Lecture 15- Nucleophilic Substit
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General
Organic Chemistry Two credits Second Semester 2009
King Saud bin Abdulaziz University for Health Science
Reference Book: Organic Chemistry: A Brief Course, by Robert C. Atkins and Francis A. Carey Third Edition
Instructor: Rabih O. Al-Kaysi, PhD.
Lecture 15
Chapter 8 Nucleophilic Substitution
Nucleophiles and Nucleophilicity
Dr. Wolf's CHM 201 & 202
8-3
Nucleophiles Nucleophiles The nucleophiles described earlier have been anions. .. – HO: HO .. :
.. – HS: HS .. :
.. – CH3O : ..
:N
– C:
etc.
Not all nucleophiles are anions. Many are neutral. .. .. CH3OH NH : HOH for example 3 .. .. All nucleophiles, however, are Lewis bases. Dr. Wolf's CHM 201 & 202
8-4
Nucleophiles Nucleophiles
Many of the solvents in which nucleophilic substitutions are carried out are themselves nucleophiles. .. .. CH3OH for example HOH .. .. The Theterm termsolvolysis solvolysisrefers refersto toaanucleophilic nucleophilic substitution substitutionininwhich whichthe thenucleophile nucleophileisisthe thesolvent. solvent.
Dr. Wolf's CHM 201 & 202
8-5
Solvolysis Solvolysis substitution by an anionic nucleophile R—X + :Nu—
R—Nu + :X—
solvolysis R—X + :Nu—H
+ R—Nu—H + :X—
step in which nucleophilic substitution occurs
Dr. Wolf's CHM 201 & 202
8-6
Solvolysis Solvolysis substitution by an anionic nucleophile R—X + :Nu—
R—Nu + :X—
solvolysis R—X + :Nu—H
+ R—Nu—H + :X—
products of overall reaction
R—Nu + HX
Dr. Wolf's CHM 201 & 202
8-7
Example: Example: Methanolysis Methanolysis Methanolysis is a nucleophilic substitution in which methanol acts as both the solvent and the nucleophile. CH3 R—X + : O:
+ R O:
H
H
Dr. Wolf's CHM 201 & 202
CH3
CH3 –H+
R
O .: .
The product is a methyl ether.
8-8
Typical Typicalsolvents solventsininsolvolysis solvolysis solvent
product from RX
water (HOH) methanol (CH3OH) ethanol (CH3CH2OH)
ROH ROCH3 ROCH2CH3 O
O formic acid (HCOH) O acetic acid (CH3COH) Dr. Wolf's CHM 201 & 202
ROCH O ROCCH3 8-9
Nucleophilicity
Rank Rank
Nucleophile Nucleophile
strong strong good good
- RS II-,-,HS , HS , RS --Br , HO Br , HO, , ---RO , CN , N RO , CN , N3 3 -- --NH , Cl , F , RCO NH3 3, Cl , F , RCO2 2 HH2O, ROH O, ROH 2 RCO RCO2H 2H
fair fair weak weak very veryweak weak Dr. Wolf's CHM 201 & 202
2
Relative Relative rate rate 5 >10 >105 44 10 10 33 10 10 11 -2-2 10 10
8-10
Major Majorfactors factorsthat thatcontrol controlnucleophilicity nucleophilicity
1) basicity 2) solvation small negative ions are highly solvated in protic solvents large negative ions are less solvated 3) polarizability
Dr. Wolf's CHM 201 & 202
8-11
Nucleophilicity
Rank Rank
Nucleophile Nucleophile
good good fair fair
– – – RO – HO , HO , RO –– RCO RCO2 2
weak weak
HH2O, ROH O, ROH 2
2
Relative Relative rate rate 4 10 104 33 10 10
11
When the attacking atom is the same (oxygen in this case), nucleophilicity increases with increasing basicity. Dr. Wolf's CHM 201 & 202
8-12
Major Majorfactors factorsthat thatcontrol controlnucleophilicity nucleophilicity
1) basicity 2) solvation small negative ions are highly solvated in protic solvents large negative ions are less solvated 3) polarizability
Dr. Wolf's CHM 201 & 202
8-13
Nucleophilicity
Rank Rank
Nucleophile Nucleophile
strong strong good good
II- -Br Br
fair fair
-- -Cl Cl, ,FF
Relative Relative rate rate 5 >10 >105 44 10 10 33 10 10
A tight solvent shell around an ion makes it less reactive. Larger ions are less solvated than smaller ones and are more nucleophilic. Dr. Wolf's CHM 201 & 202
8-14
Major Majorfactors factorsthat thatcontrol controlnucleophilicity nucleophilicity
1) basicity 2) solvation small negative ions are highly solvated in protic solvents large negative ions are less solvated 3) polarizability
Dr. Wolf's CHM 201 & 202
8-15
Nucleophilicity
Rank Rank
Nucleophile Nucleophile
strong strong good good
II- -Br Br
fair fair
-- -Cl Cl, ,FF
Relative Relative reactivity reactivity 55 >10 >10 44 10 10 33 10 10
More polarizable ions are more nucleophilic than less polarizable ones. Polarizability increases with increasing ionic size. Dr. Wolf's CHM 201 & 202
8-16
Unimolecular Nucleophilic Substitution SN1
Dr. Wolf's CHM 201 & 202
8-17
Tertiary Tertiaryalkyl alkylhalides halidesare arevery veryunreactive unreactiveinin substitutions substitutionsthat thatproceed proceedby bythe theSSNN22mechanism. mechanism.
