Title: Chapter 8 Nucleophilic Substitution
1Chapter 8Nucleophilic Substitution
28.1Functional Group Transformation By
Nucleophilic Substitution
3Nucleophilic Substitution
R
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
4Nucleophilic Substitution
Substrate cannot be on a vinylic halide or
an aryl halide, except under certain conditions
to be discussed in Chapter 23.
X
5Table 8.1 Examples of Nucleophilic Substitution
Alkoxide ion as the nucleophile
6Example
(CH3)2CHCH2ONa CH3CH2Br
Isobutyl alcohol
7Table 8.1 Examples of Nucleophilic Substitution
Carboxylate ion as the nucleophile
..
O
R'C
..
8Example
CH3(CH2)16C
OK
CH3CH2I
acetone, water
9Table 8.1 Examples of Nucleophilic Substitution
Hydrogen sulfide ion as the nucleophile
10Example
KSH CH3CH(CH2)6CH3
Br
ethanol, water
11Table 8.1 Examples of Nucleophilic Substitution
Cyanide ion as the nucleophile
12Example
NaCN
DMSO
13Table 8.1 Examples of Nucleophilic Substitution
Azide ion as the nucleophile
14Example
NaN3 CH3CH2CH2CH2CH2I
2-Propanol-water
15Table 8.1 Examples of Nucleophilic Substitution
Iodide ion as the nucleophile
16Example
acetone
NaI is soluble in acetone NaCl and NaBr are not
soluble in acetone.
178.2Relative Reactivity of Halide Leaving Groups
18Generalization
- Reactivity of halide leaving groups in
nucleophilic substitution is the same as for
elimination.
19Problem 8.2
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?
BrCH2CH2CH2Cl NaCN
- Br is a better leaving group than Cl
20Problem 8.2
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?
BrCH2CH2CH2Cl NaCN
218.3The SN2 Mechanism of Nucleophilic Substitution
22Kinetics
- Many nucleophilic substitutions follow
asecond-order rate law. CH3Br HO ?
CH3OH Br - rate kCH3BrHO
- inference rate-determining step is bimolecular
23Bimolecular mechanism
24Stereochemistry
- Nucleophilic substitutions that
exhibitsecond-order kinetic behavior are
stereospecific and proceed withinversion of
configuration.
25Inversion of Configuration
26Stereospecific Reaction
- 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
27Stereospecific Reaction
NaOH
(S)-()-2-Bromooctane
28Problem 8.4
- 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.
29Problem 8.4
- 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.
308.4Steric Effects in SN2 Reactions
31Crowding at the Reaction Site
The rate of nucleophilic substitutionby the SN2
mechanism is governedby steric effects.
Crowding at the carbon that bears the leaving
group slows the rate ofbimolecular nucleophilic
substitution.
32Table 8.2 Reactivity toward substitution by the
SN2 mechanism
RBr LiI ? RI LiBr
- Alkyl Class Relativebromide rate
- CH3Br Methyl 221,000
- CH3CH2Br Primary 1,350
- (CH3)2CHBr Secondary 1
- (CH3)3CBr Tertiary too small to measure
33Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
34Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr
35Crowding Adjacent to the Reaction Site
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.
36Table 8.3 Effect of chain branching on rate of
SN2 substitution
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
378.5Nucleophiles and Nucleophilicity
38Nucleophiles
All nucleophiles, however, are Lewis bases.
39Nucleophiles
Many of the solvents in which nucleophilic
substitutions are carried out are
themselvesnucleophiles.
..
for example
40Solvolysis
The term solvolysis refers to a
nucleophilic substitution in which the
nucleophile is the solvent.
41Solvolysis
substitution by an anionic nucleophile
RX Nu
RNu X
42Solvolysis
substitution by an anionic nucleophile
RX Nu
RNu X
solvolysis
RNuH X
RX NuH
products of overall reaction
RNu HX
43Example Methanolysis
Methanolysis is a nucleophilic substitution in
which methanol acts as both the solvent andthe
nucleophile.
