E1 and E2 reactions

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Chapter 11: Reactions of Alkyl HalidesCoverage: 1. Substitution Reactions, SN1 and SN2 2. Elimination Reactions, E1 and E2 Problems:25-39, 43,47,54

Goals: 1. Know the detailed mechanisms of SN1, SN2, E1 and E2 2. Know what is a good nucleophile and what is a poor nucleophile 3. Understand the concept of inversion of configuration (SN2) 4. Know the kinetics associated with each reaction 5. Know Zaitzevs Rule and how it applies to the elimination reactions. 6. Know what is a good leaving group in a reaction.

There are t o undamental types o reaction mechanisms to be covered: ubstitution limination De initions ucleophile electron-rich species that attacks a nucleus hich is positively charged lectrophile electron-poor species that is attacked by a nucleophile. 2 substitution nucleophilic 2 - bimolecular reaction 2 and 2 1 and 2

u-

HH C X HBackside attack

Nu

C

H H H

+ X-

Inversion o on iguration: s the nucleophile attacks, the three groups attached to the carbon undergo inversion, that is, they lip to the opposite side o the carbon. Kinetics ate = k [ u-] [ X] 2nd order reaction

k rate constant characteristic o the reaction. The larger the k, the aster the reaction. ect o lkyl3X 3 3 2X 2 2X

ubstrate tructure alide Type methyl 10 10 20 10 30 elative ate 3 x 106 1 x 105 4 x 104 2.5 x 103 1 ~0

( ( (

3)2 3)3 3)3

-X 2-X -X

Reaction Energy Diagram or SN2 Mechanism TS

Ea E

R-X + u

R- u + X

Reaction oordinate

Why this order o reactivity? What controls the relative rate o reaction o the various substrates? ns er: Steric indrance to nucleophilic attack.

H 3CNu-

H3C H3C

C X

No Reaction

The bulky methyl groups prevent backside attack by sterically hindering the nucleophile rom attacking the electrophilic carbons. ontrast this situation to that o the 3X group. Nucleophiles Nu:neutral

+

R-X

Nu-R+ + X-

Nu:- + charged

R-X

Nu-R

+ X-

Reaction: Nu- +3Br

Nu-

3

+

+

Br-

NuSNIO h-OO23 2O3 2O

Relative Rate 125,000 125,000 100,000 25,000 16,000 8,000 500 1

pKa (conjugate acid) 7.04 9.31 0.77 16 15.7 10 4.8

-

Strongest base

onclusion: The strongest base is not the best nucleophile. In other ords, basicity does not control nucleophilicity. What controls nucleophilicity?

1. olarizability.

HH

F-

HH C H

X

F-

C H

X

Electrons tightly held by the nucleus and not easily distorted

Transition state not good bonding bet een carbon and luorine atom. igh energy

HHI-

HH C H

X

I-

C H

X

Electrons loosely held by the nucleus and easily distorted

Transition state very good bonding bet een carbon and iodine atom. Lo er energy

2. Solvation F- has a high charge density due to small size

..H O H

..F-bondH H O ..H O H

ighly solvated by ater Very stabilized Less reactive in Sn2 reaction

enerally, the larger nucleophile is the better one in a given group. alogen Nucleophiles: I- > Br- > l- > FBest Worst S- > O-

NH3 > H2O

3. harge on Nucleophile harged nucleophiles are better than neutral nucleophiles in the same group. HS- > H2S OH- > H2O NH2- > NH3

Table o Nucleophilic Strengths Strong Nucleophile Strongest ( H3 H2)2 HSI(CH3CH2)2NH CNWeakest OHCH3OModerate BrNH3 H3SCH3 ClCH3CO2Weak FH2O CH3OH

4. Bulky NucleophilesCH3CH2O> (CH3)3CO-

Not Bulky nhindered

Bulky Hindered

lkoxides Ions

Effect of Leaving roup

N

C

X

N

C

+

X

Leaving roup

The L is usually displaced ith a negative charge. L s that best stabilize the negative charge are best. Electronegative L s, hich polarize the C atom are also good. L s should be polarizable to stabilize the Transition State In general, the eaker the base, the better the L .

LO H3C S O O

Rel. Reactivity 60,000 30,000 10,000 1 ~0 ~0

pKa (conjugate acid) -6.5 -9.5 -9 3.2 15.7 35 Weakest base

IBrFOHNH2-

Strongest base

O H3C S O O

Symbolized as -OTs

tosylate groupO :N C H 3C O S O CH3

O :N C-CH3 -O S O CH3

Halogens as Leaving roups I- > Br- > Cl- > F-

Stereochemistry of SN2 Recall that the nucleophile attacks from the backside. What happens hen a single enantiomer ith a reactive chiral carbon undergoes SN2 reaction??? ns er: It undergoes inversion of configurationH3C H CH3 H Br HO C X HO C CH3 H

HOC CH3CH2

+CH2CH3

X

(S)-2-bromobutane

CH2CH3

(R)-2-butanol

SN2 reaction proceeds ith 100% inversion of configuration termed Walden inversion.

