Chapter 7: Unimolecular Substitution

(SN1) And Elimination (E1, E2)

SN2, SN1
E1, E2
Relative “rates” of the
−: H
E1, E2
−:
B Nu four arrows differ and
C C depend on substrate,
reagent, and conditions
L

SN2, SN1, E1, E2

 Some Observations
Recall from Chapter 6:

Indeed:
Moderate rate
(CH3)2CH Br + H OH Hydrolysis
(CH3)2CH OH + H Br
Secondary Lousy Nu
Fast!
(CH3)3C Br + H OCH3 (CH3)3C OCH3 + H Br
Methanolysis
Tertiary! Lousy Nu

Generally: “Solvolysis”
 A New Mechanism
1. Rate = k [R−L], 1st order unimolecular, only
R-L in rate-determining TS: “bottleneck”.
2. Stereochemistry: not stereospecific, i.e.
enantiomerically pure starting material leads
to (extensively) racemic products; pure cis
(or trans) gives cis/trans mixtures, etc..

Both observations inconsistent with

SN2 mechanism
3. Accelerates with polar (best with protic, in
contrast to SN2) solvents: O
Hexane < CHCl3 < CH3CCH3 < CH3OH
4. Accelerates with better L O
L: Cl < Br < I < OSR
O
5. Product determining steps occur after
“bottleneck”: competition between Nu’s for an
intermediate.
+ − k1
(CH3)3CCl + CH3OH + Na N3 Intermediate
.. − + −

:
CH3OH
.. k :N N N :
2 k3
..
k3 > k2 > k1 (CH3)3OCH
.. 3 (CH3)3CN3 wins
 What Is The Intermediate?
Mechanism
1.

Electron deficient!
2.
3.
The Mechanism Explains The Data

• 1st Order rate law • Acceleration

with better L
• Racemization
• Product determining
• Acceleration in polar
step occurs after
solvents
rate determining step

Unimolecular nucleophilic substitution:

SN1 SN1
SN2 Versus SN1

“Bottleneck”

Bottleneck:
SN1PotE
 Racemization
“Ion pairing”
may slow
attack from
the same side

In practice: Often, slight inversion is observed,

due to “ion pairing”, R+····Br−. SN1Racem
 The Strong Effect Of Polar
Solvents On The SN1 Reaction

Increasing Increasing
solvent polarity solvent polarity
speeds reaction retards reaction
As Expected: Good Leaving Groups
Accelerate The SN1 Reaction
The Nucleophile Has No Effect On
The Rate Of The SN1 Reaction

All reactions
take place
at the same
rate k1.

But in
competition,
Better Nu in polar the better
aprotic solvent
Nu wins.
 What Makes SN1 Possible?
1. α-Branching slows competing SN2
2. α-Branched carbocations are
stabilized by hyperconjugation
Remember the same effect in radicals!

H + +
CH3 < +
CH3CH2
+
(CH3)2CH
+
(CH3)3C
C C
Energetically The only cations
inaccessible feasible in solution
in solution
Hyperconjugation

Django

Lip
 Reactivity Of R-X In Substitutions
Rprim-L : no SN1, only SN2
Rtert-L : only SN1, no SN2
Rsec-L : both

SN2/SN1 ratios difficult to predict,

except in “stacked" cases, such as:

DMF
(CH3)2CH Cl + CH3S− (CH3)2CHSCH3 + Cl−
SN2

(CH3)2CH OSO2CF3 + H2O (CH3)2CHOH +

SN1
Solvent CF3SO3H
Substitutions Of R-X
Overview
Problem:

−(CH3)2S

SN2 or S N1 ?
 Elimination: E1
In SN1, the Nu : (−)can also act as a B:(−), effecting
the deprotonation of the intermediate cations:
Elimination E1 to alkenes, a competing reaction
L
+ :B−
C C C C
C C
–L− –BH Alkene
H
H E1, proton
loss to base
SN1, B:− (solvent in
acts as Nu:− solvolysis)

Nu
C C
H
Methanolysis Of 2-Bromo-
2-methylpropane

(Increases with temperature)

 The Deprotonation Step

Hyperconjugation

We usually omit the base in deprotonations and

Orb
simply write “−H+ ”. Lip
 Mechanism Of E1

Consistent with this picture, the ratios of

SN1 to E1 products are independent of L

Ratio of SN1 to E1 Products in the Hydrolyses of

2-Halo-2-ethylpropanes (CH3)3CX
E1 Gives Mixtures Of Alkenes
All neighboring C H in the cation are acidic:
Mixture of

: :
CH3OH

: :
CH3OH
. Cl −
+
+ H
ether and
alkenes
Cl CH3 CH3O
H

:
+ + +

“Regio”isomers
(constitutional) and
+ stereoisomers (cis or
trans around the
double bond)
 E1/SN1 Ratios Are
Difficult To Predict
Generally: Increasing amounts of E1 products are formed with:

1. Higher T, because entropy of elimination is

positive: (RX is converted to alkene plus HX).
Recall: ∆G° = ∆H º–T∆Sº, hence positive ∆Sº makes ∆G°
more negative.
2. Very poorly nucleophilic medium (slows SN1),
e.g: nonhydroxylic solvent, poor nucleophiles
(e.g., SO42−, CO32−).

What about strong bases?

