Chapter 6
Nucleophilic Substitution and Elimination Reactions of Alkyl Halides
Ch. 6 - 1
Ch. 6 - 2
1. Organic Halides
Halogens are more electronegative than carbon
C Xδ+ δ−
X = Cl, Br, I
Ch. 6 - 3
C FH
HH C Cl
H
HH C Br
H
HH C I
H
HH
C–X BondLength (Å) 1.39 1.78 1.93 2.14
C–X BondStrength(kJ/mol)
472 350 293 239
Carbon-Halogen Bond Lengthsand Bond Strength
increase
decrease
Ch. 6 - 4
Chloride
-23.8
13.1
78.4
68
69
51
Group
Me
Et
Bu
sBu
iBu
tBu
Fluoride
-78.4
-37.7
32
-
-
12
Bromide
3.6
38.4
101
91.2
91
73.3
Iodide
42.5
72
130
120
119
100(dec)
1A. Physical Properties of Organic Halides:Boiling Point (bp/oC)
Ch. 6 - 5
Chloride
0.92
0.91(15)
0.89
0.87
0.87
0.84
Group
Me
Et
Bu
sBu
iBu
tBu
Fluoride
0.84(-60)
0.72
0.78
-
-
0.75(12)
Bromide
1.73(0)
1.46
1.27
1.26
1.26
1.22
Iodide
2.28
1.95
1.61
1.60
1.60
1.57(0)
Physical Properties of Organic Halides:Density (ρ)
Ch. 6 - 6
Different Types of Organic Halides Alkyl halides (haloalkanes)
Cl Br Ia 1o chloride a 2o bromide a 3o iodide
Attached to1 carbon atom
C
Attached to2 carbon atoms
C
C
Attached to3 carbon atoms
C
C
C
sp3C X
Ch. 6 - 7
Vinyl halides (Alkenyl halides)
Aryl halides
Acetylenic halides (Alkynyl halides)
sp2
X
sp2
X
benzene or aromatic ring
sp
X
Ch. 6 - 8
C X
sp3
δ+ δ−
Alkyl halides
Prone to undergo Nucleophilic Substitutions (SN) and Elimination Reactions (E) (the focus of this Chapter)
sp2
X X X
sp2sp
Different reactivity than alkyl halides, and do not undergo SN or E reactions
Ch. 6 - 9
Nu + C Xδ+ δ− CNu + X
(nucleophile) (substrate) (product) (leavinggroup)
The Nu⊖
donatesan e⊖ pairto thesubstrate
The bondbetweenC and LGbreaks,giving bothe⊖ from thebond to LG
The Nu⊖ usesits e⊖ pair toform a newcovalent bondwith thesubstrate C
The LGgains thepair of e⊖
originallybondedin thesubstrate
2. Nucleophilic Substitution Reactions
Ch. 6 - 10
Two types of mechanisms● 1st type: SN2 (concerted mechanism)
R
C Br
RR
δ+ δ−HO
R
C
RR
BrHOδ− δ−
transition state (T.S.)+ Br-
R
CHO
RR
Timing of The Bond Breaking & Bond Making Process
Ch. 6 - 11
RC BrRR
RCRR
Br(k1)
Step (1):
+slowr.d.s.
