Reactions of Alcohols

I. Oxidation and Reduction according to organic chemists:

A. Basics-
1. Oxidation- the result of an oxidation agent being added; O or O
2
, halogens X
2
, loss
of H
2.

2. Reduction- the result of a reducing agent being added; H
2
or H
-
; loss of O or O
2
, loss
of halogens X
2
.
3. Neither- addition or loss of H
+
, H
2
O, HX, etc. is neither oxidation nor reduction.
*Note that an alkane can be oxidized to a primary alcohol, further oxidation leads
to an aldehyde, and one more round of oxidation yields a carboxylic acid.
*Secondary alcohols are oxidized to yield a ketone and water.
*Tertiary alcohols cannot be oxidized without breaking bonds.

B. Secondary Alcohols-
1. Chromic acid reagent- easily oxidizes secondary alcohols to give excellent yields of
ketones. Prepared by dissolving sodium dichromate in a mixture of sulfuric acid and
water, or adding chromium trioxide to dilute sulfuric acid. Na
2
Cr
2
O
7
/ H
2
SO
4

a. The first step of this reagent is to form a chromate ester.
b. The next step is the elimination of the ester and the oxidation of the carbinol
carbon. This utilizes water as a base abstracting the proton from the carbinol
carbon with its lone pairs, and using the electrons from the bond to form a
carbonyl bond. Refer to p 463 to see electron movement.

C. Primary Alcohols-
1. Pyridinium Chlorochromate(PCC)- is used to perform limited oxidation of primary
alcohols to aldehydes in excellent yeilds. Most other oxidizing agents are too strong
and oxidize the primary alcohols all the way to carboxylic acids. Consists of complex
of chromium trioxide with pyridine and HCl. Soluble in nonpolar solvents such as
dichloromethane(CH
2
Cl
2
).
a. Can also be used as a mild reagent to oxidize secondary alcohols into ketones.
*Refer to the example on p. 464

D. Tertiary alcohols- resistance to oxidation
1. Must take place by breaking the carbon-carbon bond. Requires severe conditions
and therefore, mixed products result.
2. Chromic acid test-Upon the addition of a primary or secondary alcohol to chromic
acid reagent, the color goes from orange to green or blue. If it is nonoxidizable
such, then there is no immediate color change. Tertiary alcohols, ketone, and
alkanes

E. Additional Methods for alcohol oxidation-
1. Collins Reagent- a complex of chromium trioxide and pyridine.
2. Jones Reagent- milder form of chromic acid that consists of a solution of diluted
chromic avid in acetone.
3. Potassium Permanganate and Nitric acid- Both strong oxidants that are less
expensive than the chromium reagants, and both also give byproducts that are
environmentally less hazardous than spent chromium agents.
a. Strong oxidizers, therefore the primary alcohols to carboxylic acids, and
secondary acids to ketones.
b. So strong that they will break carbon-carbon bonds if not controlled.
4. Dehydrogenation- the least expensive method for oxidizing alcohols. Takes place at
high temperatures with copper or copper oxide as a catalyst. This results in a
hydrogen byproduct that can be used in other reactions or even sold.
a. Not useful for a laboratory setting
5. Swern Oxidation- Uses dimethyl sulfoxide(DMSO) as the oxidizing agent to convert
alcohols to ketones and aldehydes.
a. DMSO and oxalyl chloride are added to the alcohol at low temperature; this is
then followed by the addition of a hindered base such as triethylamine.
b. Byproducts are volatile, so separation of products is easy.
c. Secondary alcoholsketones; Primary alcohols aldehyde
d. See ex on p. 466.
6. Biological Oxidation of alcohols- The enzyme that breaks down alcohol, oxidiation
of the alcohol, is alcohol dehydrogenase. This is done by the removal of two
hydrogens from the alcohol.
a. Oxidizing agent is NAD; exists in two forms:
i. the oxidized form, NAD
+

