9-1Chapter 9 Nucleophilic Substitution & -Elimination
1. Nucleophilic Aliphatic Substitution 2. Solvents for Nucleophilic Substitution Reactions3. Mechanisms of Nucleophilic aliphatic substitution4. Evidence of Sn1 / Sn2 Mechanisms5. Analysis of some Nucleophilic Substitution Rx’s
IC
H
H3C DNC
CH
H3CD
(-):CN:
(-)I
6. -Elimination7. -Elimination mechanism8. Evidence for E1 and E29. Substitution vs Elimination
C
CBr
H R
CH2
CH R Br
+tBu
OHH
H
tBuO H
+ +
9-2substitution
-elimination
rxs can compete leads to by-products (additional products)
C C HC
H3C
HHNa(+) (-)Br+
Br
C C HC
H3C
Br HH
Na
+
H
H C C H+ C C HH+ Na(+) (-)Br+
4
9-3
Product(s)
Leaving group - stable with pair of e’ss, weak B:
9 Nucleophilic Substitution
Nu: + R3C-X R3C-Nu + X:(-)
conditions
Reactions with Lewis :Bases / :Nucleophiles
Conditions - solvent, temperature, etc
H-OR C C H3N,, [e- rich]
9-4
Nucleophilic SubstitutionNucleophilic Substitution(see Table 9.1 for more examples)
Rx:
H OH3C Br
H-O CH3 alcohol
H3C X Nu CH3Nu: + + :X:
H3C BretherO CH3H3C OH3C
N CH3C Br
C CH3 nitrileN
C CH3C Br
C CH3 acetyleneCH H (Chap 7)
4
9-5
Nucleophilic SubstitutionNucleophilic Substitutionexamples Table 9.1 continued
H SH3C Br
H-S CH3 thiol (mercaptan)
O
CO
CH2
CH3
C
H
Br
H
H+O
CO
CH2
CH3
C
H
H
H
ester
N
H
C
H
CH3
Br
+
H
C
H
H3C
N NNN Nazide
2
9-6
OCH2
C
CH3
C
H
I
H
H
+ C
H H
HH3C
H H
OCH2
C
CH3
H3C
H
H
OHCHIHH+ CHHHH OHH
OHCHIHH+ CHHHH OHH
OHCHIHH+ CHHHHOHH
OHCHIHH+ CHHHHOHH
H
OH
HC
H
H
I
+H
CH
H
OH
H
H
NH
HC
H
CH3
I
+H
CH
H3C
NH
H
H
H
Nucleophilic SubstitutionNucleophilic Substitutionexamples Table 9.1 continued
amine
alcohol
ether
(after -H+)
6
9-7
APROTIC
2. Solvents2. Solvents
PROTIC [H+]
NON-POLAR
dielectric constant
≥ 15
≤ 5
9-8
APROTIC PROTIC [H+]
NON-POLAR
dielectric constant
≥ 15
≤ 5
DMSO 48.9acetonitrile 37.5DMF 36.7acetone 20.7
dichloromethane 9.1
diethyl ether 4.3toluene 2.3hexane 1.9
2. Solvents of reaction (rx)2. Solvents of reaction (rx)
9-9
water 79formic acid 59methanol 33ethanol 24
acetic acid 6.2
APROTIC
2. Solvents2. Solvents
PROTIC [H+]
NON-POLAR
dielectric constant
≥ 15
≤ 5
9-10
3. Substitution Mechanisms3. Substitution Mechanisms
Difference: timing of bond-breaking and making
One simultaneous breaking & making; [SN2]
Other, break then make bonds stepwise; [SN1]
2 limiting mechanisms for substitution
(SN2, SN1)
5
9-11
CHO Br
HH
H
t.s. simultaneous bond breaking and making
C
H
H
H+H-O Br
Mechanism - SMechanism - SNN22
C
H
H
HBr+H-O
sp2
C
3
9-12
CH3CH2C
CH3
H3CBr
+ Na I
polarsolvent
CH3CH2C
CH3
H3CI
BrNa
+
C
CH2
CH3
H3C
Br+
CH3
+ other products[important!]
Mechanism - SMechanism - SNN11
4
9-13
SSNN reactions reactions
Reactant structure have on mechanism/rate?
Structure of Nu: have on mechanism/rate?
Leaving group have on rate?
What effect does the:
What is: The stereochemical course of SN reaction?
The role of the solvent?
When or why: Does rearrangement occur?