H2O(k3)
RCRR
OH
H RCRR
OH H3O+
Step (3)
+ +
RCRR
H2O(k2)
RCRR
OH
HStep (2)
+
k1 << k2 and k3
fast
fast
● 2nd type: SN1 (stepwise mechanism)
Ch. 6 - 12
C Xδ+ δ−
A reagent that seeks a positive center Has an unshared pair of e⊖
e.g.: HO , CH3O , H2N
(negative charge)
H2O, NH3 (neutral)
This is the positivecenter that theNu⊖ seeks
3. Nucleophiles
Ch. 6 - 13
Examples:
HO + CCl
ClH H
CH3(substrate) (product) (L.G.)(Nu )
COH
H H
CH3+
O + CCl
ClH H
CH3(substrate) (L.G.)(Nu )
CO
H H
CH3+
H H H
H
COH
H H
CH3H3O+
(product)
Ch. 6 - 14
To be a good leaving group, the substituent must be able to leave as a relatively stable, weakly basic molecule or ion e.g.: I⊖, Br⊖, Cl⊖, TsO⊖, MsO⊖, H2O, NH3
OMs =
OTs = O SO
OCH3
O SO
OCH3
(Tosylate)
(Mesylate)
4. Leaving Groups
Ch. 6 - 15
The rate of the substitution reaction is linearly dependent on the concentration of OH⊖ and CH3Br
Overall, a second-order reaction ⇒bimolecular
HO + CH3 Br HO CH3 +
Rate = k[CH3Br][OH-]
Br
5. Kinetics of a Nucleophilic SubstitutionReaction: An SN2 Reaction
Ch. 6 - 16
The rate of reaction can be measured by● The consumption of the reactants
(HO⊖ or CH3Cl) or● The appearance of the products
(CH3OH or Cl⊖) over time
HO + C Cl HO C +
(Nu )
ClH
H
H
H
H
H
(substrate) (product)(leavinggroup)
e.g.:
5A. How Do We Measure the Rate of This Reaction?
Ch. 6 - 17
Time, t
Conc
entr
atio
n, M [CH3Cl] ↓
[CH3OH] ↑
Graphically…
Rate =Δ[CH3Cl]
Δt= −
[CH3Cl]t=t − [CH3Cl]t=0
Time in seconds
[CH3Cl] ↓[CH3OH] ↑
Ch. 6 - 18
Time, t
Conc
entr
atio
n, M
[CH3Cl]
Initial Rate
[CH3Cl]t=0
[CH3Cl]t=t
Initial Rate(from slope) = −
[CH3Cl]t=t − [CH3Cl]t=0
Δt
Ch. 6 - 19
Example:
HO + Cl CH3 HO CH3 + Cl60oCH2O
[OH⊖]t=0 [CH3Cl]t=0Initial rate
mole L-1, s-1 Result
1.0 M 0.0010 M 4.9 10-7
1.0 M 0.0020 M 9.8 10-7 Doubled
2.0 M 0.0010 M 9.8 10-7 Doubled
2.0 M 0.0020 M 19.6 10-7 Quadrupled
Ch. 6 - 20
Conclusion:
HO + Cl CH3 HO CH3 + Cl60oCH2O
● The rate of reaction is directly proportional to the concentration of either reactant.
● When the concentration of either reactant is doubled, the rate of reaction doubles.
Ch. 6 - 21
The Kinetic Rate Expression
Rate α [OH⊖][CH3Cl]
HO + Cl CH3 HO CH3 + Cl60oCH2O
[OH⊖][CH3Cl]
Initial Ratek =
= 4.9 10-7 L mol-1 s-1
Rate = k[OH⊖][CH3Cl]
Ch. 6 - 22
H
C Br
HH
δ+ δ−HO
H
C
HH
BrHOδ− δ−
transition state (T.S.)+ Br-
H
CHO
HH
negative OH⊖
brings an e⊖pair to δ+ C; δ–
Br begins to move away with an e⊖ pair
O–C bond partially formed; C–Br bond partially broken. Configuration of C begins to invert
O–C bond formed; Br⊖
departed. Configuration of C inverted
6. A Mechanism for the SN2 Reaction
Ch. 6 - 23
A reaction that proceeds with a negative free-energy change (releases energy to its surroundings) is said to be exergonic
A reaction that proceeds with a positivefree-energy change (absorbs energy from its surroundings) is said to be endergonic
7. Transition State Theory:Free Energy Diagrams
Ch. 6 - 24
At 60oC (333 K)
CH3 Br + OH CH3 OH + Cl
∆Go = -100 kJ/mol
● This reaction is highly exergonic
● This reaction is exothermic
∆Ho = -75 kJ/mol
Ch. 6 - 25
CH3 Br + OH CH3 OH + Cl
● Its equilibrium constant (Keq) is
∆Go = –RT ln Keq
ln Keq =–∆Go
RT=
–(–100 kJ/mol)
(0.00831 kJ K-1 mol-1)(333 K)
= 36.1
Keq = 5.0 ╳ 1015
Ch. 6 - 26
A Free Energy Diagram for a Hypothetical SN2Reaction That Takes Place with a Negative ∆Go
Ch. 6 - 27
The reaction coordinate indicates the progress of the reaction, in terms of the conversion of reactants to products
The top of the energy curve corresponds to the transition state for the reaction
The free energy of activation (∆G‡) for the reaction is the difference in energy between the reactants and the transition state
The free energy change for the reaction (∆Go) is the difference in energy between the reactants and the products
Ch. 6 - 28
A Free Energy Diagram for a HypotheticalReaction with a Positive Free-Energy Change
Ch. 6 - 29
A 10°C increase in temperature will cause the reaction rate to double for many reactions taking place near room temperature
7A. Temperature, Reaction Rate, and the Equilibrium Constant
Distribution of energies at twodifferent temperatures. The number of collisions with energies greater than the free energy of activation is indicated by the corresponding shaded area under each curve.
