hougland che275 chapter8 slides
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Organic Chemistry
CHE 275
Chapter 8Nucleophilic Substitution
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 specific conditions tobe discussed in Chapter 12.
XCC
X
Nucleophilic Substitution
+ R X
Alkoxide ion as the nucleophile
..O:
..R'
–
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..O..
R'C –
O
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 –
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: :
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
..
gives an alkyl azide
+ : XR –..N N N:
– +
Examples of Nucleophilic Substitution
NaN3 + CH3CH2CH2CH2CH2I
2-Propanol, water
CH3CH2CH2CH2CH2N3 + NaI
Pentyl azide (52%)
Example
+ R X
Iodide ion as the nucleophile
–
..: I
..:
gives an alkyl iodide
+ : XR –..: I..
Examples of Nucleophilic Substitution
NaI is soluble in acetone; NaCl and NaBr are not soluble in acetone.
acetone
+ NaICH3CHCH3
Br
63%
+ NaBrCH3CHCH3
I
Example Reactivity of Leaving Groups
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
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
CH2CH2CH2Cl + NaBrCN:
• Many nucleophilic substitutions follow asecond-order rate law.
CH3Br + HO – CH3OH + Br –
• rate = k[CH3Br][HO – ]
• inference: rate-determining step is bimolecular
Kinetics and the SN2 Mechanism
HO – CH3Br+ HOCH3 Br –+
•one step•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 givestereoisomeric products.
•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
H Br
CH3
CH2(CH2)4CH3
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
Crowding at the carbon that bears the leaving group slows the rate ofbimolecular nucleophilic substitution.
Steric Effects on SN2 reactions: Crowding at the Reaction Site
The rate of nucleophilic substitutionby the SN2 mechanism is governedby 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
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 governedby 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
Effect of chain branching on rate of SN2 substitution
Interactive QuestionWhat is the major product of the reaction of the
dihalide at the right with 1 equivalent of
NaSH in dimethyl sulfoxide?
A) B)
C) D) All nucleophiles, however, are Lewis bases.
The nucleophiles described in the bookhave mostly been anions.
..
..HO:– ..
..CH3O:–..
..HS:– –
CN: : etc.
Not all nucleophiles are anions. Many are neutral.....HOH CH3OH..
..NH3: for example
Nucleophiles and Nucleophicity
..
..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: Methanolysissolvent 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
Rank Nucleophile Relative rate
strong 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
Nucleophilicity• compare 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 relative rate of 1.0.
•basicity
•solvation
–small negative ions are highly solvated in protic solvents
–large negative ions are less solvated
Major factors that control nucleophilicity
Rank Nucleophile Relative Rate
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.
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.
Solvation
Rank Nucleophile Relative Rate
strong 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.
Nucleophilicity
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.
The SN1 MechanismHydrolysis 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
+ O: :
H
H
C+
+
O :
H
H
Br..
..::–
CH3
CH3
CH3
C
CH3
CH3
CH3
Br..
.. :
This is the nucleophilic substitutionstage of the reaction; the one withwhich we are concerned.
Hydrolysis of tert-butyl bromide.
+ O: :
H
H
C+
+
O :
H
H
Br..
..::–
CH3
CH3
CH3
C
CH3
CH3
CH3
Br..
.. :
Hydrolysis of tert-butyl bromide.
The reaction rate is independentof the concentration of the nucleophileand follows a first-order rate law.
rate = k[(CH3)3CBr]
+ O: :
H
H
C+
+
O :
H
H
Br..
..::–
CH3
CH3
CH3
C
CH3
CH3
CH3
Br..
.. :
Hydrolysis of tert-butyl bromide.
The mechanism of this step isnot SN2. It is 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
(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
bimolecular fast
Mechanism
ROH2
+
carbocation formation
R+
proton transfer
ROH
carbocation capture
RX
•first order kinetics: rate = k[RX]
–unimolecular rate-determining step
•carbocation intermediate
–rate follows carbocation stability
–rearrangements sometimes observed
•reaction is not stereospecific
–Significant racemization in reactions of optically active alkyl halides
Characteristics of the SN1 mechanism
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 1
CH3CH2Br Primary 2
(CH3)2CHBr Secondary 43
(CH3)3CBr Tertiary 100,000,000
Reactivity toward substitution by the SN1 mechanism
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
Decreasing SN1 Reactivity
Nucleophilic substitutions that exhibitfirst-order kinetic behavior are
not stereospecific.
Generalization
Which alkyl halide will react faster with CH3OH under SN1 conditions?
A) B)
C) D)
Interactive Question
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
HCH3
HO
(CH2)5CH3
(S)-(+)-2-Octanol (83%)
H2O
Ionization step gives carbocation; three
bonds to chirality center become coplanar
Leaving group shields one face of carbocation; nucleophile attacks
faster at opposite face.
