamically favored).

E2 for Substrate

Regioselectivity of E2 Regioselectivity: Preference of locations in Reactions (producing isomers) In elimination reactions, Different β sites available for deprotonation to yield different alkenes Zaitsev product: more substituted alkene Hofmann product: less substituted alkene Zaitsev product Hofmann product

E2 regioselectivity depends on Base Steric Effect from base is causing the difference

Less sterically hindered base  Zaitsev Zaitsev product predominate when a base that is NOT sterically hindered is used. Less sterically hindered base has lower energy barrier (Ea)

Sterically hindered base  Hoffmann Sterically hindered base favor the Hofmann product. Common “bulky” bases for Hoffman elimination: Sterically hindered bases are useful in many reactions

Stereoselectivity of E2 for Trans When two b-H atoms are available, dehydrohalogenation of 3-bromopentane gives the following products Recall Trans isomer is more stable than cis isomer (thermodynamics) Trans has lower activation energy.

Practice: Predict E2 products Assuming both reaction proceeds E2 pathway methylene cyclohexane, 3-methylcyclohexene; 1-butene, trans-2-butene

E2 for substrate w/ single β-H When there is only one β-H to be eliminated, both E and Z alkene products may result from this reaction. Draw both E and Z products

*E2 for single β-H yields ONE isomer When the reaction is actually performed, only the E product is observed

Anti-Coplanarity in E2 transition state E2 mechanism: base and substrate are both in the rate determining step In the transition state, the C-H and C-Br bonds that are breaking must be rotated into the same plane as the pi bond that is forming Transition state structure illustrating the coplanar geometry

*Anti coplanar b-H and LG

Practice: Predict E2 products Assuming both reaction proceeds E2 pathway

Elimination on Cyclohexyl halide The chlorine atom may adapt either axial or equatorial position in the chair conformation. Only for Cl at axial-position allows elimination In the presence of alkyl group, more bulky alkyl group has priority to take equitorial position. This affects the regioselectivity in elimination of HCl

Practice: Predict major E2 products from Cyclohexyl halide

*E2 for Disubstituted Cyclohexane Which of the following molecules will NOT be able to undergo an E2 elimination reaction? Hint: Set alkyl in e-position first, then if Cl may be able to take a-position

E1 Mechanism E1 mechanism is a 2-step process Similar to SN1, the reaction rate for E1 is not affected by [Base] Loss of LG in the mechanism is the rate-determining slow step

Carbocation in E1 Like SN1 mechanism, the stability of carbocation determines the substrate reactivity trend for E1 rxn:

Potential Energy diagram for E1 More stable carbocation, lower energy for the carbocation intermediate (Hummond postulate)

E1 vs. SN1: Competition in 2nd step Because E1 and SN1 proceed by the same first step, their competition will generally result in a mixture of products

Protonation in E1 of alcohol Elimination of water (dehydration) from alcohols: the –OH group needs protonation like in SN1 In the E1 reaction below, protonation forms –OH2+ as better leaving group before the formation of carbocation. Concentration sulfuric acid help equilibrium to the right

E1 for More substituted alkene The final step of E1 mechanism determines the regioselectivity E1 reactions generally produce the Zaitsev product (more substituted alkene) predominantly.

E1 Stereoselectivity for Trans In the last step of the mechanism, a proton is removed from a β carbon adjacent to the sp2 hybridized carbocation Deprotonation from β carbon is thermodynamically driven (trans or E isomers with less steric hindrance is preferred)

Practice: Stereoselectivity for E1 Considering stereochemistry and regiochemistry, predict the products if the molecule below was treated with concentrated sulfuric acid

Complete E1 Mechanisms Recall the similarities between SN1 and E1 After the carbocation is formed and possibly rearranged, E1 proton transfer neutralizes the charge

E1 Mechanism: Alcohol to Alkene

E1 w/ Rearrangement The maximum number of steps in an E1 mechanism is generally four

E1 with rearrangement

Potential Energy Diagram for E1 Four steps in E1 mechanism suggests Four reaction intermediates.

Practice: Draw Reaction Mechanism

E2 has no protonation In E2, base removes the β proton as the LG leaves Strong base in E2 facilitates proton transfer The presence of strong base almost excludes the protonation step.

