Chapter 9: Reactions of Alcohols

Deprotonation

S N1 / S N 2

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 ) COH, 18]
3 3
:
 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+ S 1
b. R+
N
Rsec/tert OH 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
H 2O E1
Hydride shift
+
Best when Rsec + (exothermic), but
Rtert “degenerate”
+ + + +
shifts possible Rsec Rsec, Rtert Rtert
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 :Br: − H
+ 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 +
H 2O + 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 +
Rtert
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

:
+ +

: :
H 2O
: :

OH
H+
H+
: :

H 2O
 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.
Williamson
(although R’OH is OK); X = good leaving group. (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
Good Nu
hindered

− I
:I:

: :
HI +
OH +

: :
O O
: :

H
In the absence of good Nu: SN1
Poor Nu

H + , H 2O + +
H 2O

: :
O −H+ OH
O
: :

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

H+ Δ
ROH + +
:
R O

:
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: 3 1
2
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
1 OH
Priority: HO > HS 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:

δ− δ+
R S H less polar, S less e-negative.
H2S is a gas (b.p. −60°C)!
 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
R S S R + 2 HI
: :

2R S H
NaBH4

Nature: polypeptide cross linking of cysteine units.

SH enzyme

Cysteine SH S S