Cause elimination, but by yet another mechanism.
 Bimolecular Elimination E2
Strong base attacks R-L directly at β-H: E2 (faster
than SN1/E1 — and also SN2, if sterically hindered)
Mechanism:
1. Rate = k[R-L][−:B] 2nd order bimolecular TS

2. Rate: RCl < RBr < RI L leaves in TS

3. Electron-withdrawing neighbors (e.g., F)

accelerate: H+ removed in TS
R L
4. Stereochemistry: Anti-TS * *
C C
stereospecific
−: H
B
 The E2 Reaction is Stereospecific
One diastereomer of RX gives only one stereoisomer of alkene product:

R,R/S,S gives
only E double
bond:
ethyl and
methyl on
opposite sides
S,R/R,S gives double bond with ethyl and methyl on same side
The Transition State of the E2 Reaction

TS: staggered, best overlap, least e-repulsion

Van

E2 Walba
Anti Versus Syn E2
Hindered Bases Ensure E2
Steric hindrance slows or shuts down
potentially competing SN2
Mechanisms By Which Haloalkanes
React With Nucleophiles (Bases)
 Factors That Affect The
Competition Between SN And E
Factor 1: Base strength of the nucleophile
Weak Bases Substitution more probable
H2O, ROH, PR3, halides, RS−, N3−, NC −, RCOO −

Strong Bases Likelihood of elimination increased

HO−, RO−, H2N −, R2N −

Factor 2: Steric hindrance around the reacting

carbon
Sterically unhindered Sterically hindered
Primary haloalkanes β-Branched prim, or sec and tert haloalkanes
Substitution more Likelihood of elimination increased
probable
Factor 3: Steric hindrance in nucleophile
(= strong base)

Sterically unhindered Sterically hindered

− − − − − −
HO , CH3O , CH3CH2O , H2N (CH3)3CO , [(CH3)3CH]2N

Substitution may occur Elimination strongly favored

Problem:

An alkene

1. Mechanism: SN2 SN1 E2 E1?

2. At lower temperatures one of the following ratios will increase:

SN2 / SN1 SN1 / E1 E2 / E1 SN2 / E2

 Reactivity Of Primary Haloalkanes
R-X With Nucleophiles (Bases)
For unhindered primary R X :

SN2 with good nucleophiles that are not strongly basic

CH3CH2CH2Br + −CN
Acetone
CH3CH2CH2CN + Br−

SN2 with good nucleophiles that are also strong bases

CH3CH2CH2Br + CH3O − CH3OH
CH3CH2CH2OCH3 + Br−
But E2 with strong, hindered bases
CH3
− (CH3)3COH
CH3CH2CH2Br + CH3CO CH3CH CH2
−HBr
CH3
No (or exceedingly slow) reaction with poor nucleophiles (CH3OH)
For β-branched primary R X :

SN2 with good nucleophiles (although slow compared with

unhindered RX)

CH3 CH3
− Acetone
CH3CCH2Br + I CH3CCH2I + Br−
H H

E2 with strong base (not necessarily hindered)

CH3 CH3
− CH3CH2OH
CH3CCH2Br + CH3CH2O CH3C CH2
HBr
H
No (or exceedingly slow) reaction with poor nucleophiles or
neopentyl systems (in which E is not possible)
Reactivity Of Secondary Haloalkanes
R-X With Nucleophiles (Bases)

SN1 and E1 when X is a good leaving group in a

highly polar medium with weak nucleophiles

CH3 CH3
CH3CH2OH
CH3CBr CH3COCH2CH3 + CH3CH CH2
−HBr
H H
Major Minor (more on
increasing T)
SN2 with high concentrations of good, weakly basic
nucleophiles

CH3 CH3
CH3CH2OH
CH3CBr + CH3S − CH3CSCH3 + Br−
H H

E2 with high concentrations of strong base

(for example, HO− or RO− in alcohol solvent)

CH3
CH3CH2OH
CH3CBr + CH3CH2O− CH3CH CH2
HBr
H
 Reactivity Of Tertiary Haloalkanes
R-X With Nucleophiles (Bases)

SN1 and E1 in polar solvents when X is a good leaving group

and only dilute or no base is present
CH3 CH3
HOH, acetone
CH3CH2CBr CH3CH2COH + alkenes
−HBr
CH3 CH3

E2 with high concentrations of strong base

H3C CH2 CH3 CH2
CH3O−, CH3OH
CH3CH2CCl CH3CH2C
−HCl CH3
C
H3C CH2
H
 Chapter 8: Alcohols R OH
δ−− δ−− δ−−
O O O
δ+ δ+ δ+ δ+ δ+ δ+
H H CH3 H CH3 CH3
Water An alcohol An ether
 Ethanol

Industrial Building
Block, Fuel Beverage

Ethanol plant in West Burlington, Iowa

Abuse
Initial dose causes euphoria, but alcohol is a
general CNS active depressant drug.
Absorption: 20% stomach, 80% gastrointestinal.
Food slows it, but what is in, stays in……
Distribution through the body and brain is fast.
Intravenous can be lethal: sudden depression of
the respiratory system, brain centers.
Excretion: Lungs Alcoholic breath; 5% in urine.
Metabolism: Zero order in ROH! Linear with time;
10 mL/h (cocktail/hour); by oxidation:

O
Enzyme Enzyme
CH3CH2OH CH3CH CO2
Poisonous

Second step is prevented by antabuse (disulfiram):

Common misconceptions:

1. Not a stimulant

2. Doesn’t warm you

3. Doesn’t help your sleep

4. Not an aphrodisiac
 Names
1. Find the longest chain containing the –OH
function: alkane  alkanol. Note: This may not be
the longest chain in the molecule! More than one –OH
group: diol, triol, etc.

2. Number from the end closest to HO-C

3. Other rules same as in alkanes

Br
2
OH 1
9 8 7 6 5 4 3 1
7
6
5 4 3
2

4,4-Dimethyl-1-nonanol OH
or 4,4-dimethylnonan-1-ol 5-Bromo-3-propyl-2-heptanol
Cyclic Alcohols Are Called Cycloalkanols
Defined as C1,
OH OH HO
# is not necessary in
name
1 1
3
CH3
Cyclohexanol cis-3-Methyl- 1-Ethylcyclo-
cyclohexanol pentanol
-OH as a substituent is called hydroxy
-OR is alkoxy: ethers R-O-R’ = alkoxyalkanes
R’
R’
RCOH
RCH2OH RCHOH R’’
Primary Secondary Tertiary alcohol
 Structure
O can be thought of as sp3-hybridized,
“tetrahedral”, i.e. bent, not linear. Due
to electron repulsion by lone pairs.
O is relatively e-negative, attracts
bonding electrons: short = strong bonds.

