Dehydrohalogenation of Alkyl Halides E2 and E1 Reactions in Detail

Dehydrohalogenation of Alkyl Halides E2 and E1 Reactions in Detail

b-elimination Reactions Overview dehydration of alcohols: X = H; Y = OH dehydrohalogenation of alkyl halides: X = H; Y = Br, etc. X C b Ca Y C C + X Y

b-elimination Reactions Overview dehydration of alcohols: acid-catalyzed dehydrohalogenation of alkyl halides: consumes base X C b Ca Y C C + X Y

Dehydrohalogenation is a useful method for the preparation of alkenes Cl NaOCH 2 CH 3 ethanol, 55 C (100 %) likewise, NaOCH 3 in methanol, or KOH in ethanol

Dehydrohalogenation When the alkyl halide is primary, potassium tert-butoxide in dimethyl sulfoxide is the base/solvent system that is normally used. CH 3 (CH 2 ) 15 CH 2 CH 2 Cl KOC(CH 3 ) 3 dimethyl sulfoxide CH 3 (CH 2 ) 15 CH CH 2 (86%)

Regioselectivity Br KOCH 2 CH 3 ethanol, 70 C + 29 % 71 % follows Zaitsev's rule More highly substituted double bond predominates = More Stable

Zaitsev s Rule The more substituted alkene is obtained when a proton is removed from the b-carbon that is bonded to the fewest hydrogens

Conjugated alkenes are preferred!

Steric hindrance effects the product distribution

Stereoselectivity KOCH 2 CH 3 Br ethanol + (23%) (77%) more stable configuration of double bond predominates

Stereoselectivity Br KOCH 2 CH 3 ethanol + (85%) (15%) more stable configuration of double bond predominates

Mechanism of the Dehydrohalogenation of Alkyl Halides: The E2 Mechanism

Facts Dehydrohalogenation of alkyl halides exhibits second-order kinetics first order in alkyl halide first order in base rate = k[alkyl halide][base] implies that rate-determining step involves both base and alkyl halide; i.e., it is bimolecular

Facts Rate of elimination depends on halogen weaker C X bond; faster rate rate: RI > RBr > RCl > RF implies that carbon-halogen bond breaks in the rate-determining step

The E2 Mechanism concerted (one-step) bimolecular process single transition state C H bond breaks p component of double bond forms C X bond breaks

The E2 Mechanism QuickTime and a Graphics decompressor are needed to see this picture.

The E2 Mechanism R.. O.. : H C C : X.. : Reactants

The E2 Mechanism R.. O.. : H C C : X.. : Reactants

The E2 Mechanism d.. R O.. Transition state H C C : d X :..

The E2 Mechanism R.. O.. H C C : X.. :.. Products

Anti Elimination in E2 Reactions Stereoelectronic Effects

Stereochemistry of the E2 Reaction Remember: The bonds to the eliminated groups (H and X) must be in the same plane and anti to each other H X More stable conformation than syn-eclipsed

The best orbital overlap of the interacting orbitals is achieved through back side attack of the leaving group X as in an S N 2 displacement.

Regioselectivity

Configuration of the Reactant

Elimination from Cyclic Compounds H H Br Br Configuration must be trans, which is (anti).

Stereoelectronic effect Br (CH 3 ) 3 C KOC(CH 3 ) 3 (CH 3 ) 3 COH cis-1-bromo-4-tertbutylcyclohexane (CH 3 ) 3 C

Stereoelectronic effect trans-1-bromo-4-tertbutylcyclohexane (CH 3 ) 3 C (CH 3 ) 3 C Br KOC(CH 3 ) 3 (CH 3 ) 3 COH

cis Br Stereoelectronic effect (CH 3 ) 3 C (CH 3 ) 3 C Rate constant for dehydrohalogenation of cis is 500 times greater than that of trans trans Br KOC(CH 3 ) 3 (CH 3 ) 3 COH (CH 3 ) 3 C KOC(CH 3 ) 3 (CH 3 ) 3 COH

Stereoelectronic effect cis Br (CH 3 ) 3 C KOC(CH 3 ) 3 (CH 3 ) 3 COH H H (CH 3 ) 3 C H that is removed by base must be anti periplanar to Br Two anti periplanar H atoms in cis stereoisomer

