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Alcohols

Order the following compounds from most to least acidic?


HO
A) 1>2>3
OH B) 3>2>1
C) 2>1>3
C OH2
D) 3>1>2
E) 1>3>2
1 2 3

Which of the following equilibriums would not be shifted to the right?

O
OH
+ CH3OH
+ CH3O
A)

O OH

+ CH3OH + CH3O
B)

OH
OH2
+ + CH3OH
CH3O
C)

Sec. 6: Alcohols, Ethers 1


Alcohols may be weakly basic as well as being acidic. Molecules that
can be both acidic and basic are called amphoteric.

strong acid strong base


R OH2 R OH R O
mild base mild acid
Alkoxonium Alcohol Alkoxide
ion ion
Weak
Strong Acid Strong Base
acid and base

Very strong acids are required to


protonate alcohols.

Sec. 6: Alcohols, Ethers 2


Preparation of Alcohols

• SN1
• SN2

90 % 10 %

P
HMPA – hexanamethylphosphoric triamide (H3C)2N N(CH3)2
(H3C)2N
Sec. 6: Alcohols, Ethers 3
Oxidation States of Carbon
A reaction of an organic molecule usually corresponds to increasing its hydrogen
content or decreasing its oxygen content.
O [O] O
[O] [O]
RCH3 RCH2OH R C H R C OH
[H] [H] [H] Highest
Lowest Oxidation
Oxidation State
State OH [O] O
R CH R R C R
[H]
Oxidation → broad definition → a reaction that increases its content of any element
more electronegative than carbon
[O]
CH3 CH2Cl
[H]

How to figure out the oxidation state of a carbon atom


a bond to hydrogen or anything less electronegative than carbon is electron donating → -1
a bond to nitrogen, oxygen or anything more electronegative than carbon is electron withdrawing → +1
a bond to a carbon H H → 0
H O C O
H C C OH OS = Hydrogen - (2 x -1)
H C H OS = 4 x +1
OS = 4 x -1 H H Oxygen - (1 x 1)
=+4
=-4 Carbon - 0
H OS = (3 x -1) + 0
=-1
=-3
Sec. 6: Alcohols, Ethers 4
OS = oxidation state
Oxidation States of Carbon
H H H H H O
H H
H2/Pd KMnO4
C C H C C H H C C OH H C C OH
H H
Reduction H H H H Oxidation H
OS = - 2 OS = - 3 OS = - 1 OS = 3

LEO goes GER – Loss of Electrons Oxidation, Gain of Electrons Reduction

Alcohols can form by hydride reduction of the carbonyl group


The carbonyl functional group is polarized due to the high electronegativity
of the carbonyl oxygen atom:

Sec. 6: Alcohols, Ethers 5


Alcohols by Reduction of Carbonyl Compounds
with LiAlH4 and NaBH4

The carbonyl carbon can be attacked by a nucleophilic hydride ion, H¯,


furnished by a hydride reagent.
Sodium borohydride, NaBH4, and lithium aluminum hydride, LiAlH4, are
commonly used for hydride reductions because their solubilities are higher in
common organic solvents than LiH and NaH.

The carbonyl group is susceptible to


nucleophilic attack.

Nucleophile Electrophile
(base) (acid)
These reductions are achieved by the addition
of a H¯ ion (nucleophile) to the electropositive
carbon and a proton to the electronegative
oxygen

Sec. 6: Alcohols, Ethers 6


Mechanism with LiAlH4 and NaBH4
Electrophile
(acid)
Oδ R R
- CH3CH2OH +

C δ+ H C O Na + BH3 H C O BH3 + CH3CH2OH


R R solvent
R R
+
Na H3B- H R
Nucleophile
(base) H C OH + CH3CH2O BH3

R This will react


O three more times
C CH3CH2OH
R R

R R
H2O
H C OH + NaB(OH)3 4 H C OH + (CH3CH2O)4B

R + CH3CH2OH R

Sec. 6: Alcohols, Ethers 7


The reactivity of LiAlH4 is much greater than that of NaBH4 and is less
selective in its reactions.
LiAlH4 reacts vigorously with
water and ethanol and must be
used in an aprotic solvent
such as diethyl ether.