O
DHº = 119 kcal mol−1

H3 C H
 Physical Properties

Most striking: Relatively high melting and

boiling points, and water solubility. Why?
 Hydrogen Bonding
R δ− δ+ R
O H O δ−
H Extensive network:
δ+ 5 kcal mol−1

Increases
intermolecular
interactions. Allows for
solvation by water.
 Hydrophobic-Hydrophilic

R alkyl chain OH

Water solubility: Decreases with size of R.

R is hydrophobic; –OH is hydrophilic
 Acidity
K
ROH + H2O RO− + H3O+ pKa’s Sterics
and

H2O
solvation
15.7
CH3OH 15.5
CH3CH2OH 15.9
(CH3)2CHOH 17.1 Steric
(CH3)3COH 18effect
ClCH2CH2OH “Inductive”
14.3
electronic
CF3CH2OH 12.4
effect.
Tapers off
CF3CH2CH2OH 14.6 distance
with
 Alkoxides RO
Preparation:
+− K − +
CH3OH + Na NH2 CH3O Na + NH3
pKa 15.5 K = 1019.5 35

+− K − +
CH3CH2OH + Na OH CH3CH2O Na + H2O
K~1
15.9 15.7
When CH3CH2OH is solvent, equilibrium is displaced to the
right. This is how one makes solutions of alkoxides in alcohols.
 Alcohols Are Also Basic
Lone e-pairs of OH can be protonated, as in H2O
being protonated to H3O+. Molecules that are
both acids and bases are called amphoteric.
H
+
R─O─H + H2SO4 R─O + HSO4−
H
Oxonium ion pKa ~ −3

+
Compare R NH2 + H+ R NH3
Much more basic

Ammonium ion pKa ~10

Synthesis of Alcohols R-OH
1. R—X R—OH Review: SN
By SN2: Rprim-X only

I −
OH
OH

− ( OH = base)
Problem: β-Branching  E2

I −
OH
By SN1: Rsec X, Rtert X

Problem: E1

Br OH
+
H—OH

Minimize
HBr

at low T
Cl H—OH
OH
HCl +
Solution for E2 problem with −OH: Use a
less basic, “masked” OH–equivalent:
O
Acetate (works for Rprim,
CH3 C β-branched, or Rsec)
O

O O
SN2
H2O, OH
Br + O CCH3 O CCH3 Hydrolysis

O “Ester”
OH
+ −
CH3CO, removed in aqueous work-up
 Mechanism preview:
Ester Hydrolysis (Chapter 20)
 O
2. Reduction of aldehydes C and
O R H
C ketones
R R’
Redox Relationship
δ
O O O +2e reduction O
C + C C −2e oxidation C
δ+
2 e + 2 H+ equals H . There are
HO H 2
+2 H+ two practical ways to add H2:
C
−2 H+ a. as such, or b. as H−, then H+.
 red
Ketones ox
Rsec─OH What are
red
the
Aldehydes ox
Rprim─OH reagents?

Reduction Of Aldehydes and Ketones

Hydrogenation is possible, but is cumbersome: Needs H2
pressure and catalysts (e.g., Pd, Pt).
Better: Use reagent that is equivalent to H:−, but not as
basic, such as “complex” hydrides, prepared simply by:

Na+H:− + BH3 Na+BH4−

sp3
Sodium borohydride
sp2

Li+H:− + AlH3 Li+AlH4−

sp3
Lithium aluminum
sp2 hydride (LAH). Very
reactive!
Very strong base: Less basic: more
causes deprotonation nucleophilic
 These reagents are still basic and will undergo
protonation by alcohols or water to give H2.
Reactivity differs greatly:

NaBH4 is less reactive, more selective:

Na+BH4
-H-OH
4 H2 +
-
Na+B(OH)4
slow, allowing for alcohol solvents

But:
-
Li+AlH4
H-OH
4 H2 +
-
Li+Al(OH)4
violent, needs aprotic and rigorously dry solvents (e.g., ethers)

LiAlH4 (but not NaBH4) will reduce even halides:

Reaction =

RX + LiAlH4 R─H
Synthetic method = Vocabulary
Nucleophilic attack of hydrideO
Hydride
C

The resulting alkoxide is protonated by

alcohol solvent, in the case of NaBH , or on 4

aqueous work-up, in the case of LiAlH 4

Electrophilic
O NaBH4, CH3OH HO H carbonyl carbon

H
LiAlH4
H
H+, H2O
H
ether

O -
Li+H3AlO H
Work-up
HO H

The aqueous work-up step is normally not shown in eqns.

 Mechanisms
NaBH4: termolecular, concerted. Simultaneous
addition of H− (from NaBH4) and H+ (from CH3OH):
CH3O H O H O H
H BH3
C + CH3O─BH3
C

LiAlH4: Stepwise delivery of 1. H:−, 2. H+, H2O (the

work-up step)

Anim
 Oxidation Of Aldehydes and
Ketones
+3e
CrVI reagents CrIII
O
Typically, use Na2Cr2O7
HO Cr OH
VI

or CrO3 in H2O, H2SO4

O
Chromic acid
Example:
O
OH H2SO4

+ Na2Cr2O7 H 2O

Best for secondary alcohols giving ketones. Primary

alcohols are overoxidized in aqueous medium.
 O
+ −
Therefore, for Rprim–OH: Use NH OCrCl
O N
Pyridinium chlorochromate: “PCC”; soluble in organic solvents Pyridine

Avoids overoxidation with aqueous Cr reagents

OH PCC H OH
CH2Cl2

O O
VI
Mechanism of Cr oxidation:
O O
VI
RCH2OHHO Cr OH R CH O Cr OH
HOH
O O H O
O IV E2 (special)
RCH + CrOH a chromate ester

O
3. Alcohols from Organometallics R:−M+
Hexane
R-X + Li RLi + LiX
or ether R-M
Alkyllithium Alkylmetal
or
MeLi
THF

