台灣大學開放式課程

有機化學乙
蔡蘊明 教授

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Chapter 6
Ionic reactions of alkyl halides
※ Alkyl halides R-X
 Classification
CH3X RCH2X RR’CHX RR’R”CX
methyl 1o 2o 3o
halides
 Some physical properties
Me-F Me-Cl Me-Br Me-I
1.39 Å 1.78 1.93 2.14
472 kJ/mol 350 293 239
Water insoluble, good organic solvents
CH2Cl2 CHCl3 CCl4
dichloromethane chloroform carbon tetrachloride
carcinogenic
※ Nucleophilic substitution reactions
親核性取代反應

leaving group
Nu:− + R-X  R-Nu + X:−
nucleophile substrate product halide
ion
heterolysis
occurs

例 HO:− + CH3-Cl  CH3-OH + Cl:−

CH3O:− + CH3CH2-Br  CH3CH2-OCH3 + Br:−

I:− + CH3CH2CH2-Cl  CH3CH2CH2-I + Cl:−

◎ Nucleophiles:
any molecule that has an unshared electron pair
(not necessarily charged)

例 + (CH3)3C-Cl
+
(CH3)3C O H + Cl−
H O:
H H

an alkyloxonium ion

nucleophile H2O

(CH3)3C O H + H3O+ + Cl−

hydronium
ion
◎ Substrates: electrophiles

δ+ δ−
C X

electrophilic

◎ Leaving groups:
leave as a relatively stable, weakly basic molecule
or anion
Two types:
Nu:− + R LVG Nu R + −
:LVG

− +
Nu: + R LVG Nu R + :LVG
★ SN2 reaction mechanism

例 − 60 oC
+ Cl−
H3C Cl + OH H3C OH
H2O

Rate ∝ [CH3Cl][OH−]

Rate = k [CH3Cl][OH−]

rate constant

A second order reaction or bimolecular reaction

Likely involve the collision of CH3Cl and OH−
SN2
bimolecular
substitution
nucleophilic
★ Orientation: backside attack
transition state
−
δ δ− −
Nu:− C LVG Nu C LVG Nu C + :LVG

bond partially bond partially configuration is

formed broken inverted
sp2
A concerted process:
bond breaking and bond formation
occur at the same time
MO view:
E ∗
σ C L
antibonding

σ C L
bonding
Nucleophile (electron rich) prefers to react with empty σ* orbital
 ★★ Using arrows to represent electron flow ★★

−
δ δ− −
Nu:− C LVG Nu C LVG Nu C + :LVG

−
Energy profile: δ δ−
G Nu C X

transition state
∆G=

Nu:− + R-X
reactants
∆Go

Nu-R + X−
products

reaction coordinate
※ Stereochemistry of SN2 reactions:
inversion
Evidence:
H3C Cl SN2 H3C H
●
H H H OH
cis :OH− trans
● Known: H13C6 H13C6
Br OH
H H
[α] 25 = −34.25o [α] 25 = −9.90o
D D
CH3 CH3
(R)-(−)-2-bromooctane (R)-(−)-2-octanol

Experiment: H13C6 H13C6

Br HO
H NaOH H

CH3 CH3
[α] 25 = −34.25o [α] 25 = +9.90o
D D
Complete inversion
※ Substrate: good or bad? (SN2)

Relative rate of SN2 reactions:

CH3X CH3CH2X (CH3)2CHX (CH3)3CX

30 1 0.02 ~0
Steric effect: large group blocked the path of nucleophile

H H3C H3C
H H H3C
Nu:− C X Nu:− C X Nu:− C X
H H H

H3C
H3C The steric hindrance is very high for
Nu:− x C X
H3C
tertiary halides
 (CH3)3CCH2X relative rate: 0.00001
X
Neopentyl halide: also very hindered

SN2 reactivity:

Methyl > 1o > 2o > 3o

※ Nucleophiles: strong or weak?