5
9-14
Kinetics/NucleophilicityKinetics/Nucleophilicity
:Nucleophilicity - kinetic, speed of rxn.
timeNu: C X
H
HHCNu
H
HH+ X(-)
+
-
Nu: or B: H B-H+
:Basicity - equilibrium
Nucleophiles are also bases
:Nucleophilicity and :Basicity have correlations
4
9-15
Reaction rate depends on [RX] unimolecular rx
rate = k[(CH3)3CBr]
k - rate constant
1st order kinetics / stepwise
CH3CH2C
CH3
H3CBr
+ Na I
polarsolvent
CH3CH2C
CH3
H3CI
BrNa
+
C
CH2
CH3
H3C
Br+
CH3
Kinetics - SKinetics - SNN11
4
9-16
both reactants in rate limiting step bimolecular reaction
rate = k[ CH3Br ][ -OH ] 2nd order kinetics
CHO Br
HH
H
C
H
H
H+H-O Br
kinetics - Skinetics - SNN22
C
H
H
HBr+H-O
9-17rx profile:
t.s.1
t.s.2
SM products
prog of rx
H
R+
SN1
E
t.s.
SM products
prog of rx
H
C
CH3
CH3
H3CC
H
H
H
Br
OH
SN2
2
9-18substitution SN1 or SN2?
Br CNa+ + Na+ -BrN::C N: polarsolv.
:C N:Br
OR
:C N:Br
2
9-19SSNN1 or S1 or SNN2 with a 22 with a 2oo RX is RX is on nucleophile on nucleophile
nu
cleo
pil
icit
y
moderate
strong
weak
H3CSH, RSH, R2SH3N, RNH2,R2NH, R3N
H3CC OO-
RC OO-,
Cl-, F-
H2OH3COH, ROH
H3CC OOH
RC OOH
,
Br-, I-
H3CS-, RS-
HO-, H3CO-, RO-, [H2N-,(CH3)3C-O-
R C C-, R-]N C-, N3
-
strongbases
9-20
:C N:Br
substitution SN1 or SN2?
Br CNa+ + Na+ -BrN::C N: polarsolv.
:C N:Br
OR
√
9-21
APROTIC
2. Solvents2. Solvents
PROTIC [H+]
NON-POLAR
dielectric constant
≥ 15
≤ 5
E+ -Nu E+ -Nupolar
3
9-22
Solvents effects on Nu:Solvents effects on Nu:--
Protic AproticThe greater the the solvent’s dielectric
constant, the better ions of opposite charge are separated.
Polar and Nonpolar Solvents
E+ -Nu E+ -Nupolar
2
9-23
POLAR APROTIC solvents effective in solvating cations
but poorly solvate anions, e.g.:
Solvents effects on Nu:Solvents effects on Nu:--
The freer the Nucleophile’s e(-)s
the greater its Nucleophilicity
2
9-24
SO
SO
APROTIC solvents solvate cations
F-
Na+
Na+S O
SO
Na+
S
O
S
O
S O SO
SO
SO
SO
SO
F- “free” of Na+
3
9-25
APROTIC PROTIC [H+]
NON-POLAR
dielectric constant
≥ 15
≤ 5
DMSO 48.9acetonitrile 37.5DMF 36.7acetone 20.7
solvents of Ssolvents of SNN2 rx2 rx
9-26PROTIC solvents solvate cations & anions
e.g. CH3OH
F-
Na+H
OH3C
H O CH3F-
Na+H
OH3C
HO
H3C
HO
CH3
H O CH3HOH3C F-H
O CH3
HO
H3C
Na+H
OH3C H
OCH3
HO
CH3
HO
H3C
2
9-27SN1rx on separating charges (+/-) in t.s.
C
CH3
CH3
H3C Cl Br(-) insolvent C
CH3
CH3
H3C Br
rx rateTHF* - 0.05Acetone - 0.5
H2O - 4x103
*dielectric constant 7
protic polar solvents separate cations & anions
tBu-X tBu X tBu + X+ -
:Nu(-)tBu-Nu
4
9-28
water 79formic acid 59methanol 33ethanol 24
APROTIC
2. Solvents2. Solvents
PROTIC [H+]
NON-POLAR
dielectric constant
≥ 15
≤ 5
9-29StereochemistryStereochemistry S SNN11
RCH2
CCl
CH3
PhH3C
CH3OH RCH2
CO
CH3
PhCH3
H3C
CH2
CO
CH3
PhH3C CH3
S+
CH2
C
CH3
PhH3C
H3CO
H
CH2
CO
CH3
PhCH3
H3C
H
CH2
CO
CH3
PhH3C CH3
H
+
[ -H+ ]
4
9-30Stereochemistry SStereochemistry SNN2 -2 - inversion
C
CH3
BrDH
IC
H3C
I DH
+ Bracetone
S R
inversion of configuration S->R & R->S BUT . . .
