8-1Dr. Wolf's CHM 201 & 202

8.118.11

Substitution And Elimination Substitution And Elimination

As Competing ReactionsAs Competing Reactions

8-2Dr. Wolf's CHM 201 & 202

We have seen that alkyl halides can react with LewisWe have seen that alkyl halides can react with Lewis

bases in two different ways. They can undergobases in two different ways. They can undergo

nucleophilic substitution or elimination.nucleophilic substitution or elimination.

We have seen that alkyl halides can react with LewisWe have seen that alkyl halides can react with Lewis

bases in two different ways. They can undergobases in two different ways. They can undergo

nucleophilic substitution or elimination.nucleophilic substitution or elimination.

CC CC

HH

XX

++ YY::––

CC CC

YY

HH

XX::––

++

CC CC ++ HH YY XX::––

++

-elimination-elimination

nucleophilic substitutionnucleophilic substitution

8-3Dr. Wolf's CHM 201 & 202

How can we tell which reaction pathway is followedHow can we tell which reaction pathway is followed

for a particular alkyl halide?for a particular alkyl halide?

How can we tell which reaction pathway is followedHow can we tell which reaction pathway is followed

for a particular alkyl halide?for a particular alkyl halide?

CC CC

HH

XX

++ YY::––

CC CC

YY

HH

XX::––

++

CC CC ++ HH YY XX::––

++

-elimination-elimination

nucleophilic substitutionnucleophilic substitution

8-4Dr. Wolf's CHM 201 & 202

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

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

The major reaction of a secondary alkyl halideThe major reaction of a secondary alkyl halidewith an alkoxide ion is with an alkoxide ion is elimination by the E2 mechanism.elimination by the E2 mechanism.

8-5Dr. Wolf's CHM 201 & 202

ExampleExampleExampleExample

CHCH33CHCHCHCH33

BrBr

NaOCHNaOCH22CHCH33

ethanol, 55°Cethanol, 55°C

CHCH33CHCHCHCH33

OCHOCH22CHCH33

CHCH33CH=CHCH=CH22++

(87%)(87%)(13%)(13%)

8-6Dr. Wolf's CHM 201 & 202

CHCH33CHCH22 OO::........

–– BrBr

E2E2

Figure 8.11Figure 8.11Figure 8.11Figure 8.11

8-7Dr. Wolf's CHM 201 & 202

CHCH33CHCH22 OO::........––

BrBr

SSNN22

Figure 8.11Figure 8.11Figure 8.11Figure 8.11

8-8Dr. Wolf's CHM 201 & 202

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

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

1)1) decreased crowding at the carbon decreased crowding at the carbon thatthat

bears the leaving groupbears the leaving group

8-9Dr. Wolf's CHM 201 & 202

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

to elimination.to elimination.

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

to elimination.to elimination.

primary alkyl halideprimary alkyl halide

CHCH33CHCH22CHCH22BrBr

NaOCHNaOCH22CHCH33

ethanol, 55°Cethanol, 55°C

CHCH33CH=CHCH=CH22++CHCH33CHCH22CHCH22OCHOCH22CHCH33

(9%)(9%)(91%)(91%)

8-10Dr. Wolf's CHM 201 & 202

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

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

primary alkyl halide + bulky baseprimary alkyl halide + bulky base

CHCH33(CH(CH22))1515CHCH22CHCH22BrBr

KOC(CHKOC(CH33))33

tert-tert-butyl alcohol, 40°Cbutyl alcohol, 40°C

++CHCH33(CH(CH22))1515CHCH22CHCH22OC(CHOC(CH33))33 CHCH33(CH(CH22))1515CH=CHCH=CH22

(87%)(87%)(13%)(13%)

8-11Dr. Wolf's CHM 201 & 202

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

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

1)1) decreased crowding at the carbon decreased crowding at the carbon thatthat

bears the leaving groupbears the leaving group

2)2) decreased basicity of nucleophiledecreased basicity of nucleophile

8-12Dr. Wolf's CHM 201 & 202

Weakly basic nucleophile Weakly basic nucleophile increases increases substitutionsubstitution relative to elimination relative to elimination

Weakly basic nucleophile Weakly basic nucleophile increases increases substitutionsubstitution relative to elimination relative to elimination

KCNKCN

CHCH33CH(CHCH(CH22))55CHCH33

ClClppKKaa (HCN) = 9.1 (HCN) = 9.1ppKKaa (HCN) = 9.1 (HCN) = 9.1

(70%)(70%)

DMSODMSO

CHCH33CH(CHCH(CH22))55CHCH33

CNCN

secondary alkyl halide + weakly basic nucleophilesecondary alkyl halide + weakly basic nucleophile

SSNN22

8-13Dr. Wolf's CHM 201 & 202

secondary alkyl halide + weakly basic nucleophilesecondary alkyl halide + weakly basic nucleophile

NaNNaN33

II

(75%)(75%)

NN33

Weakly basic nucleophile Weakly basic nucleophile increases increases substitutionsubstitution relative to elimination relative to elimination

Weakly basic nucleophile Weakly basic nucleophile increases increases substitutionsubstitution relative to elimination relative to elimination

ppKKaa (HN (HN33) = 4.6) = 4.6ppKKaa (HN (HN33) = 4.6) = 4.6

(even weaker base)

SSNN22

8-14Dr. Wolf's CHM 201 & 202

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

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

8-15Dr. Wolf's CHM 201 & 202

ExampleExampleExampleExample (CH(CH33))22CCHCCH22CHCH33

BrBr

++CHCH33CCHCCH22CHCH33

OCHOCH22CHCH33

CHCH33

CHCH22=CCH=CCH22CHCH33

CHCH33

CHCH33C=CHCHC=CHCH33

CHCH33

++

ethanol, 25°Cethanol, 25°C

64%64% 36%36%

22MM sodium ethoxide in ethanol, 25°C sodium ethoxide in ethanol, 25°C1%1% 99%99%