But they do undergo nucleophilic substitution. But by a mechanism different from SN2. The most common examples are seen in solvolysis reactions.
Dr. Wolf's CHM 201 & 202
8-18
Example Exampleof ofaasolvolysis: solvolysis: Hydrolysis Hydrolysisof oftert tert-butyl -butylbromide bromide CH3
CH3 C
.. : Br ..
H +
: O: H
CH3
CH3
CH3 C
.. OH ..
+
H
.. Br : ..
CH3 Dr. Wolf's CHM 201 & 202
8-19
Example Exampleof ofaasolvolysis: solvolysis: Hydrolysis Hydrolysisof oftert tert-butyl -butylbromide bromide CH3
CH3 C
.. : Br ..
H +
CH3
: O:
+
H
O:
C H
CH3
CH3
H
CH3
+ CH3
CH3 C
.. OH ..
+
H
.. Br : ..
.. – : Br : ..
CH3 Dr. Wolf's CHM 201 & 202
8-20
Example Exampleof ofaasolvolysis: solvolysis: Hydrolysis Hydrolysisof oftert tert-butyl -butylbromide bromide CH3
CH3 C
.. : Br ..
CH3
H +
: O:
CH3
CH3
+
O:
C H
H
H
CH3
+ This is the nucleophilic substitution stage of the reaction; the one with which we are concerned.
Dr. Wolf's CHM 201 & 202
.. – : Br : ..
8-21
Example Exampleof ofaasolvolysis: solvolysis: Hydrolysis Hydrolysisof oftert tert-butyl -butylbromide bromide CH3
CH3 C
.. : Br ..
CH3
H +
: O:
CH3
CH3
+
O:
C H
H
H
CH3
+ The reaction rate is independent of the concentration of the nucleophile and follows a first-order rate law. rate = k[(CH3)3CBr] Dr. Wolf's CHM 201 & 202
.. – : Br : ..
8-22
Example Exampleof ofaasolvolysis: solvolysis: Hydrolysis Hydrolysisof oftert tert-butyl -butylbromide bromide CH3
CH3 C
.. : Br ..
CH3
H +
CH3
: O:
CH3
+
O:
C H
H
H
CH3
+ The mechanism of this step is not SN2. It is called SN1 and begins with ionization of (CH3)3CBr.
Dr. Wolf's CHM 201 & 202
.. – : Br : ..
8-23
rate rate==kk[alkyl [alkylhalide] halide] First-order First-orderkinetics kineticsimplies impliesaaunimolecular unimolecular rate-determining rate-determiningstep. step.
Proposed mechanism is called SN1, which stands for
substitution nucleophilic unimolecular
Dr. Wolf's CHM 201 & 202
8-24
CH3
CH3 .. : Br ..
C CH3
unimolecular slow H3C
+ C
CH3 +
.. – : Br : ..
CH3 Just for general knowledge, will not be tested on Dr. Wolf's CHM 201 & 202
8-25
H3C
CH3
+ C
H : O:
CH3
H
bimolecular fast CH3
CH3
C CH3
+
H
O: H
Just for general knowledge, will not be tested on
Dr. Wolf's CHM 201 & 202
8-26
carbocation formation
carbocation capture R+ proton transfer
RX + ROH2
Just for general knowledge, will not be tested on Dr. Wolf's CHM 201 & 202
ROH 8-27
Characteristics of the SN1 mechanism
first order kinetics: rate = k[RX] 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 Dr. Wolf's CHM 201 & 202
8-28
Carbocation Stability and SN1 Reaction Rates
Dr. Wolf's CHM 201 & 202
8-29
The Therate rateof ofnucleophilic nucleophilicsubstitution substitution by bythe theSSNN11mechanism mechanismisisgoverned governed by byelectronic electroniceffects. effects. Carbocation Carbocationformation formationisisrate-determining. rate-determining. The Themore morestable stablethe thecarbocation, carbocation,the thefaster faster its itsrate rateof offormation, formation,and andthe thegreater greaterthe the rate rateof ofunimolecular unimolecularnucleophilic nucleophilicsubstitution. substitution.