O
R-X + Mg R-Mg-X
Ether needed
for octet
O

MeMgBr François Auguste

Victor Grignard

“Grignard reagent” “RMgX” 1871-1935

Nobel Prize 1912
 δ+ δ− δ− δ+ When

Reverse Polarization RX RM(X) Gtrignard

RM(X) reagents are basic and nucleophilic

Basicity
Extremely ready hydrolysis: need to be made in
very dry solvents

Mg D2O
ether

Br MgBr D Another way

to effect
R-X  R-H
Cl Li Li H2O H
THF
 RM as Nucleophiles
Do not undergo the reaction
δ+ δ-

R:– M+ + R’—X R-R’ + M—X

(obviously, since they are made from RX).
But, carbonyl group is more reactive than RX:

δ− H
O δ− δ+ −
O M+ H2O
O
δ+ + R M
R R

Works with ketones, aldehydes,

including formaldehyde, CH2=O
Ketones: O HO CH3
H2O
+ CH3MgBr

tert
Aldehydes:

O HO H

H+ Li
sec

MgBr OH

CH2 O +
Formaldehyde
prim
Grignard
 Synthesis: How To Assemble Complex
Molecules From Simple Starting Materials
Prerequisites: Vocabulary = Reactions and
Grammar = Mechanisms

1. Reactions
Roadmaps Of Vocabulary

How is a function made? What does a function do?

2. Mechanisms
a. Can we make 1-chloro-1-methylcyclohexane by radical chlorination of methylcyclohexane in high yield?

Not really. The selectivity tertiary/secondary is

5:4, but the statistical ratio is 1:10 − We will get
mixtures.

Possible solution: Radical bromination, followed by SN1 with excess chloride.

b. What will be the result of the following reaction?

3. Retrosynthetic Analysis
Work backwards! Break up into even pieces!

Forward scheme:
Another example:
Make from starting materials 4
carbons or less
HO
H
Li
+
O

Li +
O HO H
Synthetic Planning:
• Know your reactions, forward and backward (vocabulary)
• Know your mechanisms, forward and backward (grammar)
Chapter 9: Reactions of Alcohols
Deprotonation

SN1 / SN2

E1 / E2

Oxidation
 Deprotonation

pKa (ROH) ~ 15−18.

−
Need base stronger than RO :

:
:

:
a. RLi , e.g., CH3Li [pKa(CH4) ~ 50];
+ −
b. Na NH2 ( :NH3, 35); LDA [(i-Pr)2NH, 40);

:
:
:

+ − + −
c. K H: or Li H : (H2, 38);
−
d. (CH3)3 CO [(CH 3)3COH, 18]
:

:
:
 SN1/SN2 Via Protonation
:X:−

: :
HX
a. Rprim OH Rprim +OH2 R X:

: :
: :
SN2

:
Bad leaving Preequilibrium Good leaving
group group

OH HBr Br
Note: Needs H+
with a good Nu (X)
OH I
HI
Dominates for
Rsec in H2O
H+ + SN1
b. Rsec/tert OH R R Nu
: :

H2O
: :

E1
Alkene
Problem: mixtures
Reaction Of Cyclohexanol
With HBr Or H2SO4:
SN1 Versus E1
Mechanism Of Dehydration

E1
 Carbocation Rearrangements
There is another general problem with SN1: H:− shifts

H OH H + H + HS 1
+ N
C C C C C C
H2O E1
Hydride shift
+
Best when Rsec + (exothermic), but
Rtert
+
“degenerate” shifts possible Rsec R+sec, Rtert
+ R+tert
Note reversibility
Mechanism of Hydride Shift
The Hydride Shift
Transition State

Fats
Shift Lipsh
Other Carbocation Precursors
Example: tertiary (or secondary) halides
All steps reversible  thermodynamic equilibration possible, but
hydride shift is fast, therefore some selectivity at relatively lower
temperatures and short reaction times.

CH3 H
:Br: − + CH3 :Br: −

: :
: :
: :

Br: CH3
CH2CH3 CH2CH3 + CH2CH3
H H
Note: stereospecific;
H stays on same side Attack from
H either side
CH3
Bottom line: mixtures
: :

Br:
to be expected
CH2CH3
Cis/trans
Potential-Energy Diagrams
 More Complications: E1
becomes prevalent at higher temperatures

Proton
OH H− shift loss
H2SO4 +
H2O + H+

Note: proton loss is reversible, i.e., double bonds

can be protonated to carbocations (Chapter 11).

H+ H

+ H− shifts

H +

Most stable
carbocation
More Complications: Alkyl Shifts
Slower than H− shifts, but they compete.
R R
+ +
C C C C

+
Best for Rsec R +
tert

Exclusive when there are no hydrogens to shift:

Mechanism Of Alkyl Shift

R+sec R+tert
 Alkyl shifts are especially fast
when they relieve ring strain:

:OH

:
+ +
H2O

: :
OH
: :

H+
H2O H+
: :
 Even Rprim-OH Can Rearrange
+

By concerted shifts, bypassing cations: H+, needs Δ

Push R H R
H Δ +
C C δ+ C C
H
OH2 Pull
:
+ H
Especially with neopentyl alcohols: R
R C CH2OH
R “quaternary”
carbon
Turning ROH Into RNu Without H+
R +OH2
We have HX Can have problems
R OH

: :
learned: with strong acid

:
Bad leaving Good leaving and carbocation
group group
formation

Solution: inorganic derivatives as reactive or isolable intermediates

A mild way to convert ROH RNu without H+

O
Reagents: PBr3 for RBr; PCl3 or ClSCl for RCl, e.g.:

3 ROH + PBr3 3 RBr + H3PO3 [“P(OH)3”]

Phosphorous acid
Mechanisms go through inorganic esters
as reactive intermediates (not isolated).
Mechanism Of PBr3 Reaction With ROH
Example:

Mechanism: Reactive
intermediate;
not isolable

Step 1
Bad
leaving
group Good leaving
group
Step 2 SN2

Repeat
Chloroalkane Synthesis Using SOCl2

O
N
CH3CH2CH2OH + S CH3CH2CH2Cl
Cl Cl 91%
Thionyl
+ SO2 +
chloride +
N
H Cl−

+
N + H+ Cl− N
“Mops up” acid

H Cl−
:

Pyridine
acts simply
as a base
Mechanism of SOCl2 Reaction
Good leaving
group
Bad
leaving
group

Reactive
intermediate;
not isolable

“Suicide” leaving group Gas Gas

 Isolable Sulfonates R L
O
N
ROH + CH3SO2Cl R O SCH3 Methane-
sulfonate,
O “mesylate”

ROH +
N
CH3 SO2Cl R O SO2 CH3
4-Methylbenzenesulfonate, “tosylate”

React by SN1/SN2: Two step substitution of OH function by Nu

 Ethers
H O H R O H R O R‘

: :

: :

: :
Water Alcohol Ether
Names: As substituted alkanes, alkoxyalkanes.
The larger group is the stem

No hydrogen bonds, therefore relatively low b.p.s

 Ethers Are Inert
No acidic hydrogens: Relatively unreactive  used as solvents
OCH3
O CH3O
Ethoxyethane O
(IUPAC)
Tetrahydrofuran 1,2-Dimethoxyethane, “glyme”
Diethylether
(THF)
(common)
“Ether”
(colloquial)
Cyclic polyethers can bind metal cations and dissolve salts in organic
media: crown ethers
In nature, ionophores transport
ions across cell membrane.

Hydro- Hydro-
phobic philic

18-Crown-6 18-Crown-6 K+
Valinomycin
Hole size perfect for K+
Synthesis Of Ethers:
Alcoholysis
The Williamson Ether Synthesis
SN2
Rprim X + R’O :− R OR’

: :
: :
Alkoxide is a strong base (E2!), therefore
best: for unhindered primary RX; primary or
: :
secondary R’O:-; polar aprotic solvent Alexander W.

(although R’OH is OK); X = good leaving group.

Williamson
(1824–1904)

Unsymmetrical ethers:
two retrosynthetic
choices. Analyze both
to find the best one!
 Cyclic Ethers
Intramolecular Williamson synthesis

Remember rules for the SN2 reaction: backside attack with inversion.
 High Dilution Favors
Intramolecular Reaction

Slows even more on dilution

Relative rates of ring closure:
3>5>6>4>7>8
Proximity Strained and
beats strain more distant

There is a trade off between ΔH and ΔS

in the various transition states.

Superfast Slow

Fast Fast
Ethers From Alcohols And H+
SN2 and/or SN1 depending on R groups

H2SO4
Rprim OH R O R Symmetrical
H2O
H
Mechanism SN2 via: ROH R O + Needs heat!

:
: :
Poor Nu H
Rsec/tert OH : SN1 via R+
H+
OH −H O O
: :

: :
Symmetrical
2

: :
HO
Via: OH2
: + Product
+
(CH3)3COH is used for “protection” of other
alcohols as t-butyl ethers (removes acidic H):
CH3 CH3
H+
ROH + H3C OH RO C CH3
CH3 Unymmetrical.
CH3
How?
Reactive Unreactive OtBu
OH group group; “protects” ROH
 This works because the t-Bu cation is
formed fast:

CH3 CH3
H+ RCH2OH

: :
H3C OH + RCH2OH H3C C +
CH3 CH3
Excess
CH3
RCH2O CH3
−H+
CH3
 Reactions of Ethers

Rprim O Rprim: quite unreactive

Stable to base, RLi, RMgBr, dilute aqueous H+

But, strong H + X−: SN2

Example:
Rprim O Rsec mixed ethers: both SN1 and SN2

In the presence of good Nu: SN2

Example:
Less
hindered Good Nu

− I
:I:

: :
HI +
OH +

: :
O O
: :

H
In the absence of good Nu: SN1

Poor Nu

H+, H2O + +
H2O
O

: :
−H+ OH
O
: :

H − HO
 Tert-Bu Ether Hydrolysis
H , H2O mild: “deprotection” of alcohol ROH
+

H+ Δ
R O ROH + +
:

:
R O + H+

:
:

H Gas

Protecting group strategy for alcohols:

Modify
HO , H+ H+, H2O
R to R’
ROH R O R’ O ROH
Protection Deprotection
Application:
 Strained Ethers
React by ring opening, release
ring strain (~ 27 kcal mol−1).

Basic conditions: Nu:− attacks

directly!

:O −
:

H2O
+ CH3S :
: :

Work-up

HO
: :

Leaving group stays

SCH3
: :

attached to molecule

Hydroxyethylation of :Nu : HO
: :

Nu
 Regioselective: SN2 at less hindered site

−
Many Nu: work:
OH O OH
CH3Li LiALD4 CH3
CH3
H CH3 H
CH3 H D

Regio- and stereocontrol

Recall: RLi or RMgX do not react with RX normally!
 :
With neutral Nu, we need acidic conditions to activate the ether to nucleophilic attack .

O H+ HO
+ CH3OH
No reaction
OCH3
without H+

Mechanism:
H
+O CH3OH HO + CH3

: :
:

: :
O
: :

+ H+ O
H
OCH3
H+
HO
 For unsymmetrical systems, mixtures ensue, but reaction is often regioselective to more hindered
side!

H
Regioselective
O OCH3
δ+ + CH3OH !
H HO
δ++ CH3
H CH3

Selectivity is induced by electronic effect:

the more substituted carbon bears δ + better
Coulomb’s Law wins over steric hindrance
Coulomb’s Law wins over sterics
 Sulfur Analogs Of ROH And ROR’:
Alkanethiols And Alkyl Sulfides
R SH and R S R’

: :

: :
Names:
2
3 1 3
1
2
CH3SH 4
SH
Methanethiol SH
2-Methyl-1-butanethiol 3-Pentanethiol

Thioethers: Named as CH3SCH2CH3

alkylthioalkanes Methylthioethane
(compare normal ethers: alkoxyalkanes)

Substituents: SH Mercapto, SR Alkylthio

2
OH
> HS
1
Priority: HO HS 2-Mercaptoethanol
 Acidity Of Thiols
− +
RSH + H2O RS: + HOH2

: :

: :

:
pKa ~ 9−12

More acidic than ROH, because RS H weaker and RS more polarizable

−
: :
:

Less hydrogen bonding than ROH: R S H less polar, S less e-negative. H2S is a gas (b.p. −60°C)!