Dr. Wolf's CHM 201 & 202 8-16

Mechanism SummarySN1 and SN2 and E1 and E2

Mechanism SummarySN1 and SN2 and E1 and E2

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)

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)

8-17Dr. Wolf's CHM 201 & 202

8.12Nucleophilic Substitution

of Alkyl Sulfonates

Dr. Wolf's CHM 201 & 202 8-18

Leaving GroupsLeaving 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

Dr. Wolf's CHM 201 & 202 8-19

Other RX compoundsOther RX compounds

ROSCHROSCH33

OO

OO

ROSROS

OO

OO

CHCH33

AlkylAlkylmethanesulfonatemethanesulfonate

(mesylate)(mesylate)

AlkylAlkylpp-toluenesulfonate-toluenesulfonate

(tosylate)(tosylate)

• undergo same kinds of reactions as alkyl halides

HOSOHHOSOH

OO

OO

SulfuricSulfuricacidacid

Dr. Wolf's CHM 201 & 202 8-20

PreparationPreparation

• (abbreviated as ROTs)

ROHROH ++

CHCH33 SOSO22ClCl

pyridinepyridine

ROSROS

OO

OO

CHCH33

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

Dr. Wolf's CHM 201 & 202 8-21

Tosylates undergo typical nucleophilic substitution

reactions

Tosylates undergo typical nucleophilic substitution

reactions HH

CHCH22OTsOTs

KCNKCN

ethanol-ethanol-waterwater

HH

CHCH22CNCN

(86%)(86%)SSNN22

Dr. Wolf's CHM 201 & 202 8-22

•The best leaving groups are weakly basic•The best leaving groups are weakly basic

Dr. Wolf's CHM 201 & 202 8-23

Table 8.8Approximate Relative Reactivity of

Leaving Groups

Table 8.8Approximate Relative Reactivity of

Leaving Groups•Leaving GroupRelative Conjugate acid Ka of

Rate of leaving group conj. acid• F– 10-5 HF 3.5 x 10-4 wk acid

• Cl– 1 HCl 107

• Br– 10 HBr 109

• I– 102 HI 1010

• H2O 101 H3O+ 56

• TsO– 105 TsOH 600

• CF3SO2O– 108 CF3SO2OH 106

Dr. Wolf's CHM 201 & 202 8-24

Table 8.8Approximate Relative Reactivity of

Leaving Groups

Table 8.8Approximate Relative Reactivity of

Leaving Groups•Leaving GroupRelative Conjugate acid Ka of

Rate of leaving group conj. acid• F– 10-5 HF 3.5 x 10-4

• Cl– 1 HCl 107

• Br– 10 HBr 109

• I– 102 HI 1010

• H2O 101 H3O+ 56

• TsO– 105 TsOH 600

• CF3SO2O– 108 CF3SO2OH 106

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

Dr. Wolf's CHM 201 & 202 8-25

Tosylates can be converted to alkyl halides

Tosylates can be converted to alkyl halides

NaBrNaBr

DMSODMSO

(82%)(82%)

OTsOTs

CHCH33CHCHCHCH22CHCH33

BrBr

CHCH33CHCHCHCH22CHCH33

• Tosylate is a better leaving group than bromide.

SSNN22

Dr. Wolf's CHM 201 & 202 8-26

Tosylates allow control of stereochemistry

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.

CC

HH

HH33CC

OOHH

CHCH33(CH(CH22))55 TsClTsCl

pyridinepyridine

CC

HH

HH33CC

OOTsTs

CHCH33(CH(CH22))55

Dr. Wolf's CHM 201 & 202 8-27

Tosylates allow control of stereochemistry

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.

NuNu––

SSNN22

CC

HH

HH33CC

OOTsTs

CHCH33(CH(CH22))55

CC

HH

CHCH33

(CH(CH22))55CHCH33

NuNu

8-28Dr. Wolf's CHM 201 & 202

8.13Looking Back:

Reactions of Alcoholswith

Hydrogen Halides

Dr. Wolf's CHM 201 & 202 8-29

Secondary alcoholsSecondary alcohols CC

HHHH33CC

OHOH

CHCH33(CH(CH22))55

CC

HHHH33CC

BrBr

CHCH33(CH(CH22))55

CC

HH

CHCH33

(CH(CH22))55CHCH33

BrBr

HBrHBr

87%

13%

react with hydrogen halides with net inversion of configuration

Since some racemization, can’t be SN2

Dr. Wolf's CHM 201 & 202 8-30

Secondary alcoholsSecondary alcohols CC

HHHH33CC

OHOH

CHCH33(CH(CH22))55

CC

HHHH33CC

BrBr

CHCH33(CH(CH22))55

CC

HH

CHCH33

(CH(CH22))55CHCH33

BrBr

HBrHBr

87%

13%

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

react with hydrogen halides with net inversion of configuration

Dr. Wolf's CHM 201 & 202 8-31

RearrangementsRearrangements OHOH

BrBr

BrBr

++

93% 7%

HBrHBr

can occur in the reaction of alcohols with hydrogen halides

Dr. Wolf's CHM 201 & 202 8-32

RearrangementsRearrangements OHOH

BrBr

BrBr

++

++

++

93%

7%

Br Br ––Br Br ––

HBrHBr

Dr. Wolf's CHM 201 & 202 8-33

End of Chapter 8