Chapter 8 Part 6

8/10/2019 Chapter 8 Part 6

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8.12

Nucleophilic Substitution of Alkyl Sulfonates

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Leaving Groups

We have seen numerous examples of

nucleophilic substitution in which X in RX is a

halogen.

Halogen is not the only possible leaving

group, though.


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Other RX Compounds

ROSCH3

O

O

ROS

O

O

CH3

Alkyl

methanesulfonate

(mesylate)

Alkyl

p-toluenesulfonate

(tosylate)

undergo same kinds of reactions as alkyl

halides


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Preparation

(abbreviated as ROTs)

ROH + CH3 SO2Clpyridine

ROS

O

O

CH3

Tosylates are prepared by the reaction of

alcohols withp-toluenesulfonyl chloride

(usually in the presence of pyridine).


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Tosylates Undergo Typical Nucleophilic

Substitution Reactions

H

CH2OTs

KCN

ethanol-

water

H

CH2CN

(86%)


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The best leaving groups are weakly basic.


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Table 8.8 Approximate Relative Leaving Group

Abilities

Leaving Relative Conjugate acid pKaof

Group Rate of leaving group conj. acid

F 10-5 HF 3.5

Cl 1 HCl -7

Br 10 HBr -9

I 102 HI -10

H2O 101 H3O+ -1.7TsO 105 TsOH -2.8

CF3SO2O 108 CF3SO2OH -6


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Leaving Relative Conjugate acid pKaof

Group Rate of leaving group conj. acid

F 10-5 HF 3.5

Cl 1 HCl -7

Br 10 HBr -9

I 102 HI -10

H2O 101 H3O+ -1.7TsO 105 TsOH -2.8

CF3SO2O 108 CF3SO2OH -6

Sulfonate esters are extremely good leaving groups; sulfonate ions

are very weak bases.

Table 8.8 Approximate Relative Leaving Group

Abilities


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Tosylates can be Converted to Alkyl

Halides

NaBr

DMSO

(82%)

OTs

CH3CHCH2CH3

Br

CH3CHCH2CH3

Tosylate is a better leaving group than bromide.


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Tosylates Allow Control of Stereochemistry

Preparation of tosylate does not affect any of thebonds to the chirality center, so configuration and

optical purity of tosylate is the same as the

alcohol from which it was formed.

C

H

H3C

OH

CH3(CH2)5 TsCl

pyridine

C

H

H3C

OTs

CH3(CH2)5

C-O bond is not broken


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Having a tosylate of known optical purity and

absolute configuration then allows the

preparation of other compounds of known

configuration by SN2 processes.

Nu

SN2

C

H

H3C

OTs

CH3(CH2)5

C

H

CH3

(CH2)5CH3

Nu

Tosylates Allow Control of Stereochemistry


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Tosylates also undergo Elimination

NaOCH3

CH3OH

heatOTs

CH3CHCH2CH3

CH2=CHCH2CH3

CH3CH=CHCH3

E and Z

+

The more substituted E/Trans isomer is the major

product.


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Secondary Alcohols React with Hydrogen Halides

Predominantly with Net Inversion of Configuration

C

H

H3C

OH

CH3(CH2)5

C

H

H3C

Br

CH3(CH2)5

C

H

CH3

(CH2)5CH3

Br

HBr

87%

13%


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Secondary Alcohols React with Hydrogen

Halides with Net Inversion of Configuration

C

H

H3C

OH

CH3(CH2)5

C

H

H3C

Br

CH3(CH2)5

C

H

CH3

(CH2)5CH3

Br

HBr

87%

13%

Most reasonable mechanism

is SN1 with front side of carbocation

shielded by leaving group.