δ− δ+
 Nucleophilicity Of Thiols
And Sulfides
:− :−
RS much better than RO , less basic, more polarizable. No E2 problem with RsecX.

: :
: :

− −
RS: + R’ X: : : RSR’ + :X:

: :
: :

: :
SN2

Even neutral RSR’ undergo SN2 (like NH3, PR3)

: :

+ −
CH3 S CH3 + CH3 I: (CH3)2SCH3 + I
: :

: :

: :
: :

:
Compare: CH3OCH3 no reaction.
 Neutral sulfides are good leaving groups (like
H2O)  Sulfonium salts are alkylating agents.
+
(CH3)2S+ CH3 + :Nu (CH3)2S + CH3 Nu

: :
Oxidation of thiols to disulfides
(reversible by reduction)
I2
2R S H R S S R + 2 HI
: :

NaBH4

Nature: polypeptide cross linking of cysteine units.

SH enzyme

Cysteine SH S S
 Chapter 11: Alkenes
C C Double bond

Names: ending ane ene

For example: ethene, propene, butene, etc.

Naming follows the rules for hydrocarbons (functional groups override these rules):

General guidelines:

Rings have priority, regardless of the presence of

multiple bonds.
If there are no rings: the longest chain has priority,
regardless of the presence of multiple bonds.
 Names in the absence of rings
1. Find longest chain. If it contains both Csp2 carbons  alkene. If not  alkenylalkane (see 8.)

An octene

2. Number the chain with C C close to terminus

1
A 3-octene or oct-3-ene (only the first of the two Csp2 carbons is
2 listed by a #)
3

8 6
7 5 4

3. Name and # substituents, in alphabetical order

4-Ethyl-3-methyl-3-octene
 Names in the presence of rings

4. Find largest ring. If it contains both Csp2 carbons  cycloalkene. If not  alkenylcycloalkane (see 8.)

1
2 Double bond carbons
are C 1 C 2 by definition.
3 CH3 Label in such a way as to
give substituents lowest
3-Methylcyclohexene possible numbering
 R
5. Stereoisomers:
cis trans
R R
R

Cis or trans applies only to 1,2-disubstituted ethenes.

Use R,S priority rules at each sp2-

6. For tri- and tetrasubstituted alkenes: E, Z naming.

carbon separately, to find yhe higher priority group at each end.

1 Respective higher priority groups on:

2 Opposite sides: E
3 Same side: Z

8 6
7 5 4
E-4-Ethyl-3-methyl-3-octene

Colloquial terms: double bond position

R R
CH2 Terminal Internal
R R
 7. OH ( SH)
> >
ene

8. Substituents with double bond: Alkenyl

CH2 CH Ethenyl (vinyl)

CH2 CH CH2 2-Propenyl (allyl)

 Remember the basic guidelines:

Longest chain rules Ring rules

Longest chain
containing double Functional group rules
bond rules
9. Exocyclic alkenes: Alkylidenecycloalkanes

Methylidenecyclohexane
(Methylenecyclohexane)
Structure Of The Double Bond
Two components: the -bond and the -bond

Electron rich
The Sigma Bond
The Pi Bond

Ethene
 Orbital Energies

 Bond is
relatively weak

Ethene
How Weak Is The Pi Bond?

Ea = 65 kcal mol−1
Typical C-C bond strength ~88 kcal mol−1
(Table 3-2)
Bond Strengths In Alkenes

Unusually strong because C uses sp2 hybrids

 Alkenyl Hydrogens Are
Relatively Acidic
Compare CH3CH2H pKa ~ 50
C C pKa ~ 44

Has 33% s character.

C C
sp2 In contrast:
sp3 has 25% s character

Net effect: relatively e-withdrawing

Therefore, in principle:

R H H

C C + CH3Li RCH C + CH4

H Li
H

Problems: regio-, stereoselectivity. Better via alkenyl organometallics:

H H

CH2 C + Li CH2 C
Useful:
Br Li
React
R H R H
with
carbonyls
C C + Mg C C

H Br H MgBr

Stereospecific
 Relative Stability Of
Alkenes
Measure heat of hydrogenation ΔHHydrogenation of isomers, e.g., butene

ΔH (kcal mol−1)
+ H2 cat. −30.3

+ H2 cat. −28.6

+ H2 cat. −27.6

Relative stability: Internal

> terminal trans
> cis
 H

Why? 1. Hyperconjugation C C

2. Steric hindrance (strain)

Cis is less stable than

trans because of
steric hindrance

General order of stability:

CH2 CH2
< RCH CH2
< RCH CHR cis

< RCH CHR trans

< tri
< tetrasubstituted
 Synthesis of Alkenes
E revisited. Best: E2 on RX. Regioselectivity?

CH3

CH3 CH3 H 2C
H 3C
CH3CH2 O−Na+,
CH3CH2 C CH3 CH3CH2OH C C + C CH2

Small base H CH3 H 3C

X 70% 30%
More stable Less stable

Saytzev-Rule
Non-bulky base leads to more stable
internal double bond.