ii. the reduced form, NADH
b. ethanol is oxidized to acetylaldehyde, and NAD
+
is reduced to NADH.
c. See p. 467
d. Aldehyde dehydrogenase- is the enzyme that converts the acetylaldehyde and
oxidizes it to acetic acid.
e. Some alcohols byproducts are more toxic than the alcohol itself.
i. Methanol, a toxic alcohol, is oxidized to formaldehyde and then to formic
acid both of which are more toxic than the original alcohol. Blindness and
death result.
ii. Ethylene glycol is a toxic diol found in antifreeze that is oxidized to oxalic acid
another toxic compound. Many pets are poisoned by this because of the
sweet odor of this compound. When ingested the kidneys fail and death
results.
iii. Both poisonings are treated the same, give them diluted ethanol
intravenously. The ADH enzyme is overwhelmed with ethanol, the preferred
substrate; as a result, the kidneys have time to expel the toxic elements
before oxidation takes place.

II. Alcohols as nucleophiles and electrophiles-
A. Versatility-
1. Alcohol can be weak nucleophile bonding to a strong electrophile such as a
carbocation.
a. The C-O bond is broken when alcohol acts as electrophile as in substitution
reactions.
b. The alcohol can make the poor leaving hydroxyl group into a good leaving group
through protonation of the hydroxyl group.
i. Ex: add HBr to alcohol which donates its proton to the oxygen with 2
lone pairs. This creates H
2
O with a positive charge on oxygen. This
instability results in the formation of a good leaving group, water. This
results in a carbocation which then binds Br
-
in classic S
N
2 fashion.
ii. The disadvantage of using the protonated alcohol is that a strongly
acidic solution is required to protonate the alcohol. This is a problem
because there are few nucleophiles that are stable in strongly acidic
solutions besides halide ions. Most of the nucleophiles are also basic
and will abstract a proton in acid. This makes it lose its nucleophilicity.
2. Alcohol can be converted to a strong nucleophile by conversion to an alkoxide ion.
This allows for an attack of a weaker electrophile.
a. The O-H cond is broken when alcohol is nucleophillic as in the elimination
reacton.
3. Tosylate esters the product of condensation of an alcohol with p-toluenesulfonic
acid(TsOH). The tosylate is an excellent leaving group. Depending on the reagents,
many S
N
2 products can formed when in the presence of a strong nucleophile and
the Rs must be primary or unhindered secondary alkyl group. See table p. 471.

III. Reduction of alcohols:
A. Basics-
1. Not as common because it removes a functional group; leaving fewer options for
further reactions.
2. Two step process:
a. Dehyrdrate to yield alkene.
b. Then hydrogenate to yield alkane.
3. Can also be achieved by converting the alcohol to a tosylate ester, then using a
hydride reducing agent to displace the tosylate.
a. Works best for primary and secondary alcohols



IV. Reactions of Alcohols with hydrohalic acids:
A. Common Reactions to yield alkyl halides:
1. Tosylation, followed by displacement of tosylate by a halide ion alkyl
halide.
a. Simple one step reactions are available
2. Hydrobromic acid treatment-If an alcohol is placed in an acidic solution, the
acid donates a proton to the alcohol converted to its protonated form.
a. Alcohol and protonated form are in equilibrium
b. The protonated(H
2
O
+
) version is a good leaving group
c. Then the halide anion, a weak base(b/c the acid is so strong), will act in
nucleophilic substitution 1 or 2 depending on the structure of the
alcohol.
i. Tertiary and secondary alcohols-
a. S
N
1 mechanism- forms a tertiary or secondary
carbocation.
b. Subsequent attack of the nucleophilic halide.
ii. Primary alcohols-
a. Protonation as above, results in good leaving group
b. Ionization to form carbocation is unfavorable
iii. Must have concerted reaction with backside attack of
bromide ion in S
N
2 fashion.
3. Hydrochloric acid treatment- reacts much like hydrobromic acid.
a. Chloride ion is a weaker nucleophile than bromide ion because it is
smaller and less polarizable.
i. Lewis acid such as ZnCl
2
is sometimes necessary to promote
reactions of HCl with primary and secondary alcohols.
a. The ZnCl
2
will bind to the oxygen of the hydroxyl group with
more efficiency and form the good leaving group.
ii. Lucas reagent- HCl and ZnCl
2
.
a. Secondary and tertiary alcohols react with S
N
1 mechanism.
b. Primary alcohols cannot ionize to form primary carbocation
because they are too unstable.
i. Therefore, a concerted 1 step S
N
2 mechanism is
required. This is much slower than the secondary
and tertiary reactions, that use S
N
1 mechanism, due
to the fact of rate of the S
N
1 reactions are
dependent only on the concentration of the alkyl
halide; however, both the nucleophile and alkyl
halide concentrations affect the rate in S
N
2
mechanisms. (Inc the nucleophile speeds up
kinetics in the 2s)
ii. Lucas test- A test that is used to determine the
structure of an alcohol, primary, secondary, or
tertiary. Alcohols react with lucas reagent at fairly
predictable rates. The rates can be used to
distinguish which alcohol is present.
a. Add Lucas reagent to an unkown alcohol to
form one phase.
i. The very polar HCl dissolves the alcohol-zinc
chloride complex to yield the alkyl halide, a
nonpolar substance.
ii. This will cause a second phase to emerge.
a. Primary- very slow (10min-sev days)
b. Secondary- 1 to 5 minutes
c. Tertiary- almost instantaneous