Dr. Wolf's CHM 201 & 202
8-30
Reactivity Reactivitytoward towardsubstitution substitution by bythe theSSNN11mechanism mechanism
RBr solvolysis in aqueous formic acid
Alkyl bromide Class
Relative rate
CH3Br
Methyl
1
CH3CH2Br
Primary
2
(CH3)2CHBr
Secondary
(CH3)3CBr
Tertiary
Dr. Wolf's CHM 201 & 202
43 100,000,000 8-31
Decreasing DecreasingSSNN11reactivity reactivity
(CH3)3CBr (CH3)2CHBr
CH3CH2Br Dr. Wolf's CHM 201 & 202
CH3Br
8-32
Stereochemistry of SN1 Reactions
Dr. Wolf's CHM 201 & 202
8-33
Nucleophilic Nucleophilicsubstitutions substitutionsthat thatexhibit exhibit first-order first-orderkinetic kineticbehavior behaviorare are not notstereospecific. stereospecific.
Dr. Wolf's CHM 201 & 202
8-34
Stereochemistry Stereochemistryof ofan anSSNN11Reaction Reaction CH3
H C
R-(–)-2-Bromooctane
Br
CH3(CH2)5 H CH 3 HO
C (CH2)5CH3
(S)-(+)-2-Octanol (83%) Dr. Wolf's CHM 201 & 202
CH3 H2O
H C
OH
CH3(CH2)5 (R)-(–)-2-Octanol (17%) 8-35
+
Ionization step gives carbocation; three bonds to stereogenic center become coplanar
–
Dr. Wolf's CHM 201 & 202
8-36
+
–
Dr. Wolf's CHM 201 & 202
Leaving group shields one face of carbocation; nucleophile attacks faster at opposite face. 8-37
–
+ – –
More than 50%
Less than 50%
Dr. Wolf's CHM 201 & 202
8-38
Organic Chemistry Two credits Second Semester 2009
King Saud bin Abdulaziz University for Health Science
Reference Book: Organic Chemistry: A Brief Course, by Robert C. Atkins and Francis A. Carey Third Edition
Instructor: Rabih O. Al-Kaysi, PhD.
Lecture 15
Chapter 8 Nucleophilic Substitution
Nucleophiles and Nucleophilicity
Dr. Wolf's CHM 201 & 202
8-3
Nucleophiles Nucleophiles The nucleophiles described earlier have been anions. .. – HO: HO .. :
.. – HS: HS .. :
.. – CH3O : ..
:N
– C:
etc.
Not all nucleophiles are anions. Many are neutral. .. .. CH3OH NH : HOH for example 3 .. .. All nucleophiles, however, are Lewis bases. Dr. Wolf's CHM 201 & 202
8-4
Nucleophiles Nucleophiles
Many of the solvents in which nucleophilic substitutions are carried out are themselves nucleophiles. .. .. CH3OH for example HOH .. .. The Theterm termsolvolysis solvolysisrefers refersto toaanucleophilic nucleophilic substitution substitutionininwhich whichthe thenucleophile nucleophileisisthe thesolvent. solvent.
Dr. Wolf's CHM 201 & 202
8-5
Solvolysis Solvolysis substitution by an anionic nucleophile R—X + :Nu—
R—Nu + :X—
solvolysis R—X + :Nu—H
+ R—Nu—H + :X—
step in which nucleophilic substitution occurs
Dr. Wolf's CHM 201 & 202
8-6
Solvolysis Solvolysis substitution by an anionic nucleophile R—X + :Nu—
R—Nu + :X—
solvolysis R—X + :Nu—H
+ R—Nu—H + :X—
products of overall reaction
R—Nu + HX
Dr. Wolf's CHM 201 & 202
8-7
Example: Example: Methanolysis Methanolysis Methanolysis is a nucleophilic substitution in which methanol acts as both the solvent and the nucleophile. CH3 R—X + : O:
+ R O:
H
H
Dr. Wolf's CHM 201 & 202
CH3
CH3 –H+
R
O .: .
The product is a methyl ether.