Stronger nucleophile reacts faster

<1> Charged stronger than neutral (same atom)
fast
CH3O− + CH3I CH3OCH3 + I−

slow + −
CH3OH + CH3I CH3OCH3 + I
H

CH3O− > CH3OH OH− > H2O

Same nucleophilic atom:
Nucleophilicity parallels basicity

RO− > HO− >> RCOO− > ROH > H2O

<2> In the same group: Size ↑ Nucleophilicity ↑
I− > Br− > Cl− > F− (與鹼性相反)

RS− > RO−

Reasons:
i size↑ solvation↓
nucleophile愈容易突破solvent的束縛

Solvation:

Nu

ii size↑ polarizability↑
ability to donate e− ↑
※ Solvent effects (SN2)

◎ Polar protic solvent:s

H2O, CH3CH2OH, ……

hydrogen attached to a highly

electronegative atom

solvate nucleophiles strongly: OR nucleophilicity

H decreases

RO-H Nu:− H-OR

H
OR

Relative nucleophilicity in protic solvent:

HS > CN > I > OH > N3− > Br > CH3CO2− > Cl > F > H2O
− − − − − − −

weak solvation
◎ Polar aprotic solvents
O O
O
CH3 (H3C)2N P N(CH3)2
H N S
CH3 H3C CH3 N(CH3)2
N,N-dimethylformamide dimethyl sulfoxide hexamethylphosphoramide
(DMF) (DMSO) (HMPA)

Solvate cations but not anions

S
O S
S O
O
Na+ Nu:− naked
O O
S S (not solvated)
O
S
very reactive
− − − −
例 In DMSO: F > Cl > Br > I
most basic
◎ Nonpolar solvents

Not important due to solubility problem

★ SN1 reaction mechanism

例 acetone
(CH3)3C-Cl +
−
OH (CH3)3C-OH + Cl−
H2O

Rate ∝ [t-BuCl]

Rate = k [t-BuCl]

A first order reaction: unimolecular

Rate has nothing to do with nucleophile

SN1

unimolecular
◎ Mechanism of SN1 reaction: A stepwise process
Step 1
CH3 CH3
H3C C Cl H3C C+ + Cl− slow
CH3 CH3
1. Only bond breaking
a carbocation 2. Formation of a high
highly reactive intermediate energy species
3. Charge separation
Step 2
CH3 CH3
H3C C+ + −
OH H3C C OH fast
CH3 CH3
1. Only bond forming
2. Charge combination
The slowest step is the rate determining step (RDS)
The rate is only dependent on t-butyl chloride
◎ Energy profile of SN1 reaction

δ−
CH3

G
TS: H3C C +
δ
Cl
CH3

∆G2=
∆G1=
+ Cl−
∆G1= >> ∆G2=
+ −OH
t
BuCl + −OH

BuOH + Cl−
t

Intermediate
not transition state
※ Carbocations

◎ Structure
R
C+ R trigonal planar
R
sp2

empty p orbital Better than using sp3 orbital

Has less s character
Less electronegativity
More s used in bonding
Compare with: tetrahedral structure

sp3 used in bonding R "R

C Not as good
R' as above

empty sp3
◎ Relative stability

R R H H
R C+ > R C+ > R C+ > H C+
R H H H

3o 2o 1o methyl

most stable least stable

Reason:
Alkyl groups are considered as weak electron donating
 More R groups, more stabilization
Why is alkyl group electron donating?

MO
Hyperconjugation:
π-type interaction —
H —p
C C+ R
σ—
—
Weak π-type interaction between the filled σ
orbital with the empty p orbital
(as if donating e− from filled σ to empty p)
Valence bond view:
δ+
H H+
δ+
H
+
C C C C or C C
※ Substrate: good or bad? (SN1)

Relative rate for SN1:

3o > 2o > 1o > Methyl
Parallel carbocation stablity
But why?

Recall the rate determining step:

R-X  R+ + X−
Wrong reason:
More stable carbocation Faster reaction
★ Rate depends on activation energy, not product stability
To estimate Ea, we need to know the TS energy
 ◎ How to estimate transition state energy?

Hammond-Leffler postulate:
For a highly endothermic reaction For a highly exothermic reaction
TS structure mimics the product TS structure mimics the reactant

G TS G TS

product reactant

reactant product

Now for an highly endothermic reaction, we can use the

product stability to estimate transition state energy
The rate determining step of SN1:

R-X  R+ + X− highly endothermic

More stable carbocation

More stable TS
(TS has very high carbocation character)
Smaller Ea
Faster reaction

Relative rate for SN1:

3o > 2o > 1o > Methyl
Tertiary substrate reacts faster
※ Stereochemistry of SN1 reactions:
racemization

Experiment:
Pr Pr Pr
H2O
Me Br Me OH + HO Me + HBr
Et acetone Et Et
one enantiomer retention inversion
(optically active) 1:1
a racemate
(optically inactive)

Reason:
go through a trigonal planar carbocation
Pr Has a plane of symmetry
+ Achiral (chirality lost)
C
Optical activity is lost
Et Me
 Pr
+ Pr + Pr +
HO H2O: C :OH2 OH
Me Me
H Et Et Me Et H