B. Limitations on the use of Hydrohalic Acids with Alcohols-
1. Poor yields of alkyl chlorides from primary and secondary alcohols.
a. side reactions prevent good yields
2. Elimination is preferred when an alcohol is heated in concentrated acid such as HCl
or HBr. Protonation is achieved making the hydroxyl group is then protonated
resulting in a good leaving group, can undergo elimination or substitution.
3. Rearrangements of carbocations intermediates are always prone to
rearrangenments to increase the stability of a carbocation.
4. Limited ability to make alkyl iodides due to the reactivity of alkyl iodides.


C. Reactions of alcohols with Phosphorous Halides-
1. PCl
3
, PBr
3
, PCl
5
all react to yield primary and secondary alkyl halides.
2. Doesnt work as well for PClides.
3. Phosphorous trihalides, strong electrophiles, have rearrangements that are
uncommon, and tertiary alcohols are unlikely to react.
a. the first step is for the alcohol will react with the electrophillic Phosphorous
trihalide to make the cationic oxide ion, a good leaving group, and the halide
anion.
b. The halide ion then displaces the leaving group in a backside attack.
c. No carbocation, therefore, no rearrangements are likely
d. Because of the S
N
2 backside attack, the tertiary alcohols are sterically hindered.
e. For a tertiary alcohol, ionization must occur to form the carbocation.
i. too slow; invites side reactions.



