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w3.ualg.pt\~abrigas QOI 0809 R-XR 1
Química Orgânica I
2008/09
w3.ualg.pt\~abrigas QOI 0809 R-XR 2
R-O-R; R-S-R
w3.ualg.pt\~abrigas QOI 0809 R-XR 3
w3.ualg.pt\~abrigas QOI 0809 R-XR 4
Ethoxyethane (diethyl ether):
Formally used as an anesthetic
Explosive when mixed with air.
Oxacyclopropane (oxirane, ethylene oxide)Industrial chemical intermediateFumigating agent for seeds and grainsOxacyclopropane derivatives control insect metamorphosis and are formed during enzyme-catalyzed oxidations of aromatic hydrocarbons (highly carcinogenic).
diethyl ether
w3.ualg.pt\~abrigas QOI 0809 R-XR 5
• Formula R-O-R where R is alkyl or aryl.
• Symmetrical or unsymmetrical
• Examples:
O CH3
CH3 O CH3O
=>
Types of ethers
w3.ualg.pt\~abrigas QOI 0809 R-XR 6
• system: ethers are alkoxyalkanes (Ethers are alkanes bearing an alkoxy substituent)
– The larger substituent is the stem and the
smaller substituent is the alkoxy group
(methoxyethane)
IUPAC nomenclature of ethers
w3.ualg.pt\~abrigas QOI 0809 R-XR 7
CHCH33OOCHCH2 2 CHCH33
methoxymethoxyethaneethane
CHCH33CHCH22OOCHCH2 2 CHCH33
ethoxyethoxyethaneethane
CHCH33CHCH22OOCHCH22CHCH22CHCH22ClCl
11--chlorochloro--33--ethoxyethoxypropanepropane
w3.ualg.pt\~abrigas QOI 0809 R-XR 8
CHCH33OOCHCH2 2 CHCH33
ethylethyl methylmethyl etherether
CHCH33CHCH22OOCHCH2 2 CHCH33
didiethylethyl etherether
CHCH33CHCH22OOCHCH22CHCH22CHCH22ClCl
33--chloropropylchloropropyl ethylethyl etherether
w3.ualg.pt\~abrigas QOI 0809 R-XR 9
Cyclic ethers names are based on the oxacycloalkane stem.
Oxacyclopropane (oxiranes, epoxides, ethylene oxides)
Oxacyclobutane
Oxacyclopentane (tetrahydrofurans)
Oxacyclohexanes (tetrahydropyrans)
Ring numbering starts on the oxygen atom.
Cyclic ethers
w3.ualg.pt\~abrigas QOI 0809 R-XR 10
OxiraneOxirane
(Ethylene oxide)(Ethylene oxide)OxetaneOxetane OxolaneOxolane
((tetrahydrofurantetrahydrofuran))
OxaneOxane
((tetrahydropyrantetrahydropyran))
1,41,4--DioxaneDioxane
Names of Cyclic EthersNames of Cyclic Ethers
OO OO OO
OO
OO
OO
w3.ualg.pt\~abrigas QOI 0809 R-XR 11
Cyclic polyethers based on the 1,2-ethanediol unit are called crown ethers. The crown ether, 18-crown-6, contains 18 total atoms and 6 oxygen atoms:
Note that the inside of the ring is electron rich.
crown ethers
w3.ualg.pt\~abrigas QOI 0809 R-XR 12
Structure and Polarity
• Bent molecular geometry
• Oxygen is sp3 hybridized
• Tetrahedral angle
=>
w3.ualg.pt\~abrigas QOI 0809 R-XR 13
HH
OO
HH
(CH(CH33))33CC
OO
C(CHC(CH33))33
112112°°
105105°° 108.5108.5°°
132132°°
HH
OO
CHCH33
CHCH33
OO
CHCH33
Bond angles at oxygen are sensitiveBond angles at oxygen are sensitiveto to stericsteric effectseffects
w3.ualg.pt\~abrigas QOI 0809 R-XR 14
most stable conformation of diethyl ethermost stable conformation of diethyl ether
resembles pentaneresembles pentane
An oxygen atom affects geometry in much theAn oxygen atom affects geometry in much the
same way as a CHsame way as a CH22 groupgroup
w3.ualg.pt\~abrigas QOI 0809 R-XR 15
most stable conformation of most stable conformation of tetrahydropyrantetrahydropyran
resembles resembles cyclohexanecyclohexane
An oxygen atom affects geometry in much theAn oxygen atom affects geometry in much the
same way as a CHsame way as a CH22 groupgroup
w3.ualg.pt\~abrigas QOI 0809 R-XR 16
Hydrogen Bond Acceptor
• Ethers cannot H-bond to each other.
