chapter 8 nucleophilic substitution
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Chapter 8Chapter 8
Nucleophilic SubstitutionNucleophilic Substitution
8.18.1
Functional Group Functional Group
Transformation By Nucleophilic Transformation By Nucleophilic
SubstitutionSubstitution
Y :–
R X Y R++ : X–
Nucleophile is a Lewis base (electron-pair donor),
often negatively charged and used as Na+ or K+ salt.
Substrate is usually an alkyl halide.
Nucleophilic Substitution
++
Substrate cannot be an a vinylic halide or anaryl halide, except under certain conditions tobe discussed in Chapter 12.
X
CC
X
Nucleophilic Substitution
+ R X
Alkoxide ion as the nucleophile
..O:
..R'
–
Table 8.1 Examples of Nucleophilic Substitution
gives an ether
+ : XR..O..
R' –
(CH3)2CHCH2ONa + CH3CH2Br
Isobutyl alcohol
(CH3)2CHCH2OCH2CH3 + NaBr
Ethyl isobutyl ether (66%)
Example
+ R X
Carboxylate ion as the nucleophile
..O:
..R'C
–O
..
gives an ester
+ : XR..OR'C –O
Table 8.1 Examples of Nucleophilic Substitution
OK +CH3(CH2)16C CH3CH2I
acetone, water
O
+ KIO CH2CH3CH3(CH2)16C
Ethyl octadecanoate (95%)
O
Example
+ R X
Hydrogen sulfide ion as the nucleophile
S:–
..
..H
gives a thiol
+ : XR..S..
H –
Table 8.1 Examples of Nucleophilic Substitution
KSH + CH3CH(CH2)6CH3
Br
ethanol, water
+ KBr
2-Nonanethiol (74%)
CH3CH(CH2)6CH3
SH
Example
+ R X
Cyanide ion as the nucleophile
–CN: :
Table 8.1 Examples of Nucleophilic Substitution
gives a nitrile
+ : XR –CN:
DMSO
BrNaCN +
Cyclopentyl cyanide (70%)
CN
+ NaBr
Example
Azide ion as the nucleophile
.. ..–
N N N::– +
+ R X
Table 8.1 Examples of Nucleophilic Substitution
..
gives an alkyl azide
+ : XR –..N N N:
– +
NaN3 + CH3CH2CH2CH2CH2I
2-Propanol-water
CH3CH2CH2CH2CH2N3 + NaI
Pentyl azide (52%)
Example
+ R X
Iodide ion as the nucleophile
–
..: I
..:
Table 8.1 Examples of Nucleophilic Substitution
gives an alkyl iodide
+ : XR –....I:
NaI is soluble in acetone; NaCl and NaBr are not soluble in acetone.
acetone
+ NaICH3CHCH3
Br
63%
+ NaBrCH3CHCH3
I
Example
8.28.2Relative Reactivity of Halide Relative Reactivity of Halide
Leaving GroupsLeaving Groups
Generalization
Reactivity of halide leaving groups in nucleophilic substitution is the same as for elimination.
RI
RBr
RCl
RF
most reactive
least reactive
BrCH2CH2CH2Cl + NaCN
A single organic product was obtained when 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product?
Br is a better leaving group than Cl
Problem 8.2
BrCH2CH2CH2Cl + NaCN
A single organic product was obtained when 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product?
Problem 8.2
CH2CH2CH2Cl + NaBrCN:
8.38.3
The SThe SNN2 Mechanism of 2 Mechanism of
Nucleophilic SubstitutionNucleophilic Substitution
Many nucleophilic substitutions follow asecond-order rate law.
CH3Br + HO – CH3OH + Br –
rate = k[CH3Br][HO – ]
inference: rate-determining step is bimolecular
Kinetics
HO – CH3Br+ HOCH3 Br –+one step
HO CH3 Br
transition state
Bimolecular Mechanism
Nucleophilic substitutions that exhibitsecond-order kinetic behavior are stereospecific and proceed withinversion of configuration.
Stereochemistry
Inversion of Configuration
Nucleophile attacks carbonfrom side opposite bondto the leaving group.
