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8.11 Substitution And Elimination As Competing Reactions. –. +. :. H. Y. X. C. C. –. :. Y. C. C. –. +. :. X. C. C. We have seen that alkyl halides can react with Lewis bases in two different ways. They can undergo nucleophilic substitution or elimination. b -elimination. +.

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8.11 Substitution And Elimination As Competing Reactions

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Dr wolfs chm 201 202

8.11Substitution And Elimination As Competing Reactions


Dr wolfs chm 201 202

+

:

H

Y

X

C

C

:

Y

C

C

+

:

X

C

C

We have seen that alkyl halides can react with Lewisbases in two different ways. They can undergonucleophilic substitution or elimination.

b-elimination

+

H

+

H

X

Y

nucleophilic substitution


Dr wolfs chm 201 202

+

:

H

Y

X

C

C

:

Y

C

C

+

:

X

C

C

How can we tell which reaction pathway is followedfor a particular alkyl halide?

b-elimination

+

H

+

H

X

Y

nucleophilic substitution


Dr wolfs chm 201 202

A systematic approach is to choose as a referencepoint the reaction followed by a typical alkyl halide(secondary) with a typical Lewis base (an alkoxideion).

The major reaction of a secondary alkyl halidewith an alkoxide ion is

elimination by the E2 mechanism.


Dr wolfs chm 201 202

CH3CHCH3

Br

CH3CHCH3

OCH2CH3

Example

NaOCH2CH3

ethanol, 55°C

+

CH3CH=CH2

(87%)

(13%)


Dr wolfs chm 201 202

Figure 8.11

E2

..

O:

CH3CH2

..

Br


Dr wolfs chm 201 202

..

O:

CH3CH2

..

Figure 8.11

SN2

Br


Dr wolfs chm 201 202

Given that the major reaction of a secondaryalkyl halide with an alkoxide ion is elimination by the E2 mechanism, we can expect the proportion of substitution to increase with:

1)decreased crowding at the carbon thatbears the leaving group


Dr wolfs chm 201 202

Decreased crowding at carbon that bears the leaving group increases substitution relative to elimination.

primary alkyl halide

CH3CH2CH2Br

NaOCH2CH3

ethanol, 55°C

+

CH3CH2CH2OCH2CH3

CH3CH=CH2

(9%)

(91%)


Dr wolfs chm 201 202

But a crowded alkoxide base can favor elimination even with a primary alkyl halide.

primary alkyl halide + bulky base

CH3(CH2)15CH2CH2Br

KOC(CH3)3

tert-butyl alcohol, 40°C

CH3(CH2)15CH2CH2OC(CH3)3

+

CH3(CH2)15CH=CH2

(13%)

(87%)


Dr wolfs chm 201 202

Given that the major reaction of a secondaryalkyl halide with an alkoxide ion is elimination by the E2 mechanism, we can expect the proportion of substitution to increase with:

1)decreased crowding at the carbon thatbears the leaving group

2)decreased basicity of nucleophile


Dr wolfs chm 201 202

CH3CH(CH2)5CH3

Cl

CH3CH(CH2)5CH3

CN

Weakly basic nucleophile increases substitution relative to elimination

secondary alkyl halide + weakly basic nucleophile

KCN

pKa (HCN) = 9.1

SN2

DMSO

(70%)


Dr wolfs chm 201 202

I

N3

Weakly basic nucleophile increases substitution relative to elimination

secondary alkyl halide + weakly basic nucleophile

pKa (HN3) = 4.6

NaN3

SN2

(even weaker base)

(75%)


Dr wolfs chm 201 202

Tertiary alkyl halides are so sterically hinderedthat elimination is the major reaction with allanionic nucleophiles. Only in solvolysis reactionsdoes substitution predominate over eliminationwith tertiary alkyl halides.


Dr wolfs chm 201 202

(CH3)2CCH2CH3

Br

CH3

CH3

CH3

CH3CCH2CH3

CH3C=CHCH3

CH2=CCH2CH3

OCH2CH3

ethanol, 25°C

36%

64%

Example

+

+

2M sodium ethoxide in ethanol, 25°C

1%

99%


Dr wolfs chm 201 202

Under 2nd order conditions…..

STRONG base/nucleophile eg. -OH, -OR

ELIMINATION favored with 30 , 20,

(and 10 with bulky base eg. -OtBu)

SUBSTITUTION favored with 10 (aprotic solvent helps)

Mechanism SummarySN1 and SN2 and E1 and E2

With WEAK base but good nucleophile e.g. -CN, -N3

Or Under 1st order conditions…..