H
Electrophile
O R C R
(acid)
Oδ R 3 C
R O R
R
- + R R H C O Al O C H +

C δ+ H C OAlH3 Li R
H C OAl Li
R R
O R or
R Solvent: Et2O R C R R 4
+ H
Li H3Al- H a tetra-alkyl aluminate
R H3O+
Nucleophile
(base) LiOH + Al(OH)3 + H C work-up
OH

Sec. 6: Alcohols, Ethers 8


Oxidation of Alcohols
Oxidation - loss of electrons
or add oxygens

OS = -1 OS = +1
O very hard to OS = +3 O
KMnO4 / OH¯ / heat stop oxidation
CH3CH2CH2OH CH CH CH
3 2 CH3CH2COH
or
propanol NaCr2O7 / H2SO4 propanal propanoic acid
or
H2CrO4 or CrO3  Jones reagent

OH O OH
H2CrO4 No Reaction
H2CrO4
acetone
acetone
OS = 0 OS = +2 can’t break C-C σ bond

can’t break C-C σ bond

Sec. 6: Alcohols, Ethers 9


Oxidation of Alcohols
Primary alcohols tend to overoxidize to carboxylic acids when oxidized in
aqueous solution:

Overoxidation of primary alcohols is not a problem in the absence of water. The


oxidizing agent, pyridinium chlorochromate (pyH+CrO3Cl-) can be used in
dichloromethane to successfully oxidize these alcohols:

O
CH2Cl2
CH3CH2CH2OH + PCC CH3CH2CH
Cl
stops at aldehyde C
H Cl
H
aprotic solvent

Sec. 6: Alcohols, Ethers 10


Chromic esters are intermediates in alcohol oxidation

The mechanism of chromium(VI) oxidations involves two steps:


Formation of a chromic ester
E2 elimination of a proton and a HCrO3- ion.

Oxidized farther to carboxylic acid


If using PCC stops at aldehyde

The Cr(IV) species disproportionates into Cr(III) and Cr(V) (redox reaction).
The Cr(V) may also function as an oxidizing agent. Eventually all is reduced to
Cr(III).
Sec. 6: Alcohols, Ethers 11
Examples O
OH O OS = +3
1) LiAlH4/Et2O OS = -1
O 2) H3O+
OH
A) B) C)
H
OS = +1

CH3
(H3C)2HCO OH (H3C)2HCO OH
NaBH4/H2O
A) B)

CH3 CH3

O O
O O O OH
A) D)

OH O OH O O O
B) E)
NaCr2O7 / H2SO4
H OH
OH
OS = 0 OH OS = +3
OS = +3 OH OS = +2
C) already
oxidized
Sec. 6: Alcohols, Ethers 12
Organometallic Compounds

+
δ δ+
C M - C M C M

M = Na+ or K+ M = Mg or Li M = Pb, Sn, Hg, or Tl


Primarily ionic polar covalent Primarily covalent
explosive with water relative stable in ether much less reactive

CH3Li

CH3MgCl

Sec. 6: Alcohols, Ethers 13


Organolithium Compounds
ether Li
Br + 2 Li + LiBr

ether Li + LiBr
Br + 2 Li

Grignard Reagents
Br ether MgBr
+ Mg

ether
Br + Mg MgBr

General Reactions

The actual structure of the Grignard reagents are more complex than the formula
2 RMgX R2Mg + MgX2
It also forms a complex with the solvent, ether

For convenience we will represent


the Grignard reagent
Sec. 6: asEthers
Alcohols, RMgX 14
Grignard reagents as well as organolithium compounds are very strong
bases. They act as if they have free carbanions. Organolithium
compounds will react as a Bronsted-Lowry base or as a nucleophile.