Ch. 6 - 30
The relationship between the rate constant (k) and ∆G‡
is exponential :
Distribution of energies at twodifferent temperatures. The number of collisions with energies greater than the free energy of activation is indicated by the corresponding shaded area under each curve.
k = k0 e−∆G‡/RT
e = 2.718, the base of natural logarithms
k0 = absolute rate constant, which equals the rate at which all transition states proceed to products (At 25oC,k0 = 6.2 ╳ 1012 s−1 )
Ch. 6 - 31
A reaction with a lower free energy of activation (∆G‡) will occur exponentially faster than a reaction with a higher ∆G‡, as dictated by
Distribution of energies at twodifferent temperatures. The number of collisions with energies greater than the free energy of activation is indicated by the corresponding shaded area under each curve.
k = k0 e−∆G‡/RT
Ch. 6 - 32
HO- + CH3Br
T.S.
CH3OH + Br-
Free
Ene
rgy
Reaction Coordinate
∆Go
∆G∆G =
∆Go =
free energy of activationfree energy change
Exothermic (∆Go is negative) Thermodynamically favorable process
Free Energy Diagram of SN2 Reactions
Ch. 6 - 33
(R)
(S)
CH3
C Br
CH2CH3
HHO +
+ BrCH3
CHO
CH2CH3
H
(inversion)
Inversion of configuration
8.The Stereochemistry of SN2 Reactions
Ch. 6 - 34
CH3 OCH3 + I
Example:
CH3 I + OCH3
Nu⊖ attacks from the TOP face.
(inversion of configuration)
Ch. 6 - 35
+ BrCN
Example:
+ CNBr
Nu⊖ attacks from the BACK face.
(inversion ofconfiguration)
Ch. 6 - 36
CH3C BrCH3CH3
H2OCH3C OHCH3CH3
HBr+ +
9. The Reaction of tert-Butyl Chloridewith Hydroxide Ion: An SN1 Reaction
The rate of SN1 reactions depends only on concentration of the alkyl halide and is independent on concentration of the Nu⊖
Rate = k[RX] In other words, it is a first-order reaction⇒ unimolecular nucleophilic substitution
Ch. 6 - 37
In a multistep reaction, the rate of the overall reaction is the same as the rate of the SLOWEST step, known as the rate-determining step (r.d.s)
For example:
Reactant Intermediate1
Intermediate2
Product(slow)
k1 k2 k3
(fast) (fast)
k1 << k2 or k3
9A. Multistep Reactions & the Rate-Determining Step
Ch. 6 - 38
The opening A is much smaller than openings B and C
The overall rate at which sand reaches to the bottom of the hourglass is limited by the rate at which sand falls through opening A
Opening A is analogous to the rate-determining step of a multistep reaction
A
B
C
Ch. 6 - 39
A multistep process
CH3C BrCH3CH3
CH3CCH3CH3
Br(k1)
Step (1):
+