D. Thionyl Chloride-
1. The best reagent for converting an alcohol into an alkyl chloride.
a. Byproducts, SO
2
and HCl, are gaseous so they leave the mixture preventing a
reverse reaction.
b. Steps:
i. First, nonbonding electrons of the hydroxyl oxygen atom attack the
electrophilic sulfur atom of thionyl chloride.
ii. Second, a chloride ion is displaced which then comes and removes the
hydrogen that is on the hydroxyl group to yield a chlorosulfite ester(great
leaving group)
iii. Then, provided secondary or tertiary, S
N
2 mechanism.
iv. Primary undergoes the concerted reaction of S
N
1 forming a chloride bond with
the carbon and breaking the C-O bond.
E. Formation of Alkenes-
1. Protonate alcohol, a slightly exothermic step, to convert the hydroxyl to a water
cation, an excellent leaving group.
2. Water leaves to form a carbocation in the rate limiting step
3. Water acts as a base and abstract the hydrogen from the carbon bonded to the
carbocation.
4. Must be in acidic conditions to promote protonation of hydroxyl.
5. Equilibrium can be driven to the right by the removal of the products:
a. Can be achieved by the distilling the products out of the reaction mixture or by
adding a dehydrating agent to remove the water.
i. The alcohol is mixed with the dehydrating acid, and the mixture is
heated to boiling. The alkene boils at lower temperature than the
alcohol, due to h-bonding, and the alkene distills out of the mixture.
*Note Classic E1 mechanism so the reactivity depends on the stability of the
carbocation, tertiary>secondary>and primary with rearrangements are common.
F. Bimolecular dehydration to Form Ethers-
1. Sometimes protonated primary alcohols can be attacked by another molecule of the
alcohol. The molecule can then undergo S
N
2 displacement.
2. The two joined molecules have an oxygen molecule that is positively charged and
unstable.
a. a water molecule comes and abstracts the remaining hydrogen to yield an ether
and H
3
O
+
.
3. Used to synthesize symmetrical dialkyl ethers, diethyl ether and dimethyl ether,
form unhindered primary alcohols.
4. Under acidic conditions, competition occurs:
a. Substitution to give ether, bimolecular dehydration
b. Elimination to give the alkene, unimolecular dehydration.
*Control can be achieved by controlling the temperature: the higher the temp the
more favorable the elimination path becomes favorable. 40 degrees Celsius and
below for ether formation, and 80 degrees and above for alkene formation.
G. Unique Reactions of Diols-
1. Pinacol Rearrangement- a dehydration reaction that is catalyzed by an acid. The steps
are as follows:
a. protonation of the hydroxyl group to yield unstable cationic water, good leaving grp.
b. methyl group migrates to the cationic carbon, thereby moving the charge to the carbon
that has the remaining hydroxyl group.
i. the oxygens lone pair helps to stabilize the positive charge on the carbon. This is
what drives the rearrangement.
c. Deprotonation of the resonance stabilized cation gives the product pinacolone.

H. Periodic Acid Cleavage of Glycols-
1. Periodic acid(HIO
4
)- 1,2 diols(glycols) are cleaved by this acid to yield ketones and
aldehydes. Steps:
a. Hydroxylation of the alkene to yield a glycol, using OsO
4
and H
2
O
2.
b. Periodic acid subsequently cleaves the glycol using a cyclic periodate intermediate.
*The resulting products that would be formed are the same as the products formed by the
reduction of the alkenes, ozonlysis. Useful for determining the structures of surgars.
I. Fischer esterification-
1. a process in which the hydroxyl group of a carboxylic acid with the OR of an alcohol to
yield an ester.
a. unfavorable equilibrium, so to achieve good yields an excess of alcohol or acid is used
b. adding a dehydrating agent so that water, a product, is removed also helps.
c. combining an alcohol with an acid chloride is highly favorable(exothermic)

J. Esters of Inorganic acids-
1. Inorganic esters when the alcohol is bonded to an inorganic acid, such as nitric, sulcuric,
or phosphoric acid, the product is an inorganic ester. Each still undergoes a dehydration
reaction in which the hydroxyl of the acid is replaced by the alkoxy, -OR, group of the
alcohol.
a. Sulfate esters are analogous to tosylate esters.
i. alkoxy groups are bonded to the sulfur atom through oxygens.
ii. Sulfate ions are excellent leaving groups and good electrophiles.
iii. Nucleophiles react with sulfate esters to give alkylated products.
b. Nitrate esters are famous due to nitroglycerine.
c. Phosphate esters react with 1, 2, or 3 moles of an alcohol.
i. play an important role in the formation of backbones of nucleic acids of RNA and DNA.

I. Alkoxide ion reactions-
1. The reduction of alcohol by reduction with an active metal such sodium or potassium
yields a salt of the alkoxide ion and hydrogen gas.
2. Reactivity: methyl > primary > secondary > tertiary.
3. Sodium reacts quickly with primary and secondary alcohols.
4. Potassium is more reactive than sodium and is commonly used with tertiary and some
secondary alcohols.
5. If the alcohol isnt as reactive, then sodium hydride is used in a tetrahydofuran(THF)
solution.
6. Alkoxide ion is very reactive as a strong nucleophile, and also as a powerful base.
7. Alkoxide ion, unlike alcohols, can bond with primary alkyl halides, no steric hinderance,
and tosylates to form ethers in a S
N
2 reaction known as Williamson Ether Synthesis.
a. If not primary, elimination reaction takes place.