C
CH3
BrD
H
I-
- t.s.
backside attack,
5
9-31
C
C
N
DH
CCH
SN2 product is clearly inverted but substituent priorities changed
C
C
N
Br
DH
C CH +
S rotation product S
backside attack, inversion of configuration
2
9-32
Structure of RXStructure of RX
R3CXR2CHX
RCH2XCH3X
Reactivities for SN1 and SN2 opposite
increasing stability of carbocationSN1
SN2decreasing steric hindrance
governed by steric factors
governed by electronic factors
5
9-33
SSNN2 sterics - 12 sterics - 1oo
Br C
H
H
H:Nu(-)
3o backside blocked SN1
C
CBrC
C
H HH
HHH
H
H
H
:Nu(-)
6
9-34
C
CBrC
C
H HH
HHH
H
H
H
SSNN2 sterics2 sterics
Br C
H
H
H
:Nu(-)
3o backside blocked SN1
5
9-35
hard to formeasy to form
RX - Carbocations (SRX - Carbocations (SNN1)1)
3o R-X reacts by R+ (SN1) H3C
C Br
H3CH3C
CH3
C
CH3
H3CRDS
etc.
R3C > R2CH > RCH2 > CH3
3
9-36
(S(SNN1) Other Cations1) Other Cations
allylic & benzylic cation- resonance stabilized - delocalizated (+) charge [SN1]
CC
C
H
H
H H
H
1o allylic ≈ 2o alkyl CC
C
H
H
H H
HH
H
9-37
CC
H
H
H CCH3
HC
C
H
H
H CCH3
CH3
2o & 3o allylic cations are even more sable
(S(SNN1) Other Cations1) Other Cations
allylic & benzylic cation- resonance stabilized - delocalizated + charge [SN1]
CC
C
H
H
H H
H
1o allylic
9-38
mech.
What is the effect of resonance on SN1?
CC
H
H
H3C C CH3
H
H
OH
CC
H
H
CH3CH3C
H
OH H
CC
H
H
CH3C
H3C
H
H
OH
CC
H
H
H3C C CH3
H
O HH
-H+
same
write either
CC
H
H
H3C C CH3
H
Br
CC
H
H
H3C C CH3
H
OH
H2O+ H-BrSN1rx
6
9-39
(S(SNN1) Other Cations1) Other Cations
allylic & benzylic cation- resonance stabilized - delocalizated (+)-charge [SN1]
CR2 CR2 CR2 CR2
CR2
or hybrid
4
9-40
allylic allylic (benzylic)(benzylic) facilitates S facilitates SNN22
H
H
H
H:Br:H3C-O:
Br: H3CO+ :Br:H3CO: - +
2
9-41
Leaving group
X - gains e(-)s (Lewis base ) - less basic or more stable with e(-)s
better leaving gp. e.g. (-)OH
vs (-)Cl
Nu: + R-X Nu R X Nu-R + :X
strong base
“neutral”
as leaving gp Cl(-) >>> (-)OH
8
9-42
I(-) > Br(-) > Cl(-) ~ H2O > F(-) > AcO(-) > HO(-) > RO(-) > R2N(-)
good leaving gp.
stability of group with e(-)s
special casesnot leaving gp.
Leaving group
9-43
OH
NH2
I
Cl
OCH3
Na+ -SCH3
DMF
Which of the given substrates would undergo SN2 substitution? Product(s)? Reason?
SCH3
NaI or NaCl+
strong bases: (-)OH, (-)OCH3; (-)NH2 even stronger!
not leaving groups3
9-44Other concerns - Rearrangements SN1 yes (R+); SN2 no
HBr O-CH3
O-CH3
+ + otherO CH3
H
H
O CH3
H
O
H
CH3
O-CH3
H
H
O CH3
H
H
6
9-45
Summary of SSummary of SNN Rx’s Rx’sAlkyl Halide
CH3Xmethyl
SN2 SN1
SN1 does not occur. methyl cation too unstable
SN2
R2CHXsecondary SN1 favored with poor
nucleophiles.
SN2 favored inwith good nucleophiles
RCH2Xprimary No SN1 , 1° cations
rarely observed SN2
TertiaryR3CX
SN2 does notoccur; sterichindrance
SN1 - ease offormation of 3o carbocations
stereocenter substitution
inversion racemization4
9-46
polar protic
unimolecular
Guidelines for Substitution & Elimination
H3C-X
SSNN22
C C XH
H
H
HR
weak
SSNN11 & & E1E1
C C XR'
H
H
HR C C X
R'
R"
H
HR
SSNN22
Nu:- B:-
polar aprotic bimolecular
SSNN11 & & E1E1
weak
B:- Nu:-B:- Nu:-
med. B:good
SSNN22
Nu:-
inversion racemicrearrange
8
9-47SSNN1/S1/SNN2 Problems2 Problems
Predict: products, and show (arrows) the mechanism.