Stereoelectronic effect trans (CH 3 ) 3 C H H Br KOC(CH 3 ) 3 (CH 3 ) 3 COH H H (CH 3 ) 3 C H that is removed by base must be anti periplanar to Br No anti periplanar H atoms in trans stereoisomer; all vicinal H atoms are gauche to Br

Stereoelectronic effect cis more reactive trans less reactive

Stereoelectronic effect An effect on reactivity that has its origin in the spatial arrangement of orbitals or bonds is called a stereoelectronic effect. The preference for an anti periplanar arrangement of H and Br in the transition state for E2 dehydrohalogenation is an example of a stereoelectronic effect.

E2 in a cyclohexane ring

E2 in a cyclohexane ring H 3 C CH 3 Cis or trans? Axial or equatorial? H 3 C CH 3 H 3 C CH 3 Cl a,e e,a + CH 3 CH 2 O- + CH 3 neomenthyl H 3 C CH 3 Cl + e,e a,a CH 3 CH 2 O- CH 3 CH 3 80% 20% H 3 C CH 3 CH 3 menthyl CH 3 100% Can you predict explain the products?

Cyclohexane Stereochemistry Revisited http://www.csir.co.za/biochemtek/newsletter/aug/menthol.html l-menthol How many stereoisomers are possible for menthol? http://www.library.ucsf.edu/tobacco/batco/html/9000/9036/

A Different Mechanism for Alkyl Halide Elimination: The E1 Mechanism

Example CH 3 CH 3 C CH 2 CH 3 Br Ethanol, heat CH 3 H 3 C H H 2 C C + C C CH 2 CH 3 H 3 C (25%) (75%) CH 3

The E1 Mechanism 1. Alkyl halides can undergo elimination in absence of base. 2. Carbocation is intermediate 3. Rate-determining step is unimolecular ionization of alkyl halide.

Step 1 CH 3 CH 3 C CH 2 CH 3 : Br:.. slow, unimolecular CH 3 CH 3 C + CH2 CH 3.. : Br:..

Step 2 CH 3 CH 3 C + CH2 CH 3 H + CH 2 + C CH 3 CH 3 C CH2 CH 3 CH 3 CHCH 3 Which alkene is more stable and why?

Reaction coordinate diagram for the E1 reaction of 2-chloro-2-methylbutane

Must consider possible carbocation rearrangement

Stereochemistry of the E1 Reaction

E1 Elimination from Cyclic Compounds E1 mechanism involves both syn and anti elimination

Summary & Applications (Synthesis) S N 1 / E1 vs. S N 2 / E2

E2 and E1 Reactions

Substitution vs. Elimination Alkyl halides can undergo S N 2, S N 1, E2 and E1 Reactions 1) Which reaction conditions favor S N 2/E2 or S N 1/E1? S N 2/E2 reactions are favored by a high concentration of nucleophile/strong base S N 1/E1 reactions are favored by a poor nucleophile/weak base 2) What will be the relative distribution of substitution product vs. elimination product?

Consider the Substrate

NOTE: a bulky base encourages elimination over substitution

Returning to Sn2 and E2: Considering the differences Br + CH 3 O- O + CH 3 Br OCH 3 Can you predict explain the products?

Substitution and Elimination Reactions in Synthesis

A hindered alkyl halide should be used if you want to synthesize an alkene

Which reaction produces an ether? CH 3 CH 2 Br + CH 3 CH 3 CO- CH 3 CH 3 CH 2 O- + CH 3 CH 3 CBr CH 3

Consecutive E2 Elimination Reactions: Alkynes

Intermolecular vs. Intramolecular Reactions A low concentration of reactant favors an intramolecular reaction The intramolecular reaction is also favored when a fiveor six-membered ring is formed

Three- and four-membered rings are less easily formed Three-membered ring compounds are formed more easily than four-membered ring compounds The likelihood of the reacting groups finding each other decreases sharply when the groups are in compounds that would form seven-membered and larger rings.

Designing a synthesis?

CH 3 CH? 3 Br Br