(ionization of alkyl halide)
slowr.d. step
10. A Mechanism for the SN1 Reaction
Ch. 6 - 40
Free Energy Diagram of SN1 Reactions
T.S. (1)
(CH3)3C-OH
+ Br-
Free
Ene
rgy
Reaction Coordinate
T.S. (2)
T.S. (3)
(CH3)3C -OH2
+ Br-
(CH3)3C
+ Br-
(CH3)3CBr
+ H2O
∆G1
intermediate
Ch. 6 - 41
CH3CCH3CH3
H2O(k2)
CH3CCH3CH3
OH
H
Step (2)
+fast
Ch. 6 - 42
Free Energy Diagram of SN1 Reactions
T.S. (1)
(CH3)3C-OH
+ Br-
Free
Ene
rgy
Reaction Coordinate
T.S. (2)
T.S. (3)
(CH3)3C -OH2
+ Br-
(CH3)3C
+ Br-
(CH3)3CBr
+ H2O
∆G1
intermediate
Ch. 6 - 43
H2O(k3)
CH3CCH3CH3
OH
H CH3CCH3CH3
OH
H3O+
Step (3)
+
+
CH3CCH3CH3
H2O(k2)
CH3CCH3CH3
OH
H
Step (2)
+fast
fast
Ch. 6 - 44
Free Energy Diagram of SN1 Reactions
T.S. (1)
(CH3)3C-OH
+ Br-
Free
Ene
rgy
Reaction Coordinate
T.S. (2)
T.S. (3)
(CH3)3C -OH2
+ Br-
(CH3)3C
+ Br-
(CH3)3CBr
+ H2O
∆G1
intermediate
Ch. 6 - 45
H2O(k3)
CH3CCH3CH3
OH
H CH3CCH3CH3
OH
H3O+
Step (3)
+
+
CH3CCH3CH3
H2O(k2)
CH3CCH3CH3
OH
H
Step (2)
+
k1 << k2 and k3
fast
fast
Ch. 6 - 46
2 intermediates and 3 transition states (T.S.)
CH3
CCH3
CH3
Brδ+ δ−
The most important T.S. for SN1 reactions is T.S. (1) of the rate-determining step (r.d.s.)
Ch. 6 - 47
Carbocations are trigonal planar
The central carbon atom in a carbocation is electron deficient; it has only six e⊖ in its valence shell
The p orbital of a carbocation contains no electrons, but it can accept an electron pair when the carbocation undergoes further reaction
11A. The Structure of Carbocations11. Carbocations
CH3C
H3C CH3
sp2-sp3 π bond
Ch. 6 - 48
General order of reactivity (towards SN1 reaction)● 3o > 2o >> 1o > methyl
The more stable the carbocation formed, the faster the SN1 reaction
11B. The Relative Stabilities ofCarbocations
Ch. 6 - 49
Stability of cations
R
CR R
R
CR H
R
CH H
H
CH H
> > >
most stable (positive inductive effect)
Resonance stabilization of allylic and benzylic cations
CH2 CH2etc.
Ch. 6 - 50
Ph
BrCH2CH3
CH3
CH3OH
(S)
Ph
C
CH2CH3CH3
(trigonal planar)
CH3OHattack from left
CH3OHattack from right
CH3OHPh
CCH3 OCH3
CH2CH3(R) and (S)
racemic mixture
50:50chance
12. The Stereochemistry of SN1 Reactions
Ph
CH3OCH2CH3
CH3
(R)
Ph
OCH3CH2CH3
CH3
(S)(1 : 1)
Ch. 6 - 51
Example:
Br
(R) H2O(SN1)
slowr.d.s.
(one enantiomer)
(carbocation)
H2O
attack from TOP face
H2O attack from BOTTOM face
OH H
OH H
OH
(R)
OH
(S)+
H2O
H2O
racemic mixture( 1 : 1 )
Ch. 6 - 52
tBuCH3⊕
⊕
tBu
O
Me
Me H
tBu
Me
O H
Me
tBu
I
Me MeOH
Example:
slowr.d.s.