δ δ+ δ δ+ δ δ+
CH
- 3 MgBr
- + CH3CH2-
O-H CH4 + CH3CH2O Mg2+ + X
weaker base
carbon with a negative charge is a stronger base than an oxygen with a negative charge

δ δ+ δ δ+ δ
C C H + CH
- 3MgBr C -C MgBr- + CH4
sp sp3
sp2 weaker base
OH SN2 δ
O-
δ+ δ+
C6H5 C C CH2 C CH3
CH3 OMgBr
+ MgBrCl
steric interaction
dilute HCl C6H5 C C CH2 C CH3
CH3

Sec. 6: Alcohols, Ethers 15


Alkylhalides into Alkanes

A more direct way of producing an alkane from a haloalkane is by an SN2


displacement of the halide by a hydride ion from LiAlH4.

NaBH4 is not reactive enough to carry out this displacement.


A deuterium atom can be introduced into an alkane by the reaction of D2O
with an organometallic reagent:

Sec. 6: Alcohols, Ethers 16


Grignard Reagents and Carbonyl Compounds

Step One
Mechanism

R
nucleophilic attack R
δ δ+ δ δ+ δ on carbonyl carbon
-R MgX- + C -O R C O Mg2+ X
nucleophile ether
R R
(base)
electrophile halomagnesium alkoxide
Step Two (acid)

R H R
+

R C O H O X R C OH + H2O + MgX2
Mg2+ X
H R
R
alcohol

Order of Reactivity RI > RBr > RCl


RI and RBr mostly used RCl reacts sluggishly
Sec. 6: Alcohols, Ethers 17
General Reactions

δ δ+ δ H H HBr H
δ+ δ ether
-R1MgBr- + (dilute)
C -O R1 C OMgBr R1 C OH + MgBr2
H H H
formaldehyde 1° alcohol

R2 R2 R2
δ δ+ δ HCl
δ+ δ ether
-R1MgBr- + (dilute)
C -O R1 C OMgBr R1 C OH + MgBrCl
H H H
an aldehyde 2° alcohol

R2 R2 R2
δ δ+ δ HCl
δ+ δ ether
-R1MgBr- + (dilute)
C -O R1 C OMgBr R1 C OH + MgBrCl

R3
R3 R3
a ketone
3° alcohol
Sec. 6: Alcohols, Ethers 18
General Reactions
R2 R2
δ δ+ δ R2
δ+ δ ether
-R1MgBr- + C -O R1 C O + R3OMgBr
C OMgBr

R3O R1
R3O
leaving δ δ+
a ester
group -R1MgBr

R2
R2
HCl
R1 C OH (dilute)
R3OH + MgBrCl +
R1 C OMgBr

R1
R1
3° alcohol

Grignard Reagent add twice because a ketone is created as an intermediate that can
react with the second equivalence of the Grignard Reagent

Sec. 6: Alcohols, Ethers 19


Examples
 Because Grignard reagents are very strong bases they can not be made from
compounds that have acidic hydrogens → -OH, -NH2, -SH, -CO2H, -SO3H etc.

 Limited to alkyl halides or organic compounds containing carbon-carbon


double bonds, internal triple bonds, ether linkages and -NR3 groups.

 Although we can make acetylenic Grignards through an acid base reaction and
use it to our advantage. δ O
δ δ+ OH
CH MgBr δ δ+ 1) -δ+
CH3CH2C CH - 3 CH3CH2C -CMgBr H
ether
+ CH4(g) 2) H3O+

H3C δ δ+
O 1) CH - 2Li
CH
δ+ δ H3 C
-
2) H3O+ OH

Sec. 6: Alcohols, Ethers 20


Examples
Sometimes a Grignard reaction can be completed with a compound containing an
acidic hydrogen if two equivalents of the reagent is used

O δ O δ δ+ OH
δ δ+ ether - CH- 3MgBr
CH
- 3MgBr + HOCH2CH2CCH3 BrMgOCH2CH2CCH3 HOCH2CH2C CH3
δ+ 2) H3O+