RX
44Typical solvents in solvolysis
solvent product from RX water
(HOH) ROH methanol (CH3OH) ROCH3 ethanol
(CH3CH2OH) ROCH2CH3 formic acid
(HCOH) acetic acid (CH3COH)
ROCH
ROCCH3
45Nucleophilicity is a measure of the reactivity of
a nucleophile
- 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.
46Table 8.4 Nucleophilicity
- Rank Nucleophile Relative rate
- strong I-, HS-, RS- gt105
- good Br-, HO-, 104
- RO-, CN-, N3-
- fair NH3, Cl-, F-, RCO2- 103
- weak H2O, ROH 1
- very weak RCO2H 10-2
47Major factors that control nucleophilicity
- basicity
- solvation
- small negative ions are highly solvated in
protic solvents - large negative ions are less solvated
48Table 8.4 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.
49Major factors that control nucleophilicity
- basicity
- solvation
- small negative ions are highly solvated in
protic solvents - large negative ions are less solvated
50Figure 8.3
Solvation of a chloride ion by ion-dipole
attractiveforces with water. The negatively
charged chlorideion interacts with the
positively polarized hydrogensof water.
51Table 8.4 Nucleophilicity
- Rank Nucleophile Relative rate
- strong I- gt105
- 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.
528.6The SN1 Mechanism ofNucleophilic
Substitution
53A question...
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.
54Example of a solvolysis. Hydrolysis of
tert-butyl bromide.
55Example of a solvolysis. Hydrolysis of
tert-butyl bromide.
..
C
Br
O
C
..
This is the nucleophilic substitutionstage of
the reaction the one withwhich we are
concerned.
56Example of a solvolysis. Hydrolysis of
tert-butyl bromide.
..
C
Br
O
C
..
The reaction rate is independentof the
concentration of the nucleophileand follows a
first-order rate law. rate k(CH3)3CBr
57Example of a solvolysis. Hydrolysis of
tert-butyl bromide.
The mechanism of this step isnot SN2. It is
called SN1 and begins with ionization of
(CH3)3CBr.
58Kinetics and Mechanism
rate kalkyl halide First-order kinetics
implies a unimolecularrate-determining step.
- Proposed mechanism is called SN1, which stands
forsubstitution nucleophilic unimolecular
59Mechanism
60Mechanism
61carbocation formation
carbocation capture
62Characteristics of the SN1 mechanism
- first order kinetics rate kRX
- unimolecular rate-determining step
- carbocation intermediate
- rate follows carbocation stability
- rearrangements sometimes observed
- reaction is not stereospecific
- much racemization in reactions of optically
active alkyl halides
638.7Carbocation Stability and SN1 Reaction Rates
64Electronic Effects Govern SN1 Rates
The rate of nucleophilic substitutionby the SN1
mechanism is governedby electronic
effects. Carbocation formation is
rate-determining.The more stable the
carbocation, the fasterits rate of formation,
and the greater the rate of unimolecular
nucleophilic substitution.
65Table 8.5 Reactivity toward substitution by the
SN1 mechanism
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
66Decreasing SN1 Reactivity
(CH3)3CBr
(CH3)2CHBr
CH3CH2Br
CH3Br
678.8Stereochemistry of SN1 Reactions
68Generalization
- Nucleophilic substitutions that
exhibitfirst-order kinetic behavior are not
stereospecific.
69Stereochemistry of an SN1 Reaction
R-()-2-Bromooctane
70Figure 8.5
Ionization stepgives carbocation threebonds to
chiralitycenter become coplanar
Leaving group shieldsone face of
carbocationnucleophile attacks faster at
opposite face.
71 728.9Carbocation Rearrangementsin SN1 Reactions
73Because...
- carbocations are intermediatesin SN1 reactions,
rearrangementsare possible.