MeOH
MeOH
trigonal planar
tBu
OMe
Me tBu
Me
OMe+
MeOH
MeOH
Ch. 6 - 53
The structure of the substrate
The concentration and reactivity of the nucleophile (for SN2 reactions only)
The effect of the solvent
The nature of the leaving group
13. Factors Affecting the Rates of SN1 and SN2 Reactions
Ch. 6 - 54
13A. The Effect of the Structure of the Substrate
General order of reactivity (towards SN2 reaction)
● Methyl > 1o > 2o >> 3o > vinyl or aryl
DO NOT undergo
SN2 reactions
Ch. 6 - 55
Relative Rate (towards SN2)
methyl 1o 2o neopentyl 3o
2 × 106 4 × 104 500 1 < 1Most
reactiveLeast
reactive
CH3 Br CH3CH2 Br CH3CH BrCH3
C CH2BrCH3
CH3CH3 C Br
CH3
CH3CH3
R Br HO+ R OH Br+
For example:
Ch. 6 - 56
HC Br
CH3
CH3
δ+ δ−
HC Br
HH
δ+ δ−
Compare
HO + BrH
CHO
HHfaster
HO + BrH
CHO
CH3
CH3slower
HO
Ch. 6 - 57
+ BrCH3
CHO
CH3
CH3extremely
slow
+ BrH
CHO
CH3
tBuveryslow
HC Br
HtBu
δ+ δ−
CH3
C Br
CH3
CH3
δ+ δ−
HOHO
HOHO
Ch. 6 - 58
Note NO SN2 reaction on sp2 or sp carbons
e.g.
H
H
H
I+ Nu No reaction
No reaction+ NuI
I No reaction+ Nu
sp2
sp2
sp
Ch. 6 - 59
General order of reactivity (towards SN1 reaction)● 3o > 2o >> 1o > methyl
The more stable the carbocationformed, the faster the SN1 reaction
Reactivity of the Substrate in SN1 Reactions
Ch. 6 - 60
Stability of cations
R
CR R
R
CR H
R
CH H
H
CH H
> > >
most stable (positive inductive effect)
Allylic halides and benzylic halides also undergo SN1 reactions at reasonable rates I
Br
an allylic bromide a benzylic iodide
Ch. 6 - 61
Resonance stabilization for allylic and benzylic cations
CH2 CH2etc.
Ch. 6 - 62
For SN1 reactionRecall: Rate = k[RX]● The Nu⊖ does NOT participate in
the r.d.s.● Rate of SN1 reactions are NOT
affected by either the concentration or the identity of the Nu⊖
13B. The Effect of the Concentration& Strength of the Nucleophile
Ch. 6 - 63
For SN2 reactionRecall: Rate = k[RX][RX]● The rate of SN2 reactions depends
on both the concentration and the identity of the attacking Nu⊖
Ch. 6 - 64
Identity of the Nu⊖
● The relative strength of a Nu⊖ (its nucleophilicity) is measured in terms of the relative rate of its SN2 reaction with a given substrate
rapidCH3O + CH3I CH3OCH3 + I
Good Nu⊖
VeryslowCH3OH + CH3I CH3OCH3 + I
Poor Nu⊖
Ch. 6 - 65
The relative strength of a Nu⊖ can be correlated with 3 structural features● A negatively charged Nu⊖ is always a
more reactive Nu⊖ than its conjugated acid e.g. HO⊖ is a better Nu⊖ than H2O
and RO⊖ is better than ROH● In a group of Nu⊖s in which the
nucleophilic atom is the same, nucleophilicities parallel basicities e.g. for O compounds,
RO⊖ > HO⊖ >> RCO2⊖ > ROH > H2O
Ch. 6 - 66
● When the nucleophilic atoms are different, then nucleophilicities may not parallel basicities e.g. in protic solvents HS⊖, CN⊖,
and I⊖ are all weaker bases than HO⊖, yet they are stronger Nu⊖sthan HO⊖
HS⊖ > CN⊖ > I⊖ > HO⊖
Ch. 6 - 67
Solvents
Non-polar solvents(e.g. hexane, benzene)
Polar solvents
Polar protic solvents(e.g. H2O, MeOH)
Polar aprotic solvents(e.g. DMSO, HMPA)
Classification of solvents