+ CH4(g) CH3

- +

C δ+ Na O
+
δ δ+ 1) H3C CH3
CH3CH2C CH Na NH2 CH3CH2C C C CH3
CH3CH2C C- Na
2) NH4Cl, H2O CH3
H
+
H N H
OH
H Cl
CH3CH2C C C CH3 acid
+ NH3 + NaCl CH3

Sec. 6: Alcohols, Ethers 21


Which of the following compounds could be used successfully to prepare a
Grignard reagent for alcohol synthesis by subsequent reaction with an aldehyde or
ketone?
Br acidic proton
O Br OH Cl

Cl O
A) B) C) D)
react with itself

Cyclopentylmethylmagnesium bromine, shown opposite, is


treated in ether with cyclopentanol. The major organic product CH2MgBr
after a dilute acid work up is:

C) CH2 O
A)

D) CH2
B) CH2
HO

Sec. 6: Alcohols, Ethers 22


What is the final product 3 formed in the following sequence of reactions?
O

Na2Cr2O7/H2SO4
Mg/ether 1) H
1 2 3
+
2) H3O
Br
O HO H O
O
HO
H
C) D) E)
A) B)

Sec. 6: Alcohols, Ethers 23


What is the final product 3 formed in the following sequence of reactions?

OH
1) CH3MgI 1) NaH
H2CrO4 1 2 3
2) NH4Cl
2) CH3I

O O O

A B C D

Sec. 6: Alcohols, Ethers 24


What is the final product 3 formed in the following sequence of reactions?

NaOH, H2O PCC, CH2Cl2 1) Li , Et2O


CH3CH2Cl 1 2 3

2) H3O+

O
OH
H
Cl
OH
A) OH B) C) D)

Sec. 6: Alcohols, Ethers 25


Vollhardt: Chapter 9

Which of the reagents would not produce the ethoxide ion from ethanol?
• NaNH2 ?
• LiN(CH(CH3)2)2 CH 3 CH 2 OH CH3CH2O
• KH
• NaSCH3 ¯NR2 Stronger base the alkoxide ion
• Na(s) H¯ Stronger base the alkoxide ion
Na or any alkaline metals Li, Na, K, Cs (2H2O + 2M  2M+ ¯ OH + H2(g)
Which would react faster with water Li or Cs - why
Order the following carbocations from most stable to least stable?

A) 1>2>3>4
H
B) 4>3>2>1
C) 1>2>4>3 C H
D) 3>4>2>1 H
E) 2>3>1>4 1) 2) 3) 4)
Free Energy

∆G‡ =

Sec. 6: Alcohols, Ethers 26


Acid-Catalyzed Dehydration of Alcohols?
Alcohols undergo elimination reactions via an E1 mechanism. Order the following
compounds from the most reactive to least reactive?

1) (CH3)3COH conc. H2SO4


CH2=C(CH2)2
t-butyl alcohol 60°C A) 1>2>3
B) 3 > 2 >1
conc. H2SO4 C) 2 > 1 >3
2) (CH3)2CHOH CH2=CHCH3 D) 3>1>2
2-propanol 100°C

CH3CH2OH conc. H2SO4


3) CH2=CH2
ethanol 180°C
H H
H H H H
85% H2SO4
R C C R
R C C R R C C R
60°C -H2O
R OH +
O R O
H O R
+
base O S OH
H H O S OH
O
O
acid O
Mechanism + O S OH R H
O C C
R R
Sec. 6: Alcohols, Ethers 27
What is the product of the following reaction?
OH Br OH Na OSO3H

conc. H2SO4 / NaBr

100°C
A) B) C) D) E)

Explanation:
The conjugate bases of acids such as HBr or HI are also good
nucleophiles, Br, I , whereas the conjugate bases of H2SO4 and H3PO4
are not good nucleophiles HSO4 and H2PO4 .

Which of the following SN2 reactions would react the fastest.


Cl
OH HCl
A)
Br
OH HBr
B)

Explanation:

The chloride ion is a much poorer nucleophile and reacts very slowly. This
is a very poor method to make 1o chloroalkanes but a good way to make
simple primary iodo- and bromoalkanes
Sec. 6: Alcohols, Ethers 28

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