Three-dimensionalarrangement of bonds inproduct is opposite to that of reactant.
A stereospecific reaction is one in whichstereoisomeric starting materials yieldproducts that are stereoisomers of each other.
The reaction of 2-bromooctane with NaOH (in ethanol-water) is stereospecific.
(+)-2-Bromooctane (–)-2-Octanol
(–)-2-Bromooctane (+)-2-Octanol
Stereospecific Reaction
C
H
CH3
Br
CH3(CH2)5
NaOH
(S)-(+)-2-Bromooctane
(CH2)5CH3
C
H
CH3
HO
(R)-(–)-2-Octanol
Stereospecific Reaction
The Fischer projection formula for (+)-2-bromooctaneis shown. Write the Fischer projection of the(–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration.
Problem 8.4
H Br
CH3
CH2(CH2)4CH3
The Fischer projection formula for (+)-2-bromooctaneis shown. Write the Fischer projection of the(–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration.
HO H
CH3
CH2(CH2)4CH3
Problem 8.4
8.48.4Steric Effects and Steric Effects and
SSNN2 Reaction Rates2 Reaction Rates
Crowding at the carbon that bears the leaving group slows the rate ofbimolecular nucleophilic substitution.
Crowding at the Reaction Site
The rate of nucleophilic substitutionby the SN2 mechanism is governed
by steric effects.
RBr + LiI RI + LiBr
Alkyl Class Relativebromide rate
CH3Br Methyl 221,000
CH3CH2Br Primary 1,350
(CH3)2CHBr Secondary 1
(CH3)3CBr Tertiary too smallto measure
Table 8.2 Reactivity Toward Substitution by the
SN2 Mechanism
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
Decreasing SN2 Reactivity
The rate of nucleophilic substitutionby the SN2 mechanism is governed
by steric effects.
Crowding at the carbon adjacentto the one that bears the leaving groupalso slows the rate of bimolecularnucleophilic substitution, but the effect is smaller.
Crowding Adjacent to the Reaction Site
RBr + LiI RI + LiBr
Alkyl Structure Relativebromide rate
Ethyl CH3CH2Br 1.0
Propyl CH3CH2CH2Br 0.8
Isobutyl (CH3)2CHCH2Br 0.036
Neopentyl (CH3)3CCH2Br 0.00002
Table 8.3 Effect of Chain Branching on Rate of
SN2 Substitution
8.58.5
Nucleophiles and NucleophilicityNucleophiles and Nucleophilicity
All nucleophiles, however, are Lewis bases.
The nucleophiles described in Sections 8.1-8.4have been anions.
..
..HO:– ..
..CH3O:–..
..HS:– –
CN: : etc.
Not all nucleophiles are anions. Many are neutral.....HOH CH3OH..
..NH3: for example
Nucleophiles
..
..HOH CH3OH....
for example
Many of the solvents in which nucleophilic substitutions are carried out are themselvesnucleophiles.
Nucleophiles
The term solvolysis refers to a nucleophilicsubstitution in which the nucleophile is the solvent.
Solvolysis
substitution by an anionic nucleophile
R—X + :Nu— R—Nu + :X—
+
solvolysis
R—X + :Nu—H R—Nu—H + :X—
step in which nucleophilicsubstitution occurs
Solvolysis
+
substitution by an anionic nucleophile
R—X + :Nu— R—Nu + :X—
solvolysis
R—X + :Nu—H R—Nu—H + :X—
R—Nu + HXproducts of overall reaction
Solvolysis
R—X
Methanolysis is a nucleophilic substitution in which methanol acts as both the solvent andthe nucleophile.
H
O
CH3
: :+
H
O
CH3
:R+ –H+
The product is a methyl ether.
O:..
CH3
R
Example: Methanolysis
solvent product from RX
water (HOH) ROHmethanol (CH3OH) ROCH3
ethanol (CH3CH2OH) ROCH2CH3
formic acid (HCOH)
acetic acid (CH3COH) ROCCH3
O
ROCH
OO
O
Typical solvents in solvolysis
Table 8.4 compares the relative rates of nucleophilic substitution of a variety of nucleophiles toward methyl iodide as the substrate. The standard of comparison is methanol, which is assigned a relativerate of 1.0.