13C. Solvent Effects on SN2 Reactions:Polar Protic & Aprotic Solvents
Ch. 6 - 68
SN2 Reactions in Polar Aprotic Solvents● The best solvents for SN2 reactions
are Polar aprotic solvents, which
have strong dipoles but do not have OH or NH groups
Examples
OS
CH3 CH3
O
H NCH3
CH3
OP
Me2N NMe2NMe2
CH3CN
(DMSO) (DMF) (HMPA) (Acetonitrile)
Ch. 6 - 69
Polar aprotic solvents tend to solvate metal cations rather than nucleophilic anions, and this results in “naked” anions of the Nu⊖ and makes the e⊖ pair of the Nu⊖ more available
NaDMSO
+ DMSO Na"naked anion"
CH3O CH3O
Ch. 6 - 70
CH3Br + NaI CH3I + NaBr
Solvent Relative Rate
MeOH 1
DMF 106
Tremendous acceleration in SN2 reactions with polar aprotic solvent
Ch. 6 - 71
HNu HH
H
OR
OR
ORRO
SN2 Reactions in Polar Protic Solvents● In polar protic solvents, the Nu⊖
anion is solvated by the surrounding protic solvent which makes the e⊖
pair of the Nu⊖ less available and thus less reactive in SN2 reactions
Ch. 6 - 72
Halide Nucleophilicity in Protic Solvents● I⊖ > Br⊖ > Cl⊖ > F⊖
Thus, I⊖ is a stronger Nu⊖ in proticsolvents, as its e⊖ pair is more available to attack the substrate in the SN2 reaction.
H
H
H
HH
H
OR
OR
ORRO
RO
RO
(strongly solvated)
δ+ δ+
δ+ δ+
δ+ δ+F- H
H
H
RO
OR
OR(weakly solvated)
I-
Ch. 6 - 73
Halide Nucleophilicity in Polar Aprotic Solvents (e.g. in DMSO)● F⊖ > Cl⊖ > Br⊖ > I⊖
Polar aprotic solvents do not solvate anions but solvate the cations
The “naked” anions act as the Nu⊖
Since F⊖ is smaller in size and the charge per surface area is largerthan I⊖, the nucleophilicity of F⊖ in this environment is greater than I⊖
Ch. 6 - 74
Solvent plays an important role in SN1 reactions but the reasons are different from those in SN2 reactions
Solvent effects in SN1 reactions are due largely to stabilization or destabilization of the transition state
13D. Solvent Effects on SN1 Reactions:The Ionizing Ability of the Solvent
Ch. 6 - 75
Polar protic solvents stabilize the development of the polar transition state and thus accelerate this rate-determining step (r.d.s.):
CH3
CCH3 ClCH3
slowr.d.s. C Cl
δ+ δ−
H
H
OR
OR
ORH
δ+δ−
δ+
CH2
CCH3
CH3
H3CCH3
CH3
+Cl-
Ch. 6 - 76
13E. The Nature of the Leaving Group
The better a species can stabilize a negative charge, the better the LG in an SN2 reaction
C Xslowr.d.s.
δ−δ+C X
C X
C X+
slowr.d.s.
δ−C XNu
δ−
Nu:
C X+Nu
SN1 Reaction:
SN2 Reaction:
Ch. 6 - 77
CH3O + CH3–X → CH3–OCH3 + X
OH, NH2
, RO
F Cl Br I TsO
~ 0 1 200 10,000 30,000 60,000
Relative Rate:
<< < < < <Worst X⊖ Best X⊖
Note: Normally R–F, R–OH, R–NH2, R–OR’ do not undergo SN2 reactions.
Examples of the reactivity of some X⊖:
Ch. 6 - 78
NuR OH +R Nu OH
R OH
H Nu+R Nu H2O
H
a strongbasic anion
a poorleaving group
weakbase
✔a good
leaving group
Ch. 6 - 79
14. Organic Synthesis: Functional GroupTransformation Using SN2 Reactions
HO
Br
OH
MeO
Me
HS
SH
MeS
SMe
CNCN
Ch. 6 - 80
Br
C CMe
Me
MeCOO
O Me
O
Me3N
NMe3 Br
N3
N3
II
Ch. 6 - 81
Examples:
Br O
??NaOEt, DMSO
I SMe??NaSMe, DMSO
Ch. 6 - 82
Examples:
I CN
(optically active, chiral) (optically active, chiral)
??
