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Química Orgânica I

Ciências Farmacêuticas

Bioquímica

Química

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R-O-R; R-S-R

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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

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• Formula R-O-R where R is alkyl or aryl.

• Symmetrical or unsymmetrical

• Examples:

O CH3

CH3 O CH3O

=>

Types of ethers

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� system: ethers are alkoxyalkanes(Ethers are alkanes bearing an alkoxysubstituent)

� The larger substituent is the stem and the smaller substituent is the alkoxygroup (methoxyethane)

IUPAC nomenclature of ethers

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CHCH33OOCHCH2 2 CHCH33

methoxymethoxyethaneethane

CHCH33CHCH22OOCHCH2 2 CHCH33

ethoxyethoxyethaneethane

CHCH33CHCH22OOCHCH22CHCH22CHCH22ClCl

11--chlorochloro--33--ethoxyethoxypropanepropane

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CHCH33OOCHCH2 2 CHCH33

ethylethyl methylmethyl etherether

CHCH33CHCH22OOCHCH2 2 CHCH33

didiethylethyl etherether

CHCH33CHCH22OOCHCH22CHCH22CHCH22ClCl

33--chloropropylchloropropyl ethylethyl etherether

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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

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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

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Except for strained cyclical derivatives, ethers are fairly unreactive and are often used as solvents in organic reactions.

Cyclic ethers are members of the class of cycloalkanes called heterocycles in which one or more carbon atoms have been replaced by a heteroatom.

Common ethers

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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

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Structure and Polarity

� Bent molecular geometry

� Oxygen is sp3 hybridized

� Tetrahedral angle

=>

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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 sensitive

to to stericsteric effectseffects

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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

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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

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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.

=>

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Solvent Properties

• Nonpolar solutes dissolve better in ether than in alcohol.

• Ether has large dipole moment, so polar solutes also dissolve.

• Ethers solvate cations.

• Ethers do not react with strong bases. =>

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Boiling Points

Similar to alkanes of comparable molecular weight.

=>

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The smaller alkoxyalkanes are water soluble, however solubility decreases with increasing hydrocarbon size.

Methoxymethane – completely water soluble

Ethoxyethane – 10% aqueous solution

Solubility

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Ether Complexes

• Grignard reagents

• Electrophiles

• Crown ethers

O B

H

H

H

+_

BH3 THF

=>

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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

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Three dimensional analogs of crown ethers are polyethers called cryptands. These are highly selective in alkali and other metal cation binding.

cryptands

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Synthesis

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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).

Williamson Ether Synthesis

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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

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intramolecular Williamson synthesis

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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

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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

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HH

OOHH

BrBr

HH

NaOHNaOH

HH22OO

(81%)(81%)

HH

HH

OO

halohdrine

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OO

BrBr

HHHH

••••

••••••••

••••••••

••••

––via:via:

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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

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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

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At higher temperatures, an E2 elimination of water occurs with the subsequent production of alkenes.

Side reactions

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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

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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.

Asymetric ethers

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By simply disolving a tertiary or secondary haloalkane in an alcohol and waiting until the SN1 process is complete.

Ethers also form by alcoholysis

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Ethers are usually inert, however the do react slowly with oxygen to form hydroperoxides and peroxides which can decompose explosively.

Reactions of ethers

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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.

Ether cleavage

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Ether cleavage

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HHII

150150°°CCIICHCH22CHCH22CHCH22CHCH22II

(65%)(65%)

OO

Cleavage of Cyclic EthersCleavage of Cyclic Ethers

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OO••••

••••

HHII

HH

OO••••

++

•••• II ••

••••••

••••

––

IICHCH22CHCH22CHCH22CHCH22II

HHII

HH

OO•••• II••••

•••• ••••

••••

MechanismMechanism

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Oxonium ions from secondary ethers may transform by either SN2 or SN1 reactions, depending upon conditions.

Substitution

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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

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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

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Reactions of Oxacyclopropanes

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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.

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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.