Carbocations are intermediatesin SN1 reactions, rearrangements
are possible.
Carbocation Rearrangementsin SN1 Reactions 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+
•SN1 Reaction Rates Increase in Polar Protic Solvents
Solvent Effects
Solvent Dielectric Relativeconstant rate
acetic acid 6 1methanol 33 4formic acid 58 5,000water 78 150,000
SN1 Reactivity versus Solvent Polarity
Most polar Fastest rate
R+
RX
R X
energy of RX not much affected by polarity of solvent
transition state stabilized by polar solvent
Ea
R+
RX
R X
energy of RX not much affected by polarity of solvent
transition state stabilized by polar solvent
activation energy decreases;
rate increases
Ea > Ea
•SN2 Reaction Rates Increase inPolar 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–
SN2 Reactivity vs. Type of Solvent
Interactive Question
The reaction of butyl iodide with NaSCH3 will proceed at a faster rate in which solvent?
A) acetone
B) acetic acid
C) propanol
D) water
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) in a protic solvent–SN2 mechanism in the presence of a good nucleophile in an aprotic solvent
Interactive Question
What combination is the best choice in order to prepare 3-chloro-1-iodobutane?A) 1-iodobutane + Cl2 (400°C)B) 1,3-dichlorobutane + NaI (1 equiv) in
acetoneC) 1,3-iodobutane + NaCl (1 equiv) in
acetoneD) 3-bromo-1-iodobutane + NaCl (1 equiv)
in acetone
Interactive Question
The best combination of reactants for preparing (CH3)3CSCH3 is:
A) (CH3)3CCl + CH3SK
B) (CH3)3CBr + CH3SNa
C) (CH3)3CSK + CH3OH
D) (CH3)3CSNa + CH3Br
Substitution and Eliminationas 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 TypesHow can we tell which reaction pathway is followed for a particular alkyl halide?
C C
H
X
+ Y:–
C C
Y
H
X:–
+
C C + H Y X:–
+
-elimination
nucleophilic substitution
Two Reaction Types
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
Example: E2
BrCH3CH2 O••
••••
–
Example: SN2
BrCH3CH2 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 that bears 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. Interactive Question
Which one of the following alkyl halides would be expected to give the highest ratio of
substitution to elimination on treatment with sodium ethoxide in ethanol (50°C)?
A) 1-bromopentane
B) 2-bromopentane
C) 3-bromopentane
D) 2-bromo-3-methylbutane
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 that bears 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
NaN3 pKa (HN3) = 4.6
I
(75%)N3
Weakly Basic Nucleophile
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°C1% 99%
ExampleInteractive Question
Which of the following is not a good nucleophile for an SN1 reaction?
A) NaOCH3
B) CH3OH
C) CH3CH2OH
D) H2O
Interactive Question
Which one of the following compounds gives the highest subtitution-to-elimination ratio
(most substitution least elimination) on reaction with 2-bromobutane?
A) NaOCH3
B) NaNH2
C) NaCN
D) NaCCH
Leaving Groups
We have seen numerous examples of nucleophilic substitution in which X in RX is a halogen
However, halogens are not the only possible leaving groups
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 SO2Clpyridine
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
Approximate Relative Reactivity of Leaving Groups
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
Approximate Relative Reactivity of Leaving Groups
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.
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.
TsCl
pyridine
H
C OTs
CH3
CH3(CH2)5H
C OH
CH3
CH3(CH2)5
H
C
CH3
Nu
CH3(CH2)5
C
HCH3
TosO
(CH2)5CH3
Nu–
SN2
Having a tosylate of known optical purity and absolute configuration then allows the preparation of other compounds of known configuration by SN2 processes.
Tosylates allow control of stereochemistry
Secondary alcohols react with inversion
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 inversion
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
OH
Br
Br
+
93% 7%
HBr
Rearrangements can occur
OH
Br
Br
+
+
+
93%
7%
Br –Br –
HBr
Tosylates also undergo Elimination
NaOCH3
CH3OHheat
OTs
CH3CHCH2CH3
CH2=CHCH2CH3
CH3CH=CHCH3
E and Z
+
Summary: Chapter 8Summary: Chapter 8
8.1 Nucleophilic Substitution
8.2 Relative Reactivity of Halides
8.3 The SN2 Mechanism
8.4 Steric Effects in SN2
8.5 Nucleophiles and Nucleophilicity
8.6 The SN1 Mechanism
8.7 Carbocation Stability and SN1 Rate
8.8 Stereochemistry of SN1 Reactions
8.9 Carbocation Rearrangements in SN1 Reactions
Summary: Chapter 8Summary: Chapter 8
8.10 Solvent Effects on Nucleophilic Substitution
8.11 Substitution vs. Elimination
8.12 Sulfonate Esters as Substrates in SN1 and SN2