74Example
758.10Effect of Solventon the Rate of
Nucleophilic Substitution
76In general...
- SN1 Reaction Rates Increase in Polar Solvents
77Table 8.6SN1 Reactivity versus Solvent Polarity
Solvent Dielectric Relative constant rate ace
tic acid 6 1 methanol 33 4 formic
acid 58 5,000 water 78 150,000
78transition state stabilized by polar solvent
R
energy of RX not much affected by polarity of
solvent
RX
79transition state stabilized by polar solvent
activation energy decreases rate increases
R
energy of RX not much affected by polarity of
solvent
RX
80In general...
- SN2 Reaction Rates Increase inPolar Aprotic
Solvents
An aprotic solvent is one that doesnot have an
OH group.
81Table 8.7SN2 Reactivity versus Type of Solvent
CH3CH2CH2CH2Br N3
- Solvent Type Relative rate
- CH3OH polar protic 1
- H2O polar protic 7
- DMSO polar aprotic 1300
- DMF polar aprotic 2800
- Acetonitrile polar aprotic 5000
82- Mechanism SummarySN1 and SN2
83When...
- 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
848.11Substitution and Eliminationas Competing
Reactions
85Two Reaction Types
Alkyl halides can react with Lewis bases by
nucleophilic substitution and/or elimination.
86Two Reaction Types
How can we tell which reaction pathway is
followed for a particular alkyl halide?
?-elimination
H
H
X
Y
nucleophilic substitution
87Elimination versus Substitution
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.
88Example
NaOCH2CH3 ethanol, 55C
89Figure 8.11
E2
Br
90Figure 8.7
SN2
Br
91When is substitution favored?
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
92Uncrowded Alkyl Halides
Decreased crowding at carbon that bears the
leaving group increases substitution relative to
elimination.
93But a crowded alkoxide base can favor elimination
even with a primary alkyl halide.
- primary alkyl halide bulky base
94When is substitution favored?
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
95Weakly Basic Nucleophile
Weakly basic nucleophile increases substitution
relative to elimination
secondary alkyl halide weakly basic nucleophile
96Weakly Basic Nucleophile
Weakly basic nucleophile increases substitution
relative to elimination
secondary alkyl halide weakly basic nucleophile
97Tertiary Alkyl Halides
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.
98Example
998.12Sulfonate EstersasSubstrates in
Nucleophilic Substitution
100Leaving 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
101Other RX compounds
Alkylmethanesulfonate(mesylate)
Alkylp-toluenesulfonate(tosylate)
- undergo same kinds of reactions as alkyl halides
102Preparation
Tosylates are prepared by the reaction of
alcohols with p-toluenesulfonyl
chloride(usually in the presence of pyridine)
pyridine
103Tosylates undergo typical nucleophilic
substitution reactions
KCN
ethanol-water
104- The best leaving groups are weakly basic
105Table 8.8Approximate 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 -2.8 CF3SO2O 108
CF3SO2OH -6
106Table 8.8Approximate 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 -2.8 CF3SO2O 108
CF3SO2OH -6
Sulfonate esters are extremely good leaving
groups sulfonate ions are very weak bases.
107Tosylates can be converted to alkyl halides
NaBr
DMSO
(82)
- Tosylate is a better leaving group than bromide.
108Tosylates 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
109Tosylates 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.
1108.13Looking Back Reactions of
AlcoholswithHydrogen Halides
111Secondary alcohols react with hydrogen halides
with net inversion of configuration
112Secondary alcohols react with hydrogen halides
with net inversion of configuration
- Most reasonable mechanism is SN1 with front side
of carbocation shielded by leaving group
H
CH3
C
Br
87
(CH2)5CH3
HBr
13
113Rearrangements can occur in the reaction of
alcohols with hydrogen halides
HBr
93
7
114Rearrangements can occur in the reaction of
alcohols with hydrogen halides
HBr
7
93
Br
Br