• In the presence of -OH or -NH (donor), the
lone pair of electrons
from ether forms a hydrogen bond with the -
OH or -NH.
=>
w3.ualg.pt\~abrigas QOI 0809 R-XR 17
Solvent Properties
• Nonpolar solutes dissolve better in ether than in
alcohol.
• Ether has large dipole
moment, so polar solutes
also dissolve.
• Ethers solvate cations.
• Stabilizes organometalicreagents
• Ethers do not react with strong bases. =>
w3.ualg.pt\~abrigas QOI 0809 R-XR 18
Boiling Points
Similar to alkanes of comparable molecular weight.
=>
w3.ualg.pt\~abrigas QOI 0809 R-XR 19
The smaller alkoxyalkanes are water soluble, however solubility decreases with increasing hydrocarbon size.
Methoxymethane – completely water soluble
Ethoxyethane – 10% aqueous solution
Solubility
w3.ualg.pt\~abrigas QOI 0809 R-XR 20
Ether Complexes
• Grignard reagents
• Electrophiles
• Crown ethers
O B
H
H
H
+_
BH3 THF
=>
w3.ualg.pt\~abrigas QOI 0809 R-XR 21
Crown ethers can render salts soluble in organic solvents by chelating the metal cations. This allows reagents such as KMnO4 to act as an oxidizing agent in the organic solvents.
The size of the central cavity can be tailored to selectively bind cations of differing ionic radii.
Crown ethers
w3.ualg.pt\~abrigas QOI 0809 R-XR 22
Three dimensional analogs of crown ethers are polyethers called cryptands. These are highly selective in alkali and other metal cation binding.
cryptands
w3.ualg.pt\~abrigas QOI 0809 R-XR 23
Synthesis
w3.ualg.pt\~abrigas QOI 0809 R-XR 24
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). Why?
Williamson Ether Synthesis
w3.ualg.pt\~abrigas QOI 0809 R-XR 25
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.
intramolecular Williamson
synthesis
w3.ualg.pt\~abrigas QOI 0809 R-XR 26
intramolecular Williamson
synthesis
w3.ualg.pt\~abrigas QOI 0809 R-XR 27
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 rateincrease 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).
Ring size controls the speed
w3.ualg.pt\~abrigas QOI 0809 R-XR 28
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.
intramolecular Williamson
synthesis is stereospecific
w3.ualg.pt\~abrigas QOI 0809 R-XR 29
HH
OOHH
BrBr
HH
NaOHNaOH
HH22OO
(81%)(81%)
HH
HH
OO
halohdrine
w3.ualg.pt\~abrigas QOI 0809 R-XR 30
OO
BrBr
HHHH
••••
••••••••
••••••••
••••
––via:via:
w3.ualg.pt\~abrigas QOI 0809 R-XR 31
antianti
additionadditioninversioninversion
Epoxidation via Vicinal HalohydrinsEpoxidationEpoxidation via Vicinal via Vicinal HalohydrinsHalohydrins
BrBr22
HH22OO
OOHH
NaOHNaOH
corresponds to overall corresponds to overall synsyn addition ofaddition ofoxygen to the double bondoxygen to the double bond
BrBr
OO
w3.ualg.pt\~abrigas QOI 0809 R-XR 32
Strong nucleophilic acids (HBr, HI) yield haloalkanes when reacted with alcohols.
