NC: NC Common Leaving Groups RH2C N N CH2R N N Leaving group Class of compound Leaving group

E

Diazonium salt x RH2C N N N2 c

e

l

O l

e

n

Nonaf late - t RH2C S C4F9 C4F9SO3 l

e

a

O v

i

O n - g RH C S CH Mesylate CH3SO3 g

2 3 r

o

u

O p

s - RH2C I Iodides I - RH2C Br Bromides Br

H G

o

Protonated alcohols H2O o

O d RH2C

l

H e

a

- v RH C Cl Chlorides i 2 Cl n

g

g

H r

o

Protonated ethers CH3OH u RH C O p 2 s CH3 CH3 N CH Quaternary Ammonium Salts N(CH3)3 RH2C 3 CH3 Poor Leaving Groups

V

- e RH2C F Fluorides F r

y

p

O o

o Acetates Acetate anion, CH CO - r C 3 2 l RH2C e O CH3 a

v

i

n

- g RH2C OH Alcohols Hydroxide, HO

g

- r Hydrides Hydride, H o RH2C H u - p Amide, NH2 s RH2C NH2 Amines - RH2C CH3 Alkanes CH3 Elimination Reactions

Whenever substitution reactions are possible, we must also consider whether or not elimination reactions might occur under the same reaction conditions.

In elimination reactions, a “neutral” molecule is „eliminated‟ from the substrate to form a π bond. The π bond is formed between the two carbon atoms that bore the two parts of the eliminated molecule: Elimination Reactions – The E1 Mechanism

The substrates that favour E1 reactions are the same that favour SN1 reactions: •A substrate bearing a good leaving group attached to a tetrahedral carbon atom. •A substrate that can form a relatively stable carbocation.

The difference between E1 and SN1 reactions is in the type species which reacts with the substrate. E1 reactions are favoured with: •Bases that are poor nucleophiles (good nucleophiles will favour substitution reactions).

•Remember: Substitution and Elimination reactions are always competing (whenever possible). E1 Reactions – Stereochemistry and Regiochemistry

A different elimination product is possible for every unique type of H beta (β) to the carbocation carbon.

OH γ H2SO4 α δ β β 70% 30%

H

H H Elimination Reactions - Kinetic vs. Thermodynamic Products

1-pentene is the kinetic product (meaning it is easier to form) and 2-pentene is the thermodynamic product (meaning it is more stable).

Elimination reactions that occur under thermodynamic control are said to form the Saytzeff products. Alkene Stability C atoms with more s character tend to form stronger bonds with other carbons.

R R R H R H R H R H > > = > R R R R R H H R H H

R H R R > > H R H H trans > cis Conjugate > skipped

>

Endocyclic > exocyclic Elimination Reactions - Kinetic vs. Thermodynamic Products

Alkene stability is determined by heats of hydrogenation. E1 Reactions of Alkyl Halides

H C H 3 H2C H2O, EtOH H3C C Br H3C C Br slow H3C CH3

H H2C H2O H3C C H2O CH3 kelim ksub

CH3 CH2 CH3 H3C C H C C C + H3O 3 H3C H O CH3 CH3 H O CH3 H 37% E1 product 64% SN1 product If you want SN1, what nucleophile is best?

H C 3 H3C

H3C C Br ? H C C 3 OCH3 H C 3 H3C The E2 Reaction

H C 3 H3C H C C HO 3 Br C + H2O + Br H3C CH2 H3C The mechanism:

H C HO H 3 O H CH3 H C C 2 Br H H2C C H C Br 3 CH3 Elimination Reactions – E2 Reaction

E2 reactions are favoured for: •Substrates bearing a good leaving group attached to a tetrahedral carbon atom. •Strong non-nucleophilic bases .

The Saytzeff product is generally the major product: DBU 4

+ Br 1

Propose a mechanism to account for the two products formed: E2 Reactions – Stereochemistry and Regiochemistry H O H O H H CH3 CH H 3 CH3 C C C C H CH3 H H Br Br

The β-proton pulled off by the base must be anti-periplanar to the leaving group. This reaction is referred to as a "beta-elimination".