WEAK base/nucleophile (solvolysis) e.g. H2O, ROH,

SUBSTITUTION favored (increased solvent polarity helps)


8 12 nucleophilic substitution of alkyl sulfonates

8.12Nucleophilic Substitution of Alkyl Sulfonates


Leaving groups

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


Other rx compounds

O

O

O

CH3

ROSCH3

HOSOH

ROS

O

O

O

Other RX compounds

  • undergo same kinds of reactions as alkyl halides

Alkylp-toluenesulfonate(tosylate)

Alkylmethanesulfonate(mesylate)

Sulfuricacid


Preparation

+

SO2Cl

CH3

ROH

O

CH3

ROS

O

Preparation

Tosylates are prepared by the reaction of alcohols with p-toluenesulfonyl chloride(usually in the presence of pyridine)

  • (abbreviated as ROTs)

pyridine


Tosylates undergo typical nucleophilic substitution reactions

H

H

CH2OTs

CH2CN

Tosylates undergo typical nucleophilic substitution reactions

KCN

ethanol-water

(86%)

SN2


Dr wolfs chm 201 202

  • The best leaving groups are weakly basic


Table 8 8 approximate relative reactivity of leaving groups

Table 8.8Approximate Relative Reactivity of Leaving Groups

  • Leaving GroupRelative Conjugate acidKa ofRateof leaving group conj. acid

  • F–10-5HF3.5 x 10-4 wk acid

  • Cl–1HCl107

  • Br–10HBr109

  • I–102HI1010

  • H2O101 H3O+56

  • TsO–105 TsOH600

  • CF3SO2O– 108 CF3SO2OH 106


Table 8 8 approximate relative reactivity of leaving groups1

Table 8.8Approximate Relative Reactivity of Leaving Groups

  • Leaving GroupRelative Conjugate acidKa ofRateof leaving group conj. acid

  • F–10-5HF3.5 x 10-4

  • Cl–1HCl107

  • Br–10HBr109

  • I–102HI1010

  • H2O101 H3O+56

  • TsO–105 TsOH600

  • CF3SO2O– 108 CF3SO2OH 106

Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.


Tosylates can be converted to alkyl halides

CH3CHCH2CH3

CH3CHCH2CH3

OTs

Br

Tosylates can be converted to alkyl halides

  • Tosylate is a better leaving group than bromide.

NaBr

DMSO

SN2

(82%)


Tosylates allow control of stereochemistry

H

H

CH3(CH2)5

C

C

OTs

OH

H3C

H3C

Tosylates allow control of stereochemistry

  • Preparation of tosylate does not affect any of the bonds to the stereogenic center, so configuration and optical purity of tosylate is the same as the alcohol from which it was formed.

CH3(CH2)5

TsCl

pyridine


Tosylates allow control of stereochemistry1

H

(CH2)5CH3

C

CH3

Tosylates allow control of stereochemistry

  • Having a tosylate of known optical purity and absolute configuration then allows the preparation of other compounds of known configuration by SN2 processes.

H

CH3(CH2)5

Nu–

C

Nu

OTs

SN2

H3C


8 13 looking back reactions of alcohols with hydrogen halides

8.13Looking Back: Reactions of AlcoholswithHydrogen Halides


Secondary alcohols

H

H3C

C

OH

H

CH3(CH2)5

H3C

C

Br

CH3(CH2)5

Secondary alcohols

H

react with hydrogen halides

with net inversion of configuration

CH3

C

Br

87%

(CH2)5CH3

HBr

13%

Since some racemization,

can’t be SN2


Secondary alcohols1

H

H3C

C

OH

H

CH3(CH2)5

H3C

C

Br

CH3(CH2)5

Secondary alcohols

H

react with hydrogen halides

with net inversion of configuration

CH3

  • Most reasonable mechanism is SN1 with front side of carbocation shielded by leaving group

C

Br

87%

(CH2)5CH3

HBr

13%


Rearrangements

OH

Br

Br

Rearrangements

can occur in the reaction of alcohols with hydrogen halides

HBr

+

93%

7%


Rearrangements1

OH

+

+

Br

Br

Rearrangements

HBr

7%

93%

Br –

Br –

+


End of chapter 8

End of Chapter 8


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