● Need SN2 reactions to control stereochemistry
● But SN2 reactions give the inversion of configurations, so how do you get the “retention” of configuration here??
● Solution: “double inversion” ⇒ “retention”
Ch. 6 - 83
Br
I CN
(optically active, chiral) (optically active, chiral)
??
(Note: Br⊖ is a stronger Nu thanI⊖ in polar aprotic solvent.)
NaBrDMSO
NaCNDMSO
(SN2 withinversion)
(SN2 withinversion)
Ch. 6 - 84
Vinylic and phenyl halides are generally unreactive in SN1 or SN2 reactions
14A. The Unreactivity of Vinylic andPhenyl Halides
C
X
CX
vinylic halide phenyl halide
Ch. 6 - 85
Examples
I
BrNaCN
DMSO
NaSMe
HMPA
No Reaction
No Reaction
Ch. 6 - 86
Substitution
15. Elimination Reactions of AlkylHalides
Elimination
C CH
BrBr-C C
H OCH3+(acts as a
Nu )
OCH3
C CH
H
BrC C CH3OH Br-(acts as a
base)
+ +OCH3
Ch. 6 - 87
Substitution reaction (SN) and elimination reaction (E) are processes in competition with each other
tBuOKtBuOH
e.g.
I +OtBu
SN2: 15% E2: 85%
Ch. 6 - 88
15A. Dehydrohalogenation
CH
CX halide as LG
β carbon
β hydrogenα carbon
H
BrtBuOK
tBuOH, 60oC+ KBr + tBuOHαβ
LG
β hydrogen⊖OtBu
Ch. 6 - 89
Conjugate base of alcohols is often used as the base in dehydrohalogenations
15B. Bases Used in Dehydrohalogenation
R−O⊖ + Na⊕ + H2
R−O−HR−O⊖ + Na⊕ + H2
Na
NaH
EtO Na tBuO K
sodium ethoxide potassium tert-butoxide
e.g.
Ch. 6 - 90
Rate = k[CH3CHBrCH3][EtO⊖]
Rate determining step involves both the alkyl halide and the alkoxide anion
A bimolecular reaction
16. The E2 ReactionBr
H
EtO + + EtOH + Br
Ch. 6 - 91
Mechanism for an E2 Reaction
Et O
C CBr
H
HH
CH3H
Et O
C CBr
H
HH
CH3Hδ−
δ−C C
H
H
H
CH3
Et OH + Br
+βα
EtO⊖ removes a β proton; C−H breaks; new π bond forms and Br begins to depart
Partial bonds in the transition state: C−H and C−Br bonds break, new πC−C bond forms
C=C is fully formed and the other products are EtOH and Br⊖
Ch. 6 - 92
CH3CHBrCH3
+ EtO-
T.S.
CH2=CHCH3
+ EtOH + Br-
Free
Ene
rgy
Reaction Coordinate
Free Energy Diagram of E2 Reaction
∆G‡ E2 reaction has ONEtransition state
Second-order overall ⇒ bimolecular
Rate = k[CH3CHBrCH3][EtO⊖]
Ch. 6 - 93
E1: Unimolecular elimination
C ClCH3
CH3
CH3 H2O
slowr.d.s
CCH3
CH3
CH3H2O as
nucleophile
(major (SN1))
C OHCH3
CH3
CH3
H2O asbase
+CH2 CCH3
CH3
(minor (E1))
17. The E1 Reaction
Ch. 6 - 94
Mechanism of an E1 Reaction
ClH2O
HH2O
slowr.d.s.
