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. C C + X Y X Y a b 2

b-Elimination Reactions Overview dehydration of alcohols: acid-catalyzed dehydrohalogenation of alkyl halides: consumes base C C + X Y X Y a b 2

is a useful method for the preparation of alkenes Dehydrohalogenation is a useful method for the preparation of alkenes Cl NaOCH2CH3 ethanol, 55°C (100 %) likewise, NaOCH3 in methanol, or KOH in ethanol 4

Dehydrohalogenation When the alkyl halide is primary, potassium tert-butoxide in dimethyl sulfoxide is the base/solvent system that is normally used. KOC(CH3)3 CH3(CH2)15CH2CH2Cl dimethyl sulfoxide CH2 CH3(CH2)15CH (86%) 5

More highly substituted double bond predominates = More Stable Regioselectivity Br KOCH2CH3 ethanol, 70°C + 29 % 71 % follows Zaitsev's rule More highly substituted double bond predominates = More Stable 10

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

more stable configuration of double bond predominates Stereoselectivity KOCH2CH3 ethanol Br + (23%) (77%) more stable configuration of double bond predominates 11

more stable configuration of double bond predominates Stereoselectivity Br KOCH2CH3 ethanol + (85%) (15%) more stable configuration of double bond predominates 11

Mechanism of the Dehydrohalogenation of Alkyl Halides: The E2 Mechanism 13

Dehydrohalogenation of alkyl halides exhibits second-order kinetics 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 14

Rate of elimination depends on halogen 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 14

concerted (one-step) bimolecular process single transition state 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 16

The E2 Mechanism Figure: 07-07-13UN Caption: Second-order elimination is a reliable synthetic reaction, especially if the alkyl halide is a poor SN2 substrate. E2 dehydrohalogenation takes place in one step, in which a strong base abstracts a proton from one carbon atom as the leaving group leaves the adjacent carbon.

The E2 Mechanism – R .. : O C C H X .. : Reactants 17

The E2 Mechanism – R .. : O C C H X .. : Reactants 17

The E2 Mechanism d– .. R O H .. Transition state C C d– X .. : 17

The E2 Mechanism .. R O H .. C C – X .. : Products 17

Anti Elimination in E2 Reactions Stereoelectronic Effects 20

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 SN2 displacement.

Regioselectivity

Configuration of the Reactant

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

Figure: 07-08 Caption: Figure 7-8 E2 elimination of bromocyclohexane requires that the proton and the leaving group be trans and both be axial.

Stereoelectronic effect (CH3)3C Br KOC(CH3)3 (CH3)3COH (CH3)3C cis-1-Bromo-4-tert- butylcyclohexane 21

Stereoelectronic effect (CH3)3C trans-1-Bromo-4-tert- butylcyclohexane (CH3)3C Br KOC(CH3)3 (CH3)3COH 21

Stereoelectronic effect (CH3)3C Br cis KOC(CH3)3 (CH3)3COH (CH3)3C Rate constant for dehydrohalogenation of cis is 500 times greater than that of trans (CH3)3C Br KOC(CH3)3 (CH3)3COH trans 21

Stereoelectronic effect (CH3)3C Br cis KOC(CH3)3 (CH3)3COH H (CH3)3C H H that is removed by base must be anti periplanar to Br Two anti periplanar H atoms in cis stereoisomer 21

Stereoelectronic effect trans H (CH3)3C Br KOC(CH3)3 (CH3)3COH (CH3)3C 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 21

Stereoelectronic effect cis more reactive trans less reactive 22

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. 22

E2 in a cyclohexane ring 21

Can you predict the products? Can you explain the products? E2 in a cyclohexane ring Cis or trans? Axial or equatorial? a,e  e,a e,e  a,a Can you predict the products? Can you explain the products? 21

Cyclohexane Stereochemistry Revisited http://www.csir.co.za/biochemtek/newsletter/aug/menthol.html How many stereoisomers are possible for menthol? l-menthol http://www.library.ucsf.edu/tobacco/batco/html/9000/9036/ 21

A Different Mechanism for Alkyl Halide Elimination: The E1 Mechanism 23

Example CH3 C CH3 CH2CH3 Br Ethanol, heat CH2CH3 CH3 C H2C H3C CH3 C H + (25%) (75%) 25

1. Alkyl halides can undergo elimination in absence of base. 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. 24

Step 1 CH3 C CH2CH3 Br : .. slow, unimolecular C + CH2CH3 CH3 – : Br 25

Which alkene is more stable and why? Step 2 C CH2CH3 CH3 + – H+ CH3 CH2 + C C CH3 CHCH3 CH3 CH2CH3 Which alkene is more stable and why? 27

Figure: 07-05 Caption: Figure 7-5 trans-2-Butene is more stable than 1-butene by 2.7 kcal/mol (11 kJ/mol).

Figure: 07-06 Caption: Figure 7-6 The isomer with the more highly substituted double bond has a larger angular separation between the bulky alkyl groups.

Figure: 07-07 Caption: Figure 7-7 Relative energies of typical p bonds compared with ethylene. (The numbers are approximate.)

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) SN1 / E1 vs. SN2 / E2 23

E2 and E1 Reactions

Substitution vs. Elimination Alkyl halides can undergo SN2, SN1, E2 and E1 Reactions 1) Which reaction conditions favor SN2/E2 or SN1/E1? SN2/E2 reactions are favored by a high concentration of nucleophile/strong base SN1/E1 reactions are favored by a poor nucleophile/weak base 2) What will be the relative distribution of substitution product vs. elimination product?

Consider SN1/E1 vs. SN2/E2 Consider the Substrate

NOTE: a bulky base encourages elimination over substitution

Returning to Sn2 and E2: Considering the differences Can you explain the products? Can you predict the products? 21

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?

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 five- or 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 …