Dr. Wolf's CHM 201 & 202 16-1 Chapter 16 Ethers, Epoxides, and Sulfides.
Dr. Wolf's CHM 201 & 202 8-1 8.11 Substitution And Elimination As Competing Reactions.
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Transcript of Dr. Wolf's CHM 201 & 202 8-1 8.11 Substitution And Elimination As Competing Reactions.
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