α carbonβ hydrogen
+ H3O(E1 product)fast
H2Ofast
OH
H H2OOH + H3O
(SN1 product)
Ch. 6 - 95
Free Energy Diagram of E1 Reaction
T.S. (1)
Free
Ene
rgy
Reaction Coordinate
T.S. (2)
(CH3)3C
+ Cl-
(CH3)3CCl
+ H2O
∆G1(CH3)2C=CH2
+ H3O + Cl-
Ch. 6 - 96
CH3C ClCH3CH3
CH3CCH3CH3
Cl(k1)
Step (1):
+H2O
slowr.d. stepAided by the
polar solvent, a chlorine departs with the e⊖ pair that bonded it to the carbon
Produces relatively stable 3o carbocation and a Cl⊖. The ions are solvated (and stabilized) by surrounding H2O molecules
Ch. 6 - 97
Free Energy Diagram of E1 Reaction
T.S. (1)
Free
Ene
rgy
Reaction Coordinate
T.S. (2)
(CH3)3C
+ Cl-
(CH3)3CCl
+ H2O
∆G1(CH3)2C=CH2
+ H3O + Cl-
Ch. 6 - 98
H3C
CH3C
H2O(k2)
H OH
H
Step (2)
+C H CH2H3C
H3C
+
H
Hfast
H2O molecule removes one of the β hydrogens which are acidic due to the adjacent positive charge. An e⊖ pair moves in to form a double bond between the β and αcarbon atoms
Produces alkene and hydronium ion
Ch. 6 - 99
18. How To Determine Whether Substitution or Elimination Is Favoured
All nucleophiles are potential bases and all bases are potential nucleophiles
Substitution reactions are always in competition with elimination reactions
Different factors can affect which type of reaction is favoured
Ch. 6 - 100
CNu
C X
H
E2
(b)
(a)
SN2(b)
(a)
C
CNu
H+ X
C+ X
C+ Nu H
18A. SN2 vs. E2
Ch. 6 - 101
With a strong base, e.g. EtO⊖
● Favor SN2
Primary Substrate
BrNaOEtEtOH
OEt
+
E2: (10%)
SN2: 90%
Ch. 6 - 102
With a strong base, e.g. EtO⊖
● Favor E2
Secondary Substrate
Br
NaOEtEtOH
OEt
+
+
E2: 80%
SN2: 20%
Ch. 6 - 103
With a strong base, e.g. EtO⊖
● E2 is highly favored
Tertiary Substrate
Br OEt
NaOEtEtOH
+
E2: 91% SN1: 9%
Ch. 6 - 104
Unhindered “small” base/Nu⊖
Base/Nu⊖: Small vs. Bulky
Hindered “bulky” base/Nu⊖
BrKOtButBuOH
OtBu+
E2: 85%SN2: 15%
BrNaOMeMeOH OMe+
E2: 1%SN2: 99%
Ch. 6 - 105
Basicity vs. Polarizability
Br
O CH3
O
+
OCCH3 O
(weak base)E2: 0%SN2: 100%
EtO(strong base)
OEt+
E2: 80%SN2: 20%
Ch. 6 - 106
Tertiary Halides: SN1 vs. E1 & E2
EtO
Br
OEt+
SN1: 0%E2: 100%(strongbase)
EtOHheat
OEt+
SN1: 80%E1 + E2: 20%
Ch. 6 - 107
E2E1SN2SN1CH3X
RCH2X
RCHXR'
RCXR'
R"
Mostly SN2 withweak bases;e.g. with CH3COO⊖
Very favorablewith weak bases;e.g. with H2O;MeOH
Hindered bases givemostly alkenes;e.g. with tBuO⊖
Mostly
Very little;Solvolysis possible;e.g. with H2O;MeOH
Very littleStrong basespromote E2;e.g. with RO⊖, HO⊖
Strong basespromote E2;e.g. with RO⊖, HO⊖
──
─ Always competeswith SN1
─Very fast ──
19. Overall Summary
Ch. 6 - 108
Review Problems
Br
DMF, 25oCtBu
Na CN(1)CN
tBu
NaHEt2OI O
H(2)
I O
O
H⊖
Intramolecular SN2
SN2 with inversion
Ch. 6 - 109
Cl
tBu
CH3
CH3
tBu
Cl
+
( 50 : 50)
OH
tBu
HClCH3(3)
CH3
tBu
O
tBu
CH3
H
H
sp2 hybridizedcarbocation
Cl⊖ attacksfrom top face
Cl⊖ attacksfrom bottomface
SN1 with racemization
Ch. 6 - 110
END OF CHAPTER 6