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Rearrangements can Occur in the Reaction of

Alcohols with Hydrogen Halides

OH

Br

Br

+

93% 7%

HBr


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Rearrangements can Occur in the Reaction of

Alcohols with Hydrogen Halides

OH

Br

Br

+

+

+

93%

7%

Br Br

HBr


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Substitution vs Elimination

Summary Ch 4-8


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Alcohols

R-OH + HCl substitution (Cl-not strong enough base to allow elimination)

R-OH + H2SO4 Elimination

1 R-OH SN2or E2

2/3R-OH SN1or E1


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Alkyl Halides

SN2:

most substitution reactions are SN2(1-RX)

Inversion of configuration Attack from opposite side of the leaving group

Stereospecific rxn

As crowding increase, rate of SN2decrease

(steric effect) Rate increase in polar aprotic solvents (no OH)

2-RX + strong nucleophile


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Alkyl Halides

SN1: for 3-RX

Solvolysis rxns

Carbocation formation; possible rearrangement Not stereospecific (major product via inversion of

configuration; minor product via retention of

configuration, inductive effect)

Racemization in optically active alkyl halides

Rate increase in polar protic solvents

2-RX + weak nucleophile (solvolysis)


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Reactions

2-RX + RO- E2 SN2

2-RX + weak base Substitution SN1/2 E22-RX + solvolysis Substitution SN1/2 E1

1-RX + RO-(ethoxide) SN2 E2

1-RX + RO-(tert-butoxide; bulky) E2 SN2

1-RX + weak base SN2 E2

3-RX + RO-(strong base or weak base) E2 SN1

Major Minor


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Reactions

1-RX substitution easier SN2

3-RX elimination easier E1

Elimination for R-X

1,2,3-RX + base E2

2,3

-RX + no base E1


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Alkyl Halides/Alcohols

In the presence of a halogen, will always

undergo substitution and never elimination as

halogens are not strong enough bases.

I and Br are good nucleophiles but weak bases.

Cl is a decent nucleophile but also a weak base.

F is a weak nucleophile and a weak base.


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Recommended Questions

20, 22-25, 31-34, 36-38, 40-45, 47, 48.

Interesting Descriptive Passage,MCAT Style


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Zaitsev Vs Hofmann

When a small, unhindered base - such as

sodium ethoxide - is used for an E2 elimination,

the Zaitsev product is typically favored over the

least substituted alkene, known as the Hofmannproduct.
http://localhost/var/www/apps/conversion/tmp/scratch_8//upload.wikimedia.org/wikipedia/commons/1/1b/Example_of_Zaitsev%27s_Rule.png


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Zaitsev Vs Hofmann

A bulky base such as potassium tert-butoxide

cannot abstract a proton from the more

substituted carbon, instead a less hindered beta

proton is abstracted the Hofmann product isobtained as the major product.
http://localhost/var/www/apps/conversion/tmp/scratch_8//upload.wikimedia.org/wikipedia/commons/4/48/Formation_of_the_Hofmann_Product.png


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Anticoplanar hydrogens are abstracted 500 times

faster than non-anticoplanar hydrogens.

Zaitsevs product is formed 2-3 times faster than

non-Zaitsev product.

Cl

Zaitsev product;but no anticoplmnar hydrogen

Hofmann productUsing bulky base

Anti-coplanarHydrogen

Major propduct usingsodium ethoxide


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Leaving groups

R-OH vs R-OTS

OH requires acid in order to become a

leaving group however OTS doesnt. NaCN will not replace the OH but it can

replace OTS. (NaCN doesnt protonate the

OH)

Halogens in alkyl halides are better leaving

groups than OH of R-OH because the halogen

doesnt require protonation.


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20-RX SN

For secondary alkyl halide, substitution may

occur via SN1OR SN2such as when CN-is

the nucleophile.

However SN2(DMF) is faster than SN1(Ethanol)

because DMF is a weaker base and allows

less elimination in addition no carbocation isformed in SN2 and hence intermediate is

formed faster.


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Q 21 7thEd.: Products

b) O2N

Cl

O

ONa

Acetic acid

h)

H3CO

H3CO

OCH3

CH2CH2CH2CH2OH

1. TsCl, pyridine

2. LiI, acetone

O2N

O

O

1. R-CH2-OTS

2. R-CH2-I

SN2


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Q 25 7thEd.: Which react ion

occurs faster and why?

b) 1-Chloro-2-methylbutane or 1-chloropentane

with NaCN in DMSO

e) Solvolysis of isobutyl bromide or sec-butyl

bromide in aqueous fromic acid


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Q 25 7thEd.: Wh ich react ion

occurs faster and why?

b) 1-Chloro-2-methylbutane or 1-chloropentane

with NaCN in DMSO

SN2: less sterically hindered

e) Solvolysis of isobutyl bromide or sec-butyl

bromidein aqueous fromic acid

SN1: secondary more reactive than primary

Chapter 8 Part 6

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