Strong non-nucleophilic acids yiels ethers when reacted with alcohols.
Synthesis of Ethers:
Alcohols and Mineral Acid
w3.ualg.pt\~abrigas QOI 0809 R-XR 33
At higher temperatures, an E2 elimination of water occurs with the subsequent production of alkenes.
Side reactions
w3.ualg.pt\~abrigas QOI 0809 R-XR 34
Secondary and tertiary alcohols form ethers through an SN1 reaction with a second molecule of the alcohol trapping the carbocation. The E1 pathway becomes dominate at higher temperatures.
SN1
w3.ualg.pt\~abrigas QOI 0809 R-XR 35
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.
Asymetric ethers
w3.ualg.pt\~abrigas QOI 0809 R-XR 36
By simply disolving a tertiary or secondary haloalkane in an alcohol and waiting until the SN1 process is complete.
Ethers also form by alcoholysis
w3.ualg.pt\~abrigas QOI 0809 R-XR 37
Ethers are usually inert, however the do react slowly with oxygen to form hydroperoxides and peroxides which can decompose explosively.
Reactions of ethers
w3.ualg.pt\~abrigas QOI 0809 R-XR 38
The ether oxygen atom can be protonated to generate alkyloxonium ions.
With primary groups and strong nucleophilic acids (HBr) SN2 displacement takes place.
Ether cleavage
w3.ualg.pt\~abrigas QOI 0809 R-XR 39
Ether cleavage
w3.ualg.pt\~abrigas QOI 0809 R-XR 40
HHII
150150°°CCIICHCH22CHCH22CHCH22CHCH22II
(65%)(65%)
OO
Cleavage of Cyclic EthersCleavage of Cyclic Ethers
w3.ualg.pt\~abrigas QOI 0809 R-XR 41
OO••••
••••
HHII
HH
OO••••
++
•••• II ••
••••••
••••
––
IICHCH22CHCH22CHCH22CHCH22II
HHII
HH
OO•••• II••••
•••• ••••
••••
MechanismMechanism
w3.ualg.pt\~abrigas QOI 0809 R-XR 42
Oxonium ions from secondary ethers may transform by either SN2 or SN1 reactions, depending upon conditions.
Substitution
w3.ualg.pt\~abrigas QOI 0809 R-XR 43
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.
Protecting groups
w3.ualg.pt\~abrigas QOI 0809 R-XR 44
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.
Protecting groups
w3.ualg.pt\~abrigas QOI 0809 R-XR 45
Reactions of Oxacyclopropanes
9-9
Nucleophilic ring opening of oxacyclopropanes by SN2 is regioselective and stereospecific.
The driving force for this reaction is the release of ring strain.
Oxacyclopropane can be ring opened by anionic nucleophiles. Because the molecule is symmetric, nucleophilic attack can be at either carbon atom.
w3.ualg.pt\~abrigas QOI 0809 R-XR 46
With unsymmetric systems attack will be at the less substituted carbon center. This selectivity is referred to as regioselectivity.
If the ring opens at a stereocenter, inversion is observed.
w3.ualg.pt\~abrigas QOI 0809 R-XR 47
Hydride and organometallic reagents convert strained ethers into alcohols.
LiAlH4 can open the rings of oxacyclopropanes to yield alcohols. (Ordinary ethers do not react)
In unsymmetrical systems, the hydride attacks the less substituted side.
w3.ualg.pt\~abrigas QOI 0809 R-XR 48
If the reacting carbon is a stereocenter, inversion is observed.
w3.ualg.pt\~abrigas QOI 0809 R-XR 49
Oxacyclopropanes are sufficiently reactive electrophiles to be attacked by organometallic compounds.
w3.ualg.pt\~abrigas QOI 0809 R-XR 50
This acid catalyzed ring opening is both regioselective and stereospecific.