+
Na+ -CN
CBr
CH3
H
DMF
+
Na+ -Br
C
CN
CH3H
SN2
CBr
CH3
H
HOCH3 SN1+ HBrC OCH3
CH3
H
C
CH3H
C
CH3HC
CH3H
C
CH3H
-H+
H
O CH3C OCH3
CH3
H H
11
9-48
a reaction in which a small
molecule (HCl, HBr, HI, or HOH) is eliminated.-Elimination-Elimination
+
C
C
(major )
CH3O-Na+
CH3OH
BrH
HH
HH
CH
H
HH
H
H
HH
9-49
E2: concerted break/make bonds
bimolecular, rate [R-X] [ B: or (Nu:)]
E1: break bond, then make bond unimolecular, rate [ R-X ]
2 limiting mechanisms for -elimination rxs
-Elimination-Elimination
9-50
Br
CH
H
HH H
CH
HH
H
:B:B
CH
H
H H
Zaitsev rule:
major -elimination product = the more stable alkene
(more substituted) .
--eliminationelimination
a
a
a
b
bb
9-51Mechanisms (2) timing of bond
breaking/making differs
:B
H
Br
CH
HH
H
E2
H
Br
CH
HH
H
B -
-
C
H
HHH
9-52
H
Br
CH
HH
H
H
Br
CH
HH
H
B -
-
C
H
HHH
E1
H
C
HHH
H
H
Br
CH
HH
H
-
+
Mechanisms (2) timing of bond breaking/making differs
E2
9-53
CHH
H
H
ionization, rate determining step (same as SN1)
E1 mechanismE1 mechanism
H
SM productprogress of reaction
R+
Eac
t
t.s.1t.s.2
H
Br
CH
HH
H
H
C
HHH
H
3
9-54
E2 mechanismE2 mechanismone-step mechanism; concerted bond-breaking
and bond-forming
t.s.
SM productsprog of rx
H
+O
CH2
H3CBr
HH CH3
+ +Br-
OCH2
H3C
H
H CH3
2
9-55
Stereoselectivity of E2Stereoselectivity of E2
E2 most favorable (lowest Ea) - H and X are anti and coplanar
C C
H
XH
H
HR
ButO-
C C
X-
HH
HR
ButOH
1
9-56
Stereoselectivity of E2Stereoselectivity of E2
C CHH
HR
ButO-
X
H
C C
X-
HH
HR
ButOH
E2 most favorable (lowest Ea) - H and X are anti and coplanar
9-57
Regioselectivity of E1/E2Regioselectivity of E1/E2
E1: major product is the more stable alkene
E2: the major product is usually the more stable alkene, but on orientation of H and X
(1.)
(2.)
CH3
Br
H
H
CH3
H
H
Br
*also SN1 products
CH3
H
HK+ -OtBu
CH3
HK+ -OtBu
HOEt* or
HOEt* how?
4
9-58
CH3
H
H
Br
CH3
Br
H
H
EtOH
Stereochemistry of E1Stereochemistry of E1
CH3
H
CH3
HH
CH3
H
H
(1.)
(2.)
3
9-59
CH3
H
H
H
H
CH3Br
tBuO-H
H
H
Stereochemistry of E2Stereochemistry of E2
The only anti-coplanar H to X arrangement forces formation of less stable olefin
(2.)
9-60
E2
branching hinders SN2
X
H
H3CH
HCH3
SN2Nu:-Nu:-
X -
H
H3CH
HCH3
Nu -
H3CH H
CH3
Nu:-
X -
H
H3CH
HCH3
Nu -
H
H3CH H
CH3
Nu
Nu:-
6
9-61
SSNN vs E vs E
Many nucleophiles are also strong bases (OH- and RO-), thus SN and E reactions often compete.
C CH X + Nu-
C CH Nu X-+
C C H-Nu+ X-+E
SN
9-62Guidelines for Substitution & Elimination
H3C-X
SSNN22
C C XH
H
H
HR
E2E2
strongbulky
(tBuO-)
weak
SSNN11 & & E1E1
SSNN11 & & E1E1
weak
C C XR'
H
H
HR C C X
R'
R"
H
HR
B:- Nu:-
E2E2
strong B:
med. B:good
SSNN22
E2E2strong
B:- Nu:-
SSNN22
Nu:- B:-
polar protic
unimolecular
polar aprotic bimolecular
Nu:-
inversionstereochem
racemicrearrange
11