8-8
Typical Typicalsolvents solventsininsolvolysis solvolysis solvent
product from RX
water (HOH) methanol (CH3OH) ethanol (CH3CH2OH)
ROH ROCH3 ROCH2CH3 O
O formic acid (HCOH) O acetic acid (CH3COH) Dr. Wolf's CHM 201 & 202
ROCH O ROCCH3 8-9
Nucleophilicity
Rank Rank
Nucleophile Nucleophile
strong strong good good
- RS II-,-,HS , HS , RS --Br , HO Br , HO, , ---RO , CN , N RO , CN , N3 3 -- --NH , Cl , F , RCO NH3 3, Cl , F , RCO2 2 HH2O, ROH O, ROH 2 RCO RCO2H 2H
fair fair weak weak very veryweak weak Dr. Wolf's CHM 201 & 202
2
Relative Relative rate rate 5 >10 >105 44 10 10 33 10 10 11 -2-2 10 10
8-10
Major Majorfactors factorsthat thatcontrol controlnucleophilicity nucleophilicity
1) basicity 2) solvation small negative ions are highly solvated in protic solvents large negative ions are less solvated 3) polarizability
Dr. Wolf's CHM 201 & 202
8-11
Nucleophilicity
Rank Rank
Nucleophile Nucleophile
good good fair fair
– – – RO – HO , HO , RO –– RCO RCO2 2
weak weak
HH2O, ROH O, ROH 2
2
Relative Relative rate rate 4 10 104 33 10 10
11
When the attacking atom is the same (oxygen in this case), nucleophilicity increases with increasing basicity. Dr. Wolf's CHM 201 & 202
8-12
Major Majorfactors factorsthat thatcontrol controlnucleophilicity nucleophilicity
1) basicity 2) solvation small negative ions are highly solvated in protic solvents large negative ions are less solvated 3) polarizability
Dr. Wolf's CHM 201 & 202
8-13
Nucleophilicity
Rank Rank
Nucleophile Nucleophile
strong strong good good
II- -Br Br
fair fair
-- -Cl Cl, ,FF
Relative Relative rate rate 5 >10 >105 44 10 10 33 10 10
A tight solvent shell around an ion makes it less reactive. Larger ions are less solvated than smaller ones and are more nucleophilic. Dr. Wolf's CHM 201 & 202
8-14
Major Majorfactors factorsthat thatcontrol controlnucleophilicity nucleophilicity
1) basicity 2) solvation small negative ions are highly solvated in protic solvents large negative ions are less solvated 3) polarizability
Dr. Wolf's CHM 201 & 202
8-15
Nucleophilicity
Rank Rank
Nucleophile Nucleophile
strong strong good good
II- -Br Br
fair fair
-- -Cl Cl, ,FF
Relative Relative reactivity reactivity 55 >10 >10 44 10 10 33 10 10
More polarizable ions are more nucleophilic than less polarizable ones. Polarizability increases with increasing ionic size. Dr. Wolf's CHM 201 & 202
8-16
Unimolecular Nucleophilic Substitution SN1
Dr. Wolf's CHM 201 & 202
8-17
Tertiary Tertiaryalkyl alkylhalides halidesare arevery veryunreactive unreactiveinin substitutions substitutionsthat thatproceed proceedby bythe theSSNN22mechanism. mechanism.
But they do undergo nucleophilic substitution. But by a mechanism different from SN2. The most common examples are seen in solvolysis reactions.
Dr. Wolf's CHM 201 & 202
8-18
Example Exampleof ofaasolvolysis: solvolysis: Hydrolysis Hydrolysisof oftert tert-butyl -butylbromide bromide CH3
CH3 C
.. : Br ..
H +
: O: H
CH3
CH3
CH3 C
.. OH ..
+
H
.. Br : ..
CH3 Dr. Wolf's CHM 201 & 202
8-19
Example Exampleof ofaasolvolysis: solvolysis: Hydrolysis Hydrolysisof oftert tert-butyl -butylbromide bromide CH3
CH3 C
.. : Br ..
H +
CH3
: O:
+
H
O:
C H
CH3
CH3
H
CH3
+ CH3
CH3 C
.. OH ..
+
H
.. Br : ..
.. – : Br : ..
CH3 Dr. Wolf's CHM 201 & 202
8-20
Example Exampleof ofaasolvolysis: solvolysis: Hydrolysis Hydrolysisof oftert tert-butyl -butylbromide bromide CH3
CH3 C
.. : Br ..
CH3
H +
: O:
CH3
CH3
+
O:
C H
H
H
CH3
+ This is the nucleophilic substitution stage of the reaction; the one with which we are concerned.