Substitution vs. Elimination Substitution and Elimination are always in competition Sometimes products are only observed from S or E Sometimes a mixture of products is observed

Substitution vs. Elimination To predict whether substitution or elimination will predominate, consider the factors below Determine the function of the reagent: as a base, a nucleophile, or both? Nucleophilicity favor subsitution Basicity favor elimination If base, bulky (Hoffman) or Zaitev. Structure of substrate (1°/2°/3°) affect the pathway (SN1, SN2, E1, or E2) Consider relevant regiochemical and stereochemical requirements

Nucleophile Strength : Nucleophilicity Greater the negative charge, more nucleophilic. RO- > ROH, HO- > H2O more polarizable atom/anion (larger atom/anion), the more nucleophilic, RSH > ROH, I- > Br- > Cl- > F- less sterically hindered it is, the more nucleophilic it should be. CH3O- > (CH3)3CO-

Strength of Base: Basicity Recall strong acid (low pKa ) yields weak conjugate base Strong base is the conjugate base from weak acid To predict the basicity of base, add H+ to make conjugate acid then use ARIO (atom, resonance, induction, orbital) to predict acidicity. Compare the following: CH3OH or CH3NH2 Acetate or RO-

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Base or Nucleophile? Reagents that act as nucleophiles only are either highly polarizable and/or they have very strong conjugate acids Neutral ROH as weak base or nucleophile

Reagent Only as Base Either very low polarizability and/or sterically hindered

Strong Reagent for SN2 or E2 The stronger the reagent (either as nucleophile or base), the more likely it is to promote SN2 or E2. The more sterically hindered reagents are more likely to promote Elimination than Substitution.

Weak Reagent for SN1 or E1 The weaker the reagent (nucleophile or base), the more likely it is to promote SN1 or E1, as the reagent is not affecting the rate of reaction

Only as Nucleophile? SN only A. If reagent as nucleophile only, only Substitution reaction. Pathway depends on structure. 1° has SN2 only, 3° substrate SN1 only. 2° both.

Only as Base? E2 only B. If reagent as Base only, E2 only. E1 not affected by reagent

As both strong base/nucleophile? 3. Strong Nuc:- & Base, rxn depends on substrate. 1° prefers SN2, 3° prefers E2. 2° prefers E2

Weak base/nucleophile 4. Weak Nuc-/Base practically only for SN1 and E1. Only reaction with 3° substrates useful for Practice with SkillBuilder 8.11

Predicting Major SN Products regiochemistry and stereochemistry

Predicting Elimination Products regiochemistry and stereochemistry

Substrate, Basicity, Nucleophilicity

Pathway and Stereochemistry   Substrate Nuc or Base? Solvent preference Regio-selectivity Stereo-selectivity SN1 3 > 2 >> 1 + H+? Weak nuc Polar protic Racemic SN2 1 > 2 >> 3 Strong nucleophile Polar aprotic Inversion E1 Weak base Zaitsev E/trans preferred E2 3 > 2 > 1 Strong base Zaitsev (smaller base) Hofmann (bulky base) Anti-periplanar

Additional Practice Problems For the substrate, give both the kinetically favored E2 product and the thermodynamically favored E2 product. Explain what conditions can be used to favor each.

Additional Practice Problems Consider both regioselestivity and stereoselectivity to predict the major product for the elimination below

Additional Practice Problems Predict the major product for the following reactions considering competing substitution and elimination pathways.

From Reaction to Synthesis Give the reagents for each of the transformation A: Br2/hv; B: t-BuOK; C: OH-/H2O; D. NaOMe; 2

From Reaction to Synthesis. B Give the reagents for each of the transformation A: Br2/hv; B: NaOEt; C. t-BuOK; D: CH3OH 2

Additional Practice Problems Predict the major product if the alcohol below were treated with concentrated sulfuric acid. Be aware of the possible rearrangements.

Additional Practice Problems For the substrate, give both the kinetically favored E2 product and the thermodynamically favored E2 product. Explain what conditions can be used to favor each.

Additional Practice Problems Since tertiary substrates react more readily than secondary or primary in both E1 and E2 mechanisms, what factor(s) usually controls which mechanism will dominate and why?

**Anti-periplanar transition state for E2 Experiments suggest that a strict 180° angle is NOT necessary for E2 mechanisms. Substituents on a and b carbon might have gauche interaction when achieving anti-coplanarity Similar angles (175–179°) are sufficient (anti-periplanar instead of anti-coplanar) Thus even when E isomer is usually more stable, the requirement for an anti-periplanar transition state can often lead to the less stable Z isomer. Thus the rxn is NOT thermodynamically driven, rather kinetically driven.

Practice: Predict E2 products Assuming both reaction proceeds E2 pathway How are these two substrates as stereoisomers, enantiomer or diastereomer?

More practice: Products from E2 Assuming an anti-periplanar transition state, predict all of the products for the following reaction. Hint: use Newman projection for better visualization. What factors most affect the product distribution?

*Practice: regioselestivity and stereoselectivity in E2 Predict the products for the eliminations below, and draw complete mechanisms Regioselectivity: Hoffman vs. Zaitsev Stereoselectivity: Anti-coplanarity

E1 Mechanism: Dehydration

E1 Mechanism: Dehydrohalogenation Practice with conceptual checkpoint 8.33

E1 Mechanism: Dehydration w/ Rearrangement The maximum number of steps in an E1 mechanism is generally four