SN1 Mechanism 1- nimolecularCH3 H3C C Br CH3 H2O CH3 H3C C OH CH3 H Br

30 Halide Solvent 30 alcohol Solvolysis: Solvent acts as nucleophile and reacts ith substrate. What is the mechanism? Not SN2! Remember, a 30 substrate is unreactive in SN2 ns er: SN1CH3 H3C C Br CH3 slow CH3 H3C C+ CH3

+

Br

CH3 H3C C+ CH3 CH3 H3C C OH2+ CH3 Br

CH3

+

H2O

H3C C OH2+ CH3 CH3 H3C C OH CH3

+

H Br

Reaction Energy Diagram for SN1 TS#1 TS#2

R+ + X E NuH TS#3 R-X

R-NuH+ + XR-Nu + H-X Reaction Coordinate

First step is rate-determining (highest activation energy). Rate = k [R-X] First order reaction Rate-determining Step is nimolecular

Effect of Substrate Structure on SN1 Reactivity 30 > 20 > 10 > CH3X Most Why this order 30 substrates form stable 30 carbocations in rate-determining step. They form faster ith a lo er Energy of ctivation Least Reactive

E

10 carbocation less stable higher Ea forms slo er 30 carbocation more stable lo er Ea forms faster Reaction Coordinate

Allylic and Benzylic Substrates are very reactive in SN1 reactions. Why so?? They form resonance-stabilized carbocations.Br

+

+

Allyl bromideH2O

OH

OH2+

Br

H Br

What about benzyl bromide? Write a mechanism sho ing its reaction ith ater. CH2Br

+

H2O

?

Leaving roups: The same factors that favor SN2 leaving groups also Favor SN1 leaving groups, i.e. if a L is good for SN2, it is good for SN1. Stereochemistry of SN1CH3OH B Br H3 C (CH3)2CH OCH3 C CH2CH3

+H3 C (CH3)2CH C CH2CH3 H3 C (CH3)2CH C CH2CH3

S isomer ~50%

A

S isomerCH3OH H3C (CH3)2CH CH2CH3 C OCH3

lanar, symmetric carbocation

The carbocation is attacked both from the top and the bottom by the nucleophilic methanol, resulting in a near racemic mixture of enantiomers as products

R isomer ~50%

Reactions that proceed by the SN1 reaction often undergo rearrangements. Why? Carbocations are intermediates and may undergo 1,2 ~H or 1,2 ~CH3 shifts.Br CH3CHCHCH3 CH3 CH3CH2OH OCH2CH3 CH3CHCHCH3 CH3 OCH2CH3

+ +H Br

CH3CHCHCH3 CH3

ractice: Write a mechanism for this reaction to account for both products.

Solvents in SN1 and SN2 Reactions SN2 olar, aprotic solvents are best. Aprotic - no OH or NH group present These solvents cannot H-bond to nucleophile and therefore the nucleophile is more reactive.O CH3CCH3 CH3C N O CH3SCH3

Acetone SN1

Acetonitrile

Dimethylsulfoxide (DMSO)

olar, protic solvents are best. rotic possess OH or NH group These solvents promote formation of ions through H-bonding.H2O CH3OH CH3CH2OH

Water

Methanol

Ethanol

Summary of SN1 and SN2 Topic Kinetics Nucleophile SN2 Rate=k[R-X][Nu] Strong Nu required SN1 Rate=k[RX] Weak Nu required, usually solvent olar, protic Racemization Yes

Substrate

olar, aprotic

Stereochemistry 100% inversion Rearrangements No

E2 Elimination Requirements: Alkyl substrate ith a good leaving group possessing -hydrogen

H C CE XThe -hydrogen is bonded to the -carbon, hich is bonded to the E-carbon hich is bonded to the leaving group X! A strong base is also required. Any of these ill do: OH- < CH3O- < CH3CH2O- < (CH3)3CO- < NH2Weakest Strongest

Mechanism: The E2 mechanism is a one-step mechanism ith bond-breaking and Bond-making taking place at the same time; termed a concerted mechansim. In Addition, the H and the leaving group X must be anti-coplanar for rapid reaction.

OHH X

+

H2O

+

X

Notice that H and X are anti to each other and the four atoms, H-C-C-X, are coplanar in the reactant. This situation stabilizes the transition state leading to the alkene.

CH3

O: .. H .. H R C C R H

Overlap develops in the T.S. if the anti-coplanar relationship is maintained. The overlap stabilizes the T.S. and the reaction takes place faster.

.. :Br: ..

CH3

.. O H .. H R . C . C R H .. :Br: ..

Kinetics Rate = k [B-][R-X] 2nd Order Reaction

E2 Ball and Stick Movie

Substrate Reactivity 30 > 20 > 10 Why this order of reactivity? 30 substrates yield more stable alkenes and therefore react faster. 10 substrates yield unstable alkenes and react more slo ly. Recall: Alkene Stability

R R

R R

H R

R R

H R

R H

H H

R H

H H

H H

tetrasubstituted > trisubstituted > disubstituted > monosubstituted > unsubstituted

OHH CH3 H H X CH3 H H CH3 CH3

+

H 2O

+

X

30 substrate

Disubstituted Alkene - more stable

OHH H H3C H X