Dr. Wolf's CHM 201 & 202
.. – : Br : ..
8-21
Example Exampleof ofaasolvolysis: solvolysis: Hydrolysis Hydrolysisof oftert tert-butyl -butylbromide bromide CH3
CH3 C
.. : Br ..
CH3
H +
: O:
CH3
CH3
+
O:
C H
H
H
CH3
+ The reaction rate is independent of the concentration of the nucleophile and follows a first-order rate law. rate = k[(CH3)3CBr] Dr. Wolf's CHM 201 & 202
.. – : Br : ..
8-22
Example Exampleof ofaasolvolysis: solvolysis: Hydrolysis Hydrolysisof oftert tert-butyl -butylbromide bromide CH3
CH3 C
.. : Br ..
CH3
H +
CH3
: O:
CH3
+
O:
C H
H
H
CH3
+ The mechanism of this step is not SN2. It is called SN1 and begins with ionization of (CH3)3CBr.
Dr. Wolf's CHM 201 & 202
.. – : Br : ..
8-23
rate rate==kk[alkyl [alkylhalide] halide] First-order First-orderkinetics kineticsimplies impliesaaunimolecular unimolecular rate-determining rate-determiningstep. step.
Proposed mechanism is called SN1, which stands for
substitution nucleophilic unimolecular
Dr. Wolf's CHM 201 & 202
8-24
CH3
CH3 .. : Br ..
C CH3
unimolecular slow H3C
+ C
CH3 +
.. – : Br : ..
CH3 Just for general knowledge, will not be tested on Dr. Wolf's CHM 201 & 202
8-25
H3C
CH3
+ C
H : O:
CH3
H
bimolecular fast CH3
CH3
C CH3
+
H
O: H
Just for general knowledge, will not be tested on
Dr. Wolf's CHM 201 & 202
8-26
carbocation formation
carbocation capture R+ proton transfer
RX + ROH2
Just for general knowledge, will not be tested on Dr. Wolf's CHM 201 & 202
ROH 8-27
Characteristics of the SN1 mechanism
first order kinetics: rate = k[RX] 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 Dr. Wolf's CHM 201 & 202
8-28
Carbocation Stability and SN1 Reaction Rates
Dr. Wolf's CHM 201 & 202
8-29
The Therate rateof ofnucleophilic nucleophilicsubstitution substitution by bythe theSSNN11mechanism mechanismisisgoverned governed by byelectronic electroniceffects. effects. Carbocation Carbocationformation formationisisrate-determining. rate-determining. The Themore morestable stablethe thecarbocation, carbocation,the thefaster faster its itsrate rateof offormation, formation,and andthe thegreater greaterthe the rate rateof ofunimolecular unimolecularnucleophilic nucleophilicsubstitution. substitution.
Dr. Wolf's CHM 201 & 202
8-30
Reactivity Reactivitytoward towardsubstitution substitution by bythe theSSNN11mechanism mechanism
RBr solvolysis in aqueous formic acid
Alkyl bromide Class
Relative rate
CH3Br
Methyl
1
CH3CH2Br
Primary
2
(CH3)2CHBr
Secondary
(CH3)3CBr
Tertiary
Dr. Wolf's CHM 201 & 202
43 100,000,000 8-31
Decreasing DecreasingSSNN11reactivity reactivity
(CH3)3CBr (CH3)2CHBr
CH3CH2Br Dr. Wolf's CHM 201 & 202
CH3Br
8-32
Stereochemistry of SN1 Reactions
Dr. Wolf's CHM 201 & 202
8-33
Nucleophilic Nucleophilicsubstitutions substitutionsthat thatexhibit exhibit first-order first-orderkinetic kineticbehavior behaviorare are not notstereospecific. stereospecific.
Dr. Wolf's CHM 201 & 202
8-34
Stereochemistry Stereochemistryof ofan anSSNN11Reaction Reaction CH3
H C
R-(–)-2-Bromooctane
Br
CH3(CH2)5 H CH 3 HO
C (CH2)5CH3
(S)-(+)-2-Octanol (83%) Dr. Wolf's CHM 201 & 202
CH3 H2O
H C
OH
CH3(CH2)5 (R)-(–)-2-Octanol (17%) 8-35
+
Ionization step gives carbocation; three bonds to stereogenic center become coplanar
–
Dr. Wolf's CHM 201 & 202
8-36
+
–
Dr. Wolf's CHM 201 & 202
Leaving group shields one face of carbocation; nucleophile attacks faster at opposite face. 8-37
–
+ – –
More than 50%
Less than 50%
Dr. Wolf's CHM 201 & 202
8-38
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