Nucleophilicity is a measure of the reactivity of a nucleophile
Rank Nucleophile Relativerate
very good I-, HS-, RS- >105
good Br-, HO-, 104
RO-, CN-, N3
-
fair NH3, Cl-, F-, RCO2- 103
weak H2O, ROH 1
very weak RCO2H 10-2
Table 8.4 Nucleophilicity
Basicity
Solvation
Small negative ions are highly solvated in protic solvents.
Large negative ions are less solvated.
Major factors that control nucleophilicity
Rank Nucleophile Relativerate
good HO–, RO– 104
fair RCO2– 103
weak H2O, ROH 1
When the attacking atom is the same (oxygenin this case), nucleophilicity increases with increasing basicity.
Table 8.4 Nucleophilicity
Basicity
Solvation
Small negative ions are highly solvated in protic solvents.
Large negative ions are less solvated.
Major factors that control nucleophilicity
Solvation of a chloride ion by ion-dipole attractive
forces with water. The negatively charged chloride
ion interacts with the positively polarized hydrogens
of water.
Figure 8.3
Rank Nucleophile Relativerate
Very good I- >105
good Br- 104
fair Cl-, F- 103
A tight solvent shell around an ion makes itless reactive. Larger ions are less solvated thansmaller ones and are more nucleophilic.
Table 8.4 Nucleophilicity
8.68.6
The SThe SNN1 Mechanism 1 Mechanism
ofofNucleophilic SubstitutionNucleophilic Substitution
Tertiary alkyl halides are very unreactive in substitutions that proceed by the SN2 mechanism.
Do they undergo nucleophilic substitution at all?
Yes. But by a mechanism different from SN2. The most common examples are seen in solvolysis reactions.
A question...
Example of a solvolysis. Hydrolysis of tert-butyl bromide.
.. ..
..
..
+
+
H Br..
:
O: :
H
H
C
CH3
CH3
CH3
Br
C OH..
:
CH3
CH3
CH3
..
C+
+
O :
H
H
Br..
::–
CH3
CH3
CH3
Example of a solvolysis. Hydrolysis of tert-butyl bromide.
..
..+ O: :
H
H
C
CH3
CH3
CH3
Br:
..
C+
+
O :
H
H
Br..
::–
CH3
CH3
CH3
This is the nucleophilic substitutionstage of the reaction; the one withwhich we are concerned.
Example of a solvolysis. Hydrolysis of tert-butyl bromide.
..
..+ O: :
H
H
C
CH3
CH3
CH3
Br:
..
C+
+
O :
H
H
Br..
::–
CH3
CH3
CH3
The reaction rate is independentof the concentration of the nucleophileand follows a first-order rate law.
rate = k[(CH3)3CBr]
Example of a solvolysis. Hydrolysis of tert-butyl bromide.
..
..+ O: :
H
H
C
CH3
CH3
CH3
Br:
..
C+
+
O :
H
H
Br..
::–
CH3
CH3
CH3
The mechanism of this step isnot SN2. It is called SN1 and begins with ionization of (CH3)3CBr.
rate = k[alkyl halide]First-order kinetics implies a unimolecular
rate-determining step.
Proposed mechanism is called SN1, which stands for
substitution nucleophilic unimolecular
Kinetics and Mechanism
+..
..Br–
: :
C..
..
CH3
CH3
CH3
Br:
C
H3C CH3
CH3
+
unimolecular slow
Mechanism
C
H3C CH3
CH3
+
O: :
H
H
C+O :
H
HCH3
CH3
CH3
Mechanism
bimolecular fast
ROHROH22
++
carbocation formation
RR++
proton transfer
ROHROH
carbocation capture
RXRX
first order kinetics: rate = k[RX]
unimolecular rate-determining step
carbocation intermediate
ate follows carbocation stability
rearrangements sometimes observed
reaction is not stereospecific
much racemization in reactions of optically active alkyl halides
Characteristics of the SN1 mechanism
8.78.7
Carbocation Stability and SCarbocation Stability and SNN1 1
Reaction RatesReaction Rates
The rate of nucleophilic substitutionby the SN1 mechanism is governed
by electronic effects.