Alexander
M. Saytzev
(1841–1910)
 Saytzev’s Rule: The
Transition State

The transition
states begin
to look like
product
double bond.
 Hofmann Rule
Bulky base leads to less stable terminal double bond
August Wilhelm
Largebase von Hofmann
(1818–1892)
Elimination Is Stereoselective
Recall: Stereoselectivity is the preferential
formation of one stereoisomer over possible
others. Here: cis or trans product?
Yes, but not completely.
Br

Na+−OCH3 + +

CH3OH
Non-bulky 51% 18% 31%
base: Saytzev Mainly trans

Dominant
rotamer Gauche,
minor
rotamer
 Elimination Is Stereospecific
Recall:
Stereospecificity is
the selective
conversion of one
stereoisomer of
starting material to
one of the product.
Here: One
diastereomer of
* *
C C

H X

gives only E
alkene, the other
gives only Z.
Alkenes From ROH By Dehydration
C C Acid, Δ C C + HOH

Dehydration
H OH
Carbocations: Can be messy!
Limited synthetic utility.
Rprim OH + H2SO4 conc., goes by E2, requires heat:

+ H
Δ
+ −
:

:
CH3CH2OH + H CH2 CH2 O + HSO4

H
:

H
:

CH2 CH2 + H 2O + H2SO4

:

+
Rsec, Rtert OH + H : E1 + rearrangements
Relative Reactivity
R = primary < secondary < tertiary

E2 on oxonium ion

E1

E1
Major Problem: Rearrangements

CH3 OH
H 3C H

CH3C CH2 CCH3 H2SO4, Δ C C

−HOH H 3C CH2CH3
H H

CH3 54%

+ CH3CCH CHCH3
+ other isomers
H

8%
 Chapter 12: Reactions Of
Alkenes
Fundamental building blocks for organic
transformations and polymer materials synthesis

Polyethylene Tear resistant

Addition Reactions Of Alkenes
π Bond is unsaturated: Reacts by addition.

C C +A B exothermic
C C
(usually)
A B
We can calculate ∆Hº of addition reaction from
bond strength data, using DHºπ-bond = 65 kcal mol−1.
Note, however: ∆Sº is negative (~ −30 e.u.);
−T∆Sº at RT ~ +10 kcal mol−1.
Use excess ∆Gº ~ 0
 1. Catalytic Hydrogenation

Catalyst Typical
C C +H H C C catalysts are
heterogeneous:

Pd/C, PtO2 (
H2
Pt)
H H insoluble solids

Why catalysts? Enable a lower Ea mechanism.

Alkenes + H2 Uncatalyzed
no reaction
E pathway
without catalyst
Catalyzed pathway
 Stereochemistry
Stereospecific H-H addition from the
same side (syn) of double bond. Two
possible ways: from the top or from the
bottom.
H
cat. CH3
+ H2
CH2CH3
H
Cis, racemic
H
cat. D
+ D2 R R + SS
H
trans D H2
 2. Electrophilic Additions
π Bond is electron-rich. Polar reagents
+ −
A ―B add to it.
+
Mechanism for A = H+ : Reverse of E1!
H − H B
+ + :B
C C +H C C − C C
:B
Both syn
and anti
addition
Note: Carbocation
intermediate spells trouble
 rearrangements
 a. Hydrohalogenation H+ X −
− I
0ºC + I Reverse of
+ HI elimination
H H
Br
H
HBr
Regioelective:
Cl
+ HCl
Markovnikov’s Rule
H+ (A +) adds to less substituted carbon
Vladimir

Why? Makes the more substituted cation

Vasilyevich
Markovnikov
1837-1904
Origin Of Markovnikov’s Rule

PropeneHCl
Potential Energy Diagram

Burdon

Lipshutz
 b. Markovnikov Hydration
H2O, H+ catalyst

H2SO4 CH3 Equilibrium!

+ H OH OH
Shifted to
the right by
H excess H2O
Solvent

Reversible hydration of 2-methylpropene (H+ catalyst):

H+ consumed H+ regenerated
 Alkenes And Catalytic Acid
Catalytic H+ with a nonnucelophilic
counter ion (e.g., H2SO4) effects
alkene isomerization:
H H+

At equilibrium (0ºC): 2 : 27 : 81
1

..

>99%
The equilibrium concentrations reflect 25
relative thermodynamic stabilities
 Mechanism Of Equilibration

Reversible E1:
 c. Halogenation

Br2

+ −
X X gets polarized during approach to alkene.

+ Br2 Br
Br
Racemic
Stereospecific : anti (not syn)

C C or C C
Stereospecificity

Racemic

Stereospecific 2-Butene Bromination

 Mechanism
Octet
−
Br
Br
+ Br + − Br
+ Br
C C C C
C C or
Br
Gives the anti
“Precomplex” enantiomer Racemic

Django Lip
 Halonium Ions Can Be Intercepted
By Other Nu
Br + Br
CH3
CH3 CH3
+ Br2 + H2O
OH2 −H+ OH

Remember: 2-Haloalcohol
+ H Remember: 2-Haloalcohol + base
O
 oxacyclopropane
Nu
Or X2, ROH Haloethers
(all anti and Markovnikov)

H3C CH3OH OCH3

+
+ Cl2 + CH3OH
−H+ Cl
H3C Cl+
2-Haloether
 + −
General For A ―B

Synthetically useful in oxymercuration-demercuration

d. Oxymercuration-Demercuration

A Markovnikov hydration that avoids cations

O
1. Hg(OCCH3)2, HOH CH3
2. NaBH4
OH
O
1. Hg(OCCH3)2, ROH
CH3
2. NaBH4
OR
 Mechanism

Goes through radicals

Not stereospecific
Compare
 3. Hydroboration-Oxidation
Allows anti-Markovnikov hydration:
Two steps
“one pot”
RCH=CH2 + H2O RCH2CH2OH

Key reaction: B H adds to π-bonds.

Time out: Borane, BH3, exists as dimer to get octet

H
− +
H2B BH2; or, in THF: H3B O
H
In hydroboration, all three B-H bonds react:
H H
3 C C + B H C C B Trialkylborane
H 3
Mechanism Of Hydroboration
Hydroboration Is Regioselective
Steric control of B-H addition

+ BH3 B
B goes to less
hindered end

Why is hydroboration useful?

Oxidation of alkylboranes with H2O2−, OH
gives ROH [+ B(OH)3]:
H2O2
+ BH3 BR2 OH
OH −

anti-Markovnikov hydration
Hydroboration-Oxidation Is Stereospecific

Syn addition of B—H :

CH3 H3C H H3C H
CH3 CH3 H2O2, −OH CH3
+ BH3 B
OH

Example of both regio- and stereospecificity

Mechanism Of Alkylborane Oxidation
 4. Electrophilic Carbene
Additions
Carbenes, :CR2, are 6-electron
species, the parent of which is
methylene, :CH2. They can be
thought of being derived by
deprotonating carbocations:

Methylene

Carbenes are electron deficient: electrophilic.