Attack of H2O: equal rate from both faces

(the two approaches are enantiomeric)

★ ★ Important lesson:
Optically active product can not be obtained
from optically inactive starting materials
Optically active product may be obtained from
optically active starting materials
◎ SN1 in the presence of another chiral center
:OH2

H3C CH3 H3C diastereotopic

H2O
+ CH3
approaches
H Br SN1 H

:OH2

another chiral center

No plane of symmetry for the carbocation

The two approaches are diastereomeric
The energy may be different
Obtain two diastereomeric products:
H3C OH H3C CH3

H CH3 H OH

Expected to be major due to steric effect

 H3C OH HO CH3

H CH3 H3C H

H3C CH3 H3C CH3

+ +

H Br Br H

H3C CH3 H3C CH3

H OH HO H
◎ Solvolysis

When solvent is the nucleophile: solvolysis

Hydrolysis:
t-BuBr + H2O  t-BuOH + HBr

Methanolysis:
t-BuCl + CH3OH  t-BuOCH3 + HCl
例 O O
Cl + + HCl
H OH H O
Formic acid
(as solvent)
Mechanism:
slow
Cl + + Cl−

O O
+ + +
HO H O H
H

O O
+
O H + H+
O H
H
※ Effect of nucleophile (SN1)

Key concept:
Nucleophile not involved in RDS

No effect
※ Solvent effects (SN1)

Key concept:
Charge separation is involved in RDS

Faster in polar solvent

Reasons:
•Polar solvent has higher ionizing power
(dielectric constant is high)
介電常數
•TS is more stabilized through solvation, ∆G‡ lower
R R RR
−
R R δ+ δ
C X C X C+
R R R
TS
has very high charge separation
※ The nature of leaving group

SN1:

δ
+
δ−
C LVG C LVG C+ + LVG−

SN2:

Nu:− δ− δ−
C LVG Nu C LVG Nu C + LVG−

Key concept:
In both transition states:
negative charge developed on LVG
Better ability to stabilize negative charge
Better LVG

例 I− > Br− > Cl− >> F−

Weaker base  Better LVG

Recall:
HA H+ + A:−
acid base
◎ Some other important good leaving groups
O
− −
OMs
Sulfonates O S CH3
O
O methanesulfonate
− (mesylate)
O S R
O
O
− −
O S CH3 OTs
O
p-toluenesulfonate
(tosylate)

O
− −
O S CF3 OTf
O
trifluoromethanesulfonate
(triflate)
A super LVG
O
−
Sulfates O S OR
O
H2O is a better LVG than −OH

− −
X + ROH x RX + OH

But
− +
X + R OH RX + H2O
H
+ Better LVG
H

R OH
Common mistakes for beginners:

Nu:−
C H Nu C + H− NO!

Nu:− −
C C Nu C + C NO!

−
H− and C are strong bases
hydride bad LVGs
a carbanion
※ SN1 vs SN2

In general: 3o 2o 1o methyl

SN1 SN2 *Never SN2 for 3o

SN1 prefers: stabilized carbocation
polar solvent
weak nucleophile
good LVG
*Stereochemistry: racemization

SN2 prefers: less steric hindrance

polar aprotic solvent
strong nucleophile (high conc. is better)
good LVG
*Stereochemistry: inversion
 SN2 reactions are useful in functional group transformations
RN3
azide
RNH2
R'COOR
amine
ester R'COO− N3−
NH3
− −
R' C C OH ROH alcohol
R' C C R RX or
(X = halide or sulfonate) or −OR' ROR' ether
alkyne
R = Me, 1o, 2o

HS−
CN
− R'S−

RCN RSH thiol

nitrile RSR'
thioether
例 Finkelstein reaction:

RCl NaCl
NaI
or RI + or Insoluble in acetone;
acetone
reaction is driven to
RBr NaBr the right-hand side
◎ Vinylic and phenyl halides:
unreactive in SN1 or SN2 reactions