Why? Stereochemical Consequences

H H H C H E2: Ph H 3 Base H C C C 3 C C = C C H3C Ph Ph Ph Br Ph Ph

Ph H H C Ph H Ph 3 Base H C C C 3 C C = C C H3C Ph H Ph Br Ph H

E1: H H H Ph H C C C C Ph H3C H3C Ph Br Ph In the E2 reactions of cyclohexyl substrates, the leaving group must be... trans diaxial

O H H H H H H H Br H H H H Br H H H

CH3 H CH3 CH3 CH3 H Br H Br

CH3 CH3 H CH3 H H Br H Br E2 Reactions – Elimination of Primary Alcohols

It is possible to convert 1°alcohols to alkenes:

SO3H

O H

H H H H O H H H H2SO4 H C C C C R C C R R H H H OH H OH2

What kind of problems could we expect with the above reaction? E2 Reactions – E2 vs. SN2

Because many good nucleophiles are also good bases, SN2 often competes with E2 for those substrates that are good for SN2

H3CH2C O CH3CH2Br H3CH2C O CH2CH3 99%

H Br H CH C O 3 2 H C OCH2CH3 H H3C CH3 C 79% H3C C CH3 H3C 21% CH2

H3C Br CH3 H3CH2C O C 100% H3C C CH3 H3C CH2 E2 Reactions – E2 vs. SN2

To promote E2 over SN2 we want to use strong bases that are non-nucleophilic.

Br H3C(H2C)15 NaOCH3

H3C O K C H C OCH3 3 H C(H C) CH3 3 2 15 96%

Ot-Bu H3C(H2C)15 12% H3C(H2C)15 1%

H3C(H2C)15 85% E2 Reactions – Preparation of Alkynes

Elimination reactions can be used to prepare alkynes:

Br Ph Ph Ph H Br Ph Br2 H2N Br H H H Ph Ph H

H2N

Ph Ph

H H2N

Br E1 vs. E2 vs. SN1 vs. SN2 - Summary

•As a general rule, elimination reactions can always compete with substitution reactions. We can, however, alter the reaction conditions to favour one process over another.

•To favour E1 over SN1 for alcohols, use an acid with a non-nucleophilic conjugate base (H2SO4, H3PO4). To favour SN1 over E1, use a good nucleophile.

•To favour E2 over SN2, use a strong, bulky non-nucleophilic base. To favour SN2 over E2, use good nucleophiles that are relatively weak bases.

•It is important to keep in mind that although you might choose reaction conditions that will favour one reaction over another, more often than not you will still see traces of the competing reaction.

•Before considering the possibility of an elimination reaction, make sure there are β-hydrogen atoms available to eliminate! SN1, SN2, E1 and E2 - Summary

SN1 SN2 E1 E2

Mechanism 2 or more steps 1 step bimolecular 2 or more steps 1 step bimolecular process involving carbocation process involving intermediate carbocation intermediate Kinetics First order in Second order, first in First order in Second order, first in substrate substrate substrate and substrate and base nucleophile

Substrate Those substrates that Those substrates that Those substrates Requires strong base and any Dependence form stable are uncluttered at the that form stable substrate with beta proton. carbocations. reaction site: 1°, 2°. carbocations. 3°, allylic, benzylic Good nucleophiles. 3°, allylic, benzylic Stereochem Racemization. Stereospecific Usually mixtures. Stereospecific involving inversion. antiperiplanar relationship of beta-proton and leaving group. Importance of Not involved in RDS, Reactivity of If a good, non-basic Strong, non-nucleophilic bases Base/nucleophile but less basic form of nucleophile is nucleophile is (KOtBu, LDA) best to limit SN2. nucleophile will limit important since it is present (halides, E1. involved in RDS. bisulfate) then SN1. Importance of Involved in RDS so is Involved in RDS so is Involved in RDS so Involved in RDS so is important. Leaving group important. important. is important. Competes with.. E1 and E2 E2 when basic SN1 SN2 nucleohiles employed.

Solvent Polar protic best Polar aprotic best Polar protic best Varies. Weak base/ Weak base/ Moderate/strong Strong base/ poor Nu good Nu base/good Nu poor Nu H O, Br-, RS-, NC-, t-Bu—O- 2 - ROH I , RNH2, NH3 - H2S N3 LDA - - HO , RO N

Methyl, CH3X NR SN2 SN2 SN2

1°, RCH2X NR SN2 SN2 E2

2°, RCHXR SN1 E1 SN2 SN2 E2 E2

3°, R3CX SN1 E1 SN1 E1 E2 E2

1° benzylic SN1 SN2 SN2 SN2

2° benzylic SN1 E1 SN2 SN2 E2 E2

3° benzylic SN1 E1 SN1 E1 E2 E2

1° allylic SN1 SN2 SN2 SN2

2° allylic SN1 E1 SN2 SN2 E2 E2

3° allylic SN1 E1 SN1 E1 E2 E2

Aryl, PhX NR NR NR E2 Alkenyl, NR NR NR E2 H2C=CHX