Carbocation formation is rate-determining.The more stable the carbocation, the faster
its rate of formation, and the greater the rate of unimolecular nucleophilic substitution.
Electronic Effects Govern SN1 Rates
RBr solvolysis in aqueous formic acid
Alkyl bromide Class Relative rate
CH3Br Methyl 0.6
CH3CH2Br Primary 1.0
(CH3)2CHBr Secondary 26
(CH3)3CBr Tertiary ~100,000,000
Table 8.5 Reactivity of Some Alkyl Bromides Toward Substitution by the SN1 Mechanism
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
Decreasing SN1 Reactivity
8.88.8Stereochemistry of SStereochemistry of SNN1 Reactions1 Reactions
Nucleophilic substitutions that exhibitfirst-order kinetic behavior are
not stereospecific.
Generalization
R-(–)-2-Bromooctane
H
C
CH3
Br
CH3(CH2)5
Stereochemistry of an SN1 Reaction
(R)-(–)-2-Octanol (17%)
H
C
CH3
OH
CH3(CH2)5
C
H CH3
HO
(CH2)5CH3
(S)-(+)-2-Octanol (83%)
H2O
Leaving group shields
one face of carbocation;
nucleophile attacks
faster at opposite face.
+
Figure 8.6
Ionization step
gives carbocation; three
bonds to chirality
center become coplanar
8.98.9Carbocation RearrangementsCarbocation Rearrangements
in Sin SNN1 Reactions1 Reactions
carbocations are intermediatesin SN1 reactions, rearrangements
are possible.
Because...
CH3 C
H
CHCH3
Br
CH3H2O
CH3 C
OH
CH2CH3
CH3
(93%)
Example
CH3 C
H
CHCH3
CH3
+
H2O
CH3 C CHCH3
CH3
H
+
8.108.10Effect of SolventEffect of Solvent
on the on the Rate of Nucleophilic SubstitutionRate of Nucleophilic Substitution
SN1 Reaction Rates Increase
in Polar Solvents
In general...
R+
RX
RR X X
Energy of RX not much affected by polarity of solvent.
R+
RX
RR X X
Energy of RX not much affected by polarity of solvent.
transition state stabilized by polar solvent
activation energy decreases;
rate increases
SN2 Reaction Rates Increase in
Polar Aprotic Solvents
An aprotic solvent is one that doesnot have an —OH group.
In general...
Solvent Type Relative rate
CH3OH polar protic 1
H2O polar protic 7
DMSO polar aprotic 1300
DMF polar aprotic 2800
Acetonitrile polar aprotic 5000
CH3CH2CH2CH2Br + N3–
Table 8.7 Relative Rate of SN2
Reactivity versus Type of Solvent
Mechanism SummarySN1 and SN2
When...
Primary alkyl halides undergo nucleophilic substitution: they always react by the SN2
mechanism.
Tertiary alkyl halides undergo nucleophilic substitution: they always react by the SN1
mechanism.
Secondary alkyl halides undergo nucleophilic substitution: they react by the
SN1 mechanism in the presence of a weak nucleophile (solvolysis).SN2 mechanism in the presence of a good nucleophile.
8.118.11
Substitution and EliminationSubstitution and Elimination
as Competing Reactionsas Competing Reactions
Alkyl halides can react with Lewis bases by nucleophilic substitution and/or elimination.
C C
H
X
+ Y:–
C C
Y
H
X:–
+
C C + H Y X:–
+
-elimination
nucleophilic substitution
Two Reaction Types
C C
H
X
+ Y:–
C C
Y
H
X:–
+
C C + H Y X:–
+
-elimination
nucleophilic substitution
Two Reaction Types
How can we tell which reaction pathway is followed for a particular alkyl halide?
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 E2mechanism.