X
X

vinylic halide phenyl halide

Reasons:
•Stronger bond:
carbon uses sp2 orbital which has higher s character
 hard to break (bad for SN1 and SN2 )
•Backside is blocked (phenyl halide) or hindered (vinylic halide)
(bad for SN2)
•Vinyl carbocation and phenyl carbocation are less stable:
empty sp2 orbital which has higher s character
(bad for SN1) +
+

empty sp2
※ Elimination reactions (消去反應):
dehydrohalogenations

H
β α − + HB + X:−
C C + :B C C
X
A β-elimination or 1,2-elimination reaction

例 C2H5ONa
CH2=CHCH3 + NaBr + C2H5OH
CH3CHCH3 o
C2H5OH, 55 C
Br

CH3
C2H5ONa
H3C C Br CH3C=CH2 + NaBr + C2H5OH
o
CH3 C2H5OH, 25 C
CH3
◎ The base
− +
 2ROH + 2Na 2RONa + H2
sodium
alkoxide
(an oxidation-reduction reaction)
例 2CH3CH2OH + 2Na 2CH3CH2ONa + H2
used in excess sodium NaOEt or EtONa
(as solvent) ethoxide

CH3 CH3
2 H3C C OH + 2K 2 H3C C OK + H2
CH3 CH3
potassium t-BuOK
tert-butoxide

 ROH + NaH RONa + H2

sodium
hydride
(a strong base)
※ The mechanism: E1 and E2

◎ E2

CH3CHCH3 + −
OEt CH2=CHCH3 + Br− + EtOH
Br

Rate ∝ [CH3CHBrCH3][EtO−]

Rate = k [CH3CHBrCH3][EtO−]
A bimolecular elimination reaction (E2):
likely involves the collision of the two
★ E2 mechanism
EtO−

H H H H
CH3
C C + EtOH + Br−
H C C
H Br H CH3

☆ Stereochemical requirement:
antiperiplanar for C-H and C-Br
(反式共平面)
Transition state: δ−
EtO
H
H
H C C CH3
Partial bond breaking: C-H, C-Br H δ−
Partial bond formation: O-H, π Br

The reason for the stereochemical requirement is obvious

◎ E1
CH3 CH3 CH3
80% EtOH
H3C C Cl H3C C OH + H3C C OEt
20% H2O CH3
CH3 CH3
25 oC
(83%)
SN1
CH3
+ H2C C 2-methylpropene
CH3 (17%)

Rateelim ∝ [t-BuCl]

Rateelim = k [t-BuCl]
An unimolecular elimination process  E1
★ E1 mechanism

Step 1
CH3 CH3
slow
H3C C Cl C
H3C + CH3
CH3

Step 2

H2C
H :OH2 CH2 H3O+
fast
+ or C + or
C H3C CH3
H3C + CH3 EtOH
EtOH2
+

The nature and concentration of the base is not

important for E1
Stability of carbocation is important for E1
★ Substitution vs elimination

 1o halides
SN2 vs E2
(1o carbocation is not stable: SN1 and E1 not possible)

In general: SN2 unless strong and hindered base is used

CH3OH
CH3(CH2)15CH2CH2Br + CH3O− CH3(CH2)15CH2CH2OCH3
o
65 C
SN2 (99%)

+ CH3(CH2)15CH=CH2
E2 (1%)

CH3 OH
CH3(CH2)15CH2CH2Br + H3C C O− o
E2 + RO
40 C (85%)
CH3
SN2 (15%)
A hindered base (bulky base)
Prefers to attack smaller H but not larger C (from backside)
 2o halides
SN2 vs E2
(2o carbocation is not stable: SN1 and E1 not easy)

Weak base: SN2 (例: RCOO−)

Strong base: E2 (例: RO−)
EtOH
+ NaOEt +
o
Br 55 C OEt
SN2 E2
21:79

O
+ + Br−
O−
Br O CH3
H3C
O
~100%

Recall: there are weak bases but strong nucleophiles

− −
RS , I  favor SN2
  3o halides
SN1 vs (E1 + E2)
(SN2 not possible for steric reason; E2 has no steric effect)

Weak base: SN1 preffered over E1

Strong base: (E1 + E2) preferred over SN1
High T favors elimination
Reason: entropy is more positive for elimination (∆G = ∆H － T∆S)

EtOH
+ NaOEt +
o
Br 25 C OEt
SN1 E2 (E1)
9:91
EtOH
+ NaOEt 0:100
o
Br 55 C

80% EtOH
SN1 + E1
Cl 20% H2O
83:17
25 oC
※ Biological relevance
O
− S
O
NH3+
NH2
NH2
methionine
N N
N N O
O− O− O−
− S N N
HO P O P O P O N N O + O
O O O O NH3+

OH OH
OH OH
S-adenosylmethionine
ATP
O− O− O−
less nucleophilc than N + HO P O P O P O−
O O O

N CH2CH2OH triphosphate ion

(as LVG)

O
O
− S A
− S A N CH2CH2OH + O
O + + O
O NH3+
NH3+
choline
OH OH
OH OH