Carbenes As Reactive Intermediates
a. Methylene from diazomethane, CH2N2

b. Dichlorocarbene from chloroform

c. Simmons-Smith reagent Carbenes pick up

the two  electrons
CH2I2 + Zn-Cu  “CH2” of alkenes to form
cyclopropanes.
 Carbene Additions Are Stereospecific

a.

b.
c. Simmons-Smith reagent in cyclopropane synthesis

H CH3 CH2
Zn-Cu, (CH3CH2)2O
C C + CH2I2 C C
−Metal iodide H CH3
H3C H
H3C H

Cyclopropanes are made by nature…

H3C (+)-Chrysanthemic acid

COOH (used by flowers against
H3C insects); the “mother” of
the Pyrethroids.
H3C CH3 US market: 1.5 billion $!!
 5. Electrophilic Oxidation
O − +
a. Peroxycarboxylic acids
RCO OH
O O O
C C + RCO OH C C + RCOH

Commonly used peroxycarboxylic acids:

O O O

CH3COOH, CF3COOH, COOH

meta-Chloroperbenzoic acid
Peracetic Trifluoro-
acid peracetic acid “MCPBA”
Cl
Examples:
O O
C O OH CHCl3 COH
+ 90%
+
O
Cl Cl

Stereospecific: syn

D H O O O
C C + RCOOH + RCOH
H D 95% D H
H D Aqueous
work up
trans-2,3-Di-
deuteriooxa-
cyclopropane
 Mechanism: concerted
O R
C O R C C
O C O +
C C O
H O
H
Application:
Ocacp

O HO H
:Nu1 CH3
1.CH3SO2Cl
C C
H3C 2. :Nu2
H3C CH3 Nu1
H Turns OH into
mesylate

H3C H leaving group

H CH3
C C Double nucleophilic syn –
addition to double bond
Nu2 Nu1
 Rates of oxacyclopropanation
increase with alkyl substitution:
O
CHCl3
+ CH3COOH 10ºC
O
1 equiv 86%

Sequence 1. RCO3H, 2. H+, H2O or –OH, H2O

constitutes an anti-dihydroxylation of alkenes.
H C H O
3 RCO3H
C C H
H3C
H CH3 H CH3
HO H
H+, H2O CH3
C C meso
or –OH, H2O H3C
H OH
 b. OsO4 syn-dihydroxylation
O O
OsO4 Os is reduced to OsVI.
O VIII O

OH
1. OsO4

2. H2S, H2O OH
cis-1,2-Cyclohexanediol
Gives complementary stereochemistry to anti-dihydroxylation
Mechanism:
C OVIII O C O VI O H2S
Os Os
C C
O O O O
Six electron TS
Osmate ester

C OH HS O
Can be reoxidized by added
+
VI

Os H2O2, therefore can be

C OH HS O made catalytic in Os

Good because Os is expensive; OsO4, H2S are toxic.

c. Ozonolysis Complete oxidative cleavage by
1. O3, 2. Reduction of “ozonide”
Ozone generator:

O+
Arc discharge
O2 2-4%− in O2
O O
1. O3
C C
2. Reduction
C O +O C
O O
CH3CH2 CH3 1. O
C C 3
CH3CH2CCH3 + CH3CH
H3C H 2. Zn, CH3COOH
90%
Zn2+
CH3 1. O3 O
H
2. H2 , Pt
85%
H2O Ring opening O
H3C CH2 H3C O
1. O3
76%
2. (CH3)2S
Clipped off
H (CH3)2SO H carbon atom

O3
 6. Radical Hydrobromination
Recall: + HBr 90%
Markovnikov
Br
RO-OR Anti-
But: + HBr Br Markovnikov!
65%

Mechanism different; goes via faster radical chain.

Started by peroxide
radical initiators
(the O-O bond is
weak, ~39 kcal mol−1):
Mechanism Of Radical Hydrobromination

Compare to
radical
halogenation of
hydrocarbons
(Chapter 3):

RadicalHbr
Does not work for HCl, HI: In each case, one of
the propagation steps endothermic:
Which one?  Exercise 12-31
Hence radical mechanism too slow, and ionic
mechanism of Markovnikov addition wins.
But works for RSH anti-Markovnikov addition:

CS Bond
dissociation energy
~72 kcal mol-1

Initiation:
7. Alkene Polymerization
 R R
etc.
a. Cationic: C C + H+ H C C+
R R
etc.
b. Radical: RO + C C RO C C
H H
N N
C − C etc
−B
c. Anionic: + C C B C C
Resonance
d. Metal (Ti, Zr, lanthanides): Ziegler-Natta;
Kaminski-Brintzinger. Organometallic mechanism
R R
Insertion CH3 CH3
R Ti CH3 R Ti Ti
 Acid-catalyzed Polymerization
Proceeds through carbocations! Polymerization is yet another
complication of carbocations, in addition to SN1, E1, and
rearrangements; dominates at high concentrations.

At low concentrations: dimerization……oligomerization:

Dimerization of 2-methylpropene
 Continued oligomerization:

Can lead to synthetically useful cyclizations:

Mechanism:
 8. Alkenes in Nature: Pheromones
Sex, war, communication (trail, alarm, defence)
NO2

Termite defence

O
O
Termite queen
O O
Black tail deer (hoof
excretion); recognition OH
and status
“Queen bee substance”, inhibits
ovary development in workers,
attracts–excites drones

Sex pheromone of the

western black widow
(Latrodectus
hesperus)
The Holy Grail: Human Sex
Pheromones

Androstadienone Component of male sweat; has been

suggested to be a human sex
pheromone. Controversial: the
olfactory sense organ responsible
for the detection of pheromones as
more than just an odor has no active
function in humans.