Acid catalyzed oxacyclopropane
ring opening
w3.ualg.pt\~abrigas QOI 0809 R-XR 51
The acid catalyzed methanolysis of 2,2-dimethyloxacyclopropane is ring opened at the more hindered carbon.
w3.ualg.pt\~abrigas QOI 0809 R-XR 52
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.
w3.ualg.pt\~abrigas QOI 0809 R-XR 53
S derivatives
w3.ualg.pt\~abrigas QOI 0809 R-XR 54
Lower MW thiols and sulfides are notorious for their foul smells.
The odor of the skunk’s defensive spray are thiols and a sulfide:
w3.ualg.pt\~abrigas QOI 0809 R-XR 55
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:
w3.ualg.pt\~abrigas QOI 0809 R-XR 56
Drugs such as the sulfonamides (sulfa drugs) contain sulfur in their molecular framework:
w3.ualg.pt\~abrigas QOI 0809 R-XR 57
The sulfur analogs of alcohols and ethers are 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.
Sulfur Analogs of Alcohols and Ethers
w3.ualg.pt\~abrigas QOI 0809 R-XR 58
The sulfur analogs of ethers are called sulfides (common name, thioethers).
The RS group is called alkylthio, and the RS- group is called alkanethiolate.
sulfur analogs
w3.ualg.pt\~abrigas QOI 0809 R-XR 59
CHCH33SSCHCH2 2 CHCH33
methylthiomethylthioethaneethane
CHCH33CHCH22SSCHCH2 2 CHCH33
ethylthioethylthioethaneethane
((methylthio)cyclopentanemethylthio)cyclopentane
Substitutive IUPAC Names of SulfidesSubstitutive IUPAC Names of Sulfides
SCHSCH33
w3.ualg.pt\~abrigas QOI 0809 R-XR 60
cyclopentylcyclopentyl methylmethyl sulfidesulfide
analogous to ethers, but replace analogous to ethers, but replace ““etherether”” as lastas last
word in the name by word in the name by ““sulfide.sulfide.””
CHCH33SSCHCH2 2 CHCH33
ethylethyl methyl sulfidemethyl sulfide
CHCH33CHCH22SSCHCH2 2 CHCH33
didiethylethyl sulfidesulfide
Functional Class IUPAC Names of SulfidesFunctional Class IUPAC Names of Sulfides
SSCHCH33
w3.ualg.pt\~abrigas QOI 0809 R-XR 61
ThiiraneThiirane ThietaneThietane ThiolaneThiolane
ThianeThiane
Names of Cyclic SulfidesNames of Cyclic Sulfides
SS SS SS
SS
w3.ualg.pt\~abrigas QOI 0809 R-XR 62
Thiols are less hydrogen 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 thiolsare similar to those of the analogous haloalkanes.
Bloiling points
w3.ualg.pt\~abrigas QOI 0809 R-XR 63
Thiols are more acidic than water and can therefore be easily deprotonated by hydroxide and alkoxide ions:
acidity
w3.ualg.pt\~abrigas QOI 0809 R-XR 64
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.
synthesis of thiols
w3.ualg.pt\~abrigas QOI 0809 R-XR 65
Sulfides are prepared by the alkylation of thiols in the presence of 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.
synthesis of sulfides
w3.ualg.pt\~abrigas QOI 0809 R-XR 66
Sulfides can attack haloalkanes to form sulfonium ions.
Sulfonium ions are subject to nucleophilic attack, the leaving group being a sulfide.
Sulfonium ions
w3.ualg.pt\~abrigas QOI 0809 R-XR 67
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 sulfonicacids:
Oxydation of S
w3.ualg.pt\~abrigas QOI 0809 R-XR 68
Milder oxidizing agents (I2) yield disulfides.
These can be reduced back to thiols by alkali metals.
Thiol-disulfide redox reaction
w3.ualg.pt\~abrigas QOI 0809 R-XR 69
Reversible disulfide formation is important in stabilizing the folding of biological enzymes:
folding of proteins
w3.ualg.pt\~abrigas QOI 0809 R-XR 70
Sulfides can also be oxidized to sulfoxides and then sulfones: