Transcript thiols and sulfides.

9-6
Williamson Ether Synthesis
Ethers are prepared by SN2 reactions.
Ethers can be prepared by the reaction of an alkoxide with a
primary haloalkane or sulfonate ester under SN2 conditions.
The parent alcohol of the alkoxide can be used as the solvent,
however other polar solvents are often better, such as DMSO
(dimethyl sulfoxide) or HMPA (hexamethylphosphoric triamide).
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Use of alkoxides in ether synthesis is limited to primary unhindered
alkylating agents, otherwise E2 products are formed in major.
Cyclic ethers: intramolecular Williamson synthesis.
Haloalcohols serve as the starting point for the Williamson
synthesis of cyclic ethers.
The intramolecular reaction is usually much faster than the
intermolecular reaction. If necessary, the intermolecular reaction
can be suppressed by using a high dilution of the haloalcohol.
Cyclic ethers of even small rings can be prepared using the
Williamson synthesis.
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Ring size controls the speed of cyclic ether formation.
The rate of ring closure is based on both enthalpic and entropic
contributions.
These rate differences can be explained based on the interplay
between strain, entropy, and proximity.
Entropy reduction (due to ring closure) increases with increasing
ring size. (Reaction rate decrease with increasing ring size.)
Ring strain decreases with increasing ring size. (Reaction rate
increase with increasing ring size.)
Transition-state strain is reduced in the 2-haloalkoxides because the
2-haloalkoxide is already strained by the proximity of the halide and
hydroxyl. (Reaction rate increase for the 2-haloalkoxides.)
The intramolecular Williamson synthesis is stereospecific
Since the Williamson synthesis is a SN2 substitution reaction, an
inversion of configuration occurs at the carbon bearing the leaving
group.
The leaving group must be on the opposite side of the molecule
from the attacking nucleophile in order for the reaction to occur.
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9-7
Synthesis of Ethers: Alcohols and Mineral Acid
Alcohols give ethers by both SN2 and SN1 mechanisms.
Strong nucleophilic acids (HBr, HI) yield haloalkanes when
reacted with alcohols.
Strong non-nucleophilic acids yields ethers when reacted with
alcohols.
At higher temperatures, an E2 elimination of water occurs with
the subsequent production of alkenes.
Secondary / tertiary alcohols form ethers via an SN1 reaction
with a second molecule of the alcohol trapping the carbocation.
The E1 pathway becomes dominate at higher temperatures.
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Mixed ethers containing one tertiary and one primary or
secondary alcohol can be prepared in the presence of dilute acid.
The tertiary carbocation is trapped by the less hindered alcohol.
Ethers also form by alcoholysis
This occurs by simply dissolving a
tertiary or secondary haloalkane in an
alcohol and waiting until the SN1
process is complete.
9-8
Reactions of Ethers
Ethers are usually inert, however, they do react slowly with
oxygen to form hydroperoxides and peroxides which can
decompose explosively.
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The ether oxygen atom can be protonated to generate
alkyloxonium ions.
With primary groups and strong nucleophilic acids (HBr), SN2
displacement takes place.
Oxonium ions from secondary ethers may transform by either SN2
or SN1 reactions, depending upon conditions.
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Tertiary ethers are protecting groups for alcohols.
Esters containing tertiary alkyl groups react in dilute acid to give
carbocations which are either trapped (SN1) by good nucleophiles
or deprotonated in the absence of good nucleophiles.
Because they are readily formed (and equally readily hydrolyzed),
tertiary ethers are commonly used as protecting groups during
chemical reactions which might otherwise interact with the
unprotected alcohol.
9-9
Reactions of Oxacyclopropanes
Nucleophilic ring opening of oxacyclopropanes by
SN2 is regioselective and stereospecific.
Oxacyclopropane can be ring-opened by anionic nucleophiles.
Because the molecule is symmetric, nucleophilic attack can be at
either carbon atom.
The driving force for this reaction is the release of ring strain.
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With unsymmetric epoxides, attack is at the less substituted
carbon center.
This selectivity is referred to as “regioselectivity”
If the ring opens at a stereocenter, inversion is observed.
Hydride and organometallic reagents convert strained ethers
into alcohols.
LiAlH4 can open the rings of oxacyclopropanes to yield alcohols.
(Ordinary ethers do not react)
Asymmetrical systems: hydride attacks less substituted side.
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If the reacting carbon is a stereocenter, inversion is observed.
Oxacyclopropanes are sufficiently reactive electrophiles to be
attacked by organometallic compounds.
Acids catalyze oxacyclopropane ring opening.
Ring opening of oxacyclopropane by acid catalysis proceeds
through an initial cyclic alkyloxonium ion.
This acid catalyzed ring opening is both regioselective and
stereospecific.
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The acid catalyzed methanolysis of 2,2-dimethyloxacyclopropane
is ring-opened at the more hindered carbon.
In the alkyloxonium ion, more positive charge is located on the
tertiary carbon than on the primary carbon.
This effect counteracts the effect of steric hindrance and the
alcohol attacks the tertiary carbon.
Because inversion of configuration occurs during ring opening,
free carbocations cannot be involved in the reaction
mechanism.
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9-10 Sulfur Analogs of Alcohols and Ethers
Sulfur analogs of alcohols and ethers: thiols and sulfides.
The IUPAC system calls the sulfur analogs of alcohols, R-SH,
“thiols.”
The –SH group in more complicated compounds is referred to
as “mercapto”
The sulfur analogs of ethers are called “sulfides” (common
name, thioethers).
The RS group is called “alkylthio” and the RS- group is called
“alkanethiolate”
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Thiols are less H-bonded and more acidic than alcohols
Compared to oxygen, sulfur has a
large size, diffuse orbitals and a
relatively nonpolarized S-H bond.
The boiling points of thiols are
similar to those of the
analogous haloalkanes.
Thiols are more acidic than water and
can therefore be easily deprotonated by
hydroxide and alkoxide ions:
Thiols and sulfides react much like alcohols and ethers
The sulfur in thiols and sulfides is more nucleophilic than the
oxygen in the analogous compounds.
Thiols and sulfides are readily made through nucleophilic attack
by RS- or HS- on haloalkanes:
A large excess of HS- is used to prevent the reaction of the
product with the starting halide.
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Sulfides are prepared by the alkylation of thiols in the presence of
a base, such as hydroxide.
The nucleophilicity of the generated thiolates is much
greater than that of hydroxide which eliminates the competing
SN2 substitution by hydroxide ion.
Sulfides can attack haloalkanes to form sulfonium ions.
Sulfonium ions are subject to nucleophilic attack, the leaving
group being a sulfide.
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Valence-shell expansion of sulfur accounts for the
special reactivity of thiols and sulfides.
Sulfur can expand its valence shell from 8 to
10 or 12 electrons using its available 3d
orbitals, allowing oxidation states not
available to its oxygen analogs.
Oxidation of thiols with strong oxidizing
agents (H2O2, KMnO4) gives the
corresponding sulfonic acids:
Milder oxidizing agents (I2) yield disulfides.
These can be reduced back to thiols by alkali metals.
Reversible disulfide formation is important in stabilizing the
folding of biological enzymes:
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Sulfides can also be oxidized to
sulfoxides and then sulfones:
9-11 Physiological Properties and Uses of Alcohols and
Ethers
Methanol:
Formed by catalytic reduction of CO and H2 at high
temperatures and pressure.
Used as a solvent, a fuel for camp stoves and soldering
torches, and as a synthetic intermediate.
Highly poisonous. May lead to blindness or death.
A possible precursor of gasoline.
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Ethanol:
Alcohol in alcoholic beverages
General depressant
High in calories, little nutritional value
Metabolically degraded linearly with time
Poisonous (lethal concentration ~ 0.4%)
Near toxic dose used to treat methanol poisoning
Produced by fermentation of sugars and starch
Commercially produced by the hydration of ethylene.
Used as a solvent, a synthetic intermediate, and as a
gasoline additive (gasahol)
2-Propanol:
Toxic, but not absorbed through the skin
Used as a rubbing alcohol, a solvent, and as a cleaning agent
1,2-Ethanediol (ethylene glycol):
Used as an antifreeze (completely miscible with water)
Produced from ethene:
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1,2,3-Propanetriol (glycerol, glycerine):
Non-toxic
Major component of fatty tissue
Liberated by the action of alkali on fats to form soaps:
Phosphoric esters of glycerols are major cell membrane
components.
Used in lotions, cosmetics, and medicinal preparations.
Forms nitroglycerine upon
treatment with nitric acid.
Cholesterol:
An important steroid alcohol
Ethoxyethane (diethyl ether):
Formally used as an anesthetic
Explosive when mixed with air
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Oxacyclopropane (oxirane, ethylene oxide)
Industrial chemical intermediate
Fumigating agent for seeds and grains
Oxacyclopropane derivatives control insect metamorphosis
and are formed during enzyme-catalyzed oxidations of
aromatic hydrocarbons (highly carcinogenic).
Alcohol and ether groups are
found in natural products
such as morphine and
tetrahydrocannabinol:
Lower MW thiols and sulfides are notorious for their foul smells.
The odor of the skunk’s defensive spray are thiols and a sulfide:
When highly diluted, thiols and
sulfides have a pleasant odor:
freshly chopped onion or
garlic, black tea, grapefruit.
The compound responsible for the
taste of grapefruit can be tasted
in concentrations in the ppb
range:
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Drugs such as the sulfonamides (sulfa drugs) contain sulfur in
their molecular framework:
9
Important Concepts
1. Reactivity of ROH With Alkali Metals –
•
R=
CH3 > primary > secondary > tertiary
2. Reactions with Acid and a Nucleophilic
Counterion –
•
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Primary Alcohols – SN2 reactions
Secondary and Tertiary Alcohols – Form
carbocations capable of E1 and SN1 reactions,
before and after rearrangement
3. Carbocation Rearrangements –
•
•
•
Hydride and alkyl group shifts
Result in interconversion of secondary carbocations
or conversion of secondary to tertiary carbocation
Primary alkyloxonium can rearrange to secondary
or tertiary carbocations
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Important Concepts
4. Haloalkane Synthesis – Methods using inorganic
esters yield primary and secondary haloalkanes with
less chance of rearrangement.
5. Ether Preparation –
•
Williamson ether synthesis – Best when SN2
reactivity is high
• Reaction of alcohols with strong non-nucleophilic
acids – elimination completes at higher
temperatures
6. Crown Ethers and Cryptands – Examples of
ionophores which solubilize metal ions in hydrophobic
media.
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Important Concepts
7. Ring Opening of Oxacyclopropanes –
•
•
Nucleophilic attack at the less substituted ring
carbon
Acid-catalyzed attack favors the more substituted
ring carbon
8. Sulfur –
•
•
•
More diffuse orbitals than oxygen
The thiol S-H bond is less polarized than the O-H
bond in alcohols (less hydrogen bonding)
Acidity of S-H is greater than O-H