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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.

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If the reacting carbon is a stereocenter, inversion is observed.

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Oxacyclopropanes are sufficiently reactive electrophiles to be attacked by organometallic compounds.

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This acid catalyzed ring opening is both regioselective and stereospecific.

Acid catalyzed oxacyclopropanering opening

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The acid catalyzed methanolysis of 2,2-dimethyloxacyclopropane is ring opened at the more hindered carbon.

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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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S derivatives

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Lower MW thiols and sulfides are notorious for their foul smells.

The odor of the skunk’s defensive spray are thiols and a sulfide:

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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:

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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

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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

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CHCH33SSCHCH2 2 CHCH33

methylthiomethylthioethaneethane

CHCH33CHCH22SSCHCH2 2 CHCH33

ethylthioethylthioethaneethane

((methylthio)cyclopentanemethylthio)cyclopentane

Substitutive IUPAC Names of SulfidesSubstitutive IUPAC Names of Sulfides

SCHSCH33

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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

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ThiiraneThiirane ThietaneThietane ThiolaneThiolane

ThianeThiane

Names of Cyclic SulfidesNames of Cyclic Sulfides

SS SS SS

SS

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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

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Thiols are more acidic than water and can therefore be easily deprotonated by hydroxide and alkoxide ions:

acidity

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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

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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

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Sulfides can attack haloalkanes to form sulfonium ions.

Sulfonium ions are subject to nucleophilic attack, the leaving group being a sulfide.

Sulfonium ions

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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

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Milder oxidizing agents (I2) yield disulfides.

These can be reduced back to thiols by alkali metals.

Thiol-disulfide redox reaction

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Reversible disulfide formation is important in stabilizing the folding of biological enzymes:

folding of proteins

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Sulfides can also be oxidized to sulfoxides and then sulfones:

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2000200035003500 30003000 25002500 1000100015001500 500500

Wave number, cmWave number, cm--11

Infrared Spectrum of Dipropyl Ether Infrared Spectrum of Infrared Spectrum of DipropylDipropyl Ether Ether

CC——OO——CC

CHCH33CHCH22CHCH22OCHOCH22CHCH22CHCH33

CC——O stretching: 1070 and 1150 cmO stretching: 1070 and 1150 cm--1 (strong)1 (strong)

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Dr. Wolf's CHM 201 & 202 16-107

HH——CC——O proton is O proton is deshieldeddeshielded by O; range isby O; range isca. ca. δδ 3.33.3--4.0 4.0 ppmppm..

1H NMR11H NMRH NMR

CHCH3 3 CCHH22 CCHH22 OCOCHH22 CCHH22 CHCH33

δδ 0.8 0.8 ppmppm δδ 0.8 0.8 ppmppmδδ 1.4 1.4 ppmppm

δδ 3.2 3.2 ppmppm

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Dr. Wolf's CHM 201 & 202 16-108

01.02.03.04.05.06.07.08.09.010.0

Chemical shift (Chemical shift (δδ, , ppmppm))

CHCH3 3 CCHH22 CCHH22 OCOCHH22 CCHH22 CHCH33

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Dr. Wolf's CHM 201 & 202 16-109

68.0 68.0 ppmppm

Carbons of CCarbons of C——OO——C appearC appear

in the range in the range δδ 5757--87 87 ppmppm..

26.0 26.0 ppmppm

13C NMR1313C NMRC NMR

OO

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Dr. Wolf's CHM 201 & 202 16-111

Molecular ion fragments to give oxygenMolecular ion fragments to give oxygen--stabilized stabilized carbocationcarbocation..

m/zm/z 102102CHCH33CHCH22OO CHCHCHCH22CHCH33

CHCH33

CHCH33CHCH22OO++

CHCH

CHCH33

CHCH33CHCH22OO++

CHCHCHCH22CHCH33

m/zm/z 8787m/zm/z 7373

Mass SpectrometryMass SpectrometryMass Spectrometry

••++

••••

•••• ••••