Elimination versus Substitution
CH3CHCH3
Br
NaOCH2CH3
ethanol, 55°C
CH3CHCH3
OCH2CH3
CH3CH=CH2+
(87%)(13%)
Example
Br
E2
Figure 8.8
CH3CH2 O••
••••–
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
When is Substitution Favored?
Decreased crowding at carbon that bears the leaving group increases substitution relative to elimination.
primary alkyl halide
CH3CH2CH2Br
NaOCH2CH3
ethanol, 55°C
CH3CH=CH2+CH3CH2CH2OCH2CH3
(9%)(91%)
Uncrowded Alkyl Halides
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
(87%)(13%)
But a Crowded Alkoxide Base Can Favor Elimination Even with a Primary Alkyl Halide
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 the nucleophile.
When is Substitution Favored?
Weakly basic nucleophile increases substitution relative to elimination
(70%)CH3CH(CH2)5CH3
CN
KCN
CH3CH(CH2)5CH3
ClpKa (HCN) = 9.1
DMSO
secondary alkyl halide + weakly basic nucleophile
Weakly Basic Nucleophile
Weakly basic nucleophile increases substitution relative to elimination
secondary alkyl halide + weakly basic nucleophile
Weakly Basic Nucleophile
NaN3 pKa (HN3) = 4.6
I
(75%)
N3
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.
Tertiary Alkyl Halides
(CH3)2CCH2CH3
Br
+CH3CCH2CH3
OCH2CH3
CH3
CH2=CCH2CH3
CH3
CH3C=CHCH3
CH3
+
ethanol, 25°C64% 36%
2M sodium ethoxide in ethanol, 25°C
1% 99%
Example
8.128.12Nucleophilic Substitution of Alkyl SulfonatesNucleophilic Substitution of Alkyl Sulfonates
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
ROSCH3
O
O
ROS
O
O
CH3
Alkylmethanesulfonate
(mesylate)
Alkylp-toluenesulfonate
(tosylate)
undergo same kinds of reactions as alkyl halides
Preparation
(abbreviated as ROTs)
ROH +
CH3 SO2Cl
pyridine
ROS
O
O
CH3
Tosylates are prepared by the reaction of alcohols with p-toluenesulfonyl chloride(usually in the presence of pyridine).
Tosylates Undergo Typical Nucleophilic Substitution Reactions
H
CH2OTs
KCN
ethanol-water
H
CH2CN
(86%)
The best leaving groups are weakly basic.
Table 8.8 Approximate Relative Leaving Group Abilities
Leaving Relative Conjugate acid pKa ofGroup 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+ -1.7
TsO– 105 TsOH -2.8CF3SO2O– 108 CF3SO2OH -6
Leaving Relative Conjugate acid pKa ofGroup 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+ -1.7
TsO– 105 TsOH -2.8CF3SO2O– 108 CF3SO2OH -6
Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.
Table 8.8 Approximate Relative Leaving Group Abilities
Tosylates can be Converted to Alkyl Halides
NaBr
DMSO
(82%)
OTs
CH3CHCH2CH3
Br
CH3CHCH2CH3
Tosylate is a better leaving group than bromide.
Tosylates Allow Control of Stereochemistry
Preparation of tosylate does not affect any of the bonds 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
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
Tosylates also undergo Elimination
NaOCH3
CH3OHheat
OTs
CH3CHCH2CH3
CH2=CHCH2CH3
CH3CH=CHCH3
E and Z
+
Secondary Alcohols React with Hydrogen Halides Predominantly with Net Inversion of Configuration
C
HH3C
OH
CH3(CH2)5
C
HH3C
Br
CH3(CH2)5
C
H
CH3
(CH2)5CH3
Br
HBr
87%
13%
Secondary Alcohols React with Hydrogen Halides with Net Inversion of Configuration
C
HH3C
OH
CH3(CH2)5
C
HH3C
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.
Rearrangements can Occur in the Reaction of Alcohols with Hydrogen Halides
OH Br
Br
+
93% 7%
HBr
Rearrangements can Occur in the Reaction of Alcohols with Hydrogen Halides
OH Br
Br
+
+
+
93%
7%
Br –Br –
HBr
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