Ether and epoxides

Introduction to Ether & Epoxides:

We know alcohols family with their rich chemical reactivity but ethers - compounds containing a R-O- R unit are less reactive and
gives relatively few chemical reactions. This lack of reactivity of ether makes them valuable as inert solvents in a number of
chemical reactions.

Unlike most ethers, epoxides compounds in which the C O C unit forms a three-membered ring - are very reactive substances
due to molecular strain.
Ethers are defined as symmetrical or unsymmetrical depending on whether the two groups bonded to oxygen are the same or
different. Unsymmetrical ethers are also called mixed ethers. Dimethyl ether is a symmetrical while ethyl methyl ether is an
unsymmetrical ether.
Cyclic ethers have their oxygen as part of a ring. They are heterocyclic compounds. Oxygen heterocycles of commonly
encountered ring sizes have specific IUPAC nomenclature.


In each case the ring is numbered starting at the oxygen. The IUPAC rules also permit oxirane (without substituents) to be called
ethylene oxide. Tetrahydrofuran and tetrahydropyran are acceptable synonyms for oxolane and oxane, respectively.

There are many compounds, often used as reaction solvents, are the
diethers
1,2,-dimethoxy ethane and 1,4-dioxane. Diglyme, also a commonly used solvent, is a
tri ether


The sulfur analogs (RS ) of alkoxy groups are called
alkyl thio
groups while RSH are known as alkane thiol. Sulfur hetero cycles have names analogous to their oxygen relatives, except that
ox
- is replaced by
thi-
Thus the sulfur heterocycles containing three-, four-, five-, and six- membered rings are named
thiirane, thietane, thiolane,
& thiane respectively.
































Structure and bondangle in ethers and epoxides
Structure and bondangle in ethers and epoxides


Bonding in ethers is readily understood by comparing ethers with water and alcohols. Van der Waals strain involving alkyl groups
causes the bond angle at oxygen to be larger in ether than alcohols, and larger in alcohols than in water. An extreme example is di-
Isopropyl ether, where steric hindrance between the isopropyl groups is responsible for a dramatic increase in the C O C bond
angle.


Carbon-oxygen bond distances are some what shorter than carbon-carbon bond distances. The C O bond distances in dimethyl
ether (141 pm) and methanol (142pm) are similar to one another, and both are shorter than the C C bond distance in ethane (153
pm).

Insertion of an oxygen atom into a three-membered ring requires its bond angle to be seriously distorted form the normal
tetrahedral value. In ethylene oxide, for example, the bond angle at oxygen is 61.5.


Thus epoxides, like cyclopropanes, are strained. They tend to undergo reactions that open the three-membered ring by cleavage of
one of the carbon-oxygen bonds.

Physical properties
Physical properties of ethers are very similar with alkanes and alcohols. With respect to boiling point, ethers resemble alkanes
more than alcohols due to less polarity than alcohol while; with respect to solubility in water, ethers resemble alcohols mor e than
alkanes due to Hbonding with water.


In general, the boiling point of alcohols are unusually high because of hydrogen bonding. Attractive forces are present in li quid
phase of ethers and alkanes, but lack OH groups so cannot take part in intermolecular hydrogen bonding, are much weaker, so
their boiling points are less.

If we think about structure of ether, the presence of an oxygen atom permits ethers to participate in hydrogen bonding to wat er
molecules. These attractive forces are responsible for solubility of ethers in water to approximately the same extent as comparably
constituted alcohols. Alkanes cannot take part in hydrogen bonding with water.

Crown ethers
Cyclic compounds containing 4 or more ether linkages in a ring of 12 or more atoms. these compounds is known as
crown ethers
, because their molecular models are similar to crowns. Systematic nomenclature of crown ethers is actually a short hand
description where by the word
crown
is followed by the total number of atoms in the ring and is followed by the number of oxygen atoms.


15-Crown-5 and 18-crown-6 are a cyclic pentamer and hexamer, respectively, of repeating -OCH2CH2- units; they are polyethers
based on ethylene glycol (HOCH
2CH2OH) as the parent alcohol.

The metal ion-complexing nature of crown ethers are explain by their effects on the solubility and reactivity of salts in nonpolar
solvents. Potassium fluoride is ionic and insoluble in benzene (covalent), but 0.05
M
solutions can be prepared when 18-crown-6 is present. This high solubility of potassium fluoride in benzene is explain by the
formation of a stable complex, cage like structure, is stabilized by ion-dipole forces between K
+

and the six oxygen atoms of the crownether. Potassium ion, with an ionic radius of 265 pm, adjust completely with in the 260- to
320-pm inside cavity of 18-crown-6. Nonpolar CH2
groups dominate the outer side of the complex, make its polar interior, and permit the complex to soluble in nonpolar solvents such
as covalent benzene. Every K
+

that is carried into benzene brings a fluoride ion (F

) with it, resulting in a solution containing strongly complexed potassium ions

and relatively unsolvated fluoride ions.



















In polar matrix such as water and alcohols, fluoride ion is strongly solvated by hydrogen bonding and is neither very basic nor very
nucleophilic. On the other part, the poorly solvated, or naked, fluoride ions that are present when potassium fluoride dissolves in
benzene in the presence of a crown ether are better able to express their anionic reactivity. Thus, alkyl halides react with ionic
potassium fluoride in covalent benzene solvent like 18-crown-6, easily gives a method of the preparation of different floride.








Preparation
Preparation



(i) Willamsons continous ethrification



Diethyl ether and many others, for example, are prepared by acid-catalyzed reaction of the corresponding alcohols, as we already
studuied in alkenes, known as williamson contineous etherification.


In general, this method is limited to the preparation of symmetrical ethers in which both alkyl groups are primary. Isopropyl
alcohol, however, is readily available at low cost and gives yields of diisopropyl ether high enough to justify making
(CH3)2CHOCH(CH3)2
by this method on an industrial approach.

(ii) Williamson synthesis
A method of long standing for the preparation of ethers is the Williamson ether synthesis. Nucleophilic substitution of an al kyl
halide by an alkoxide gives the carbon-oxygen bond of an ether.


Preparation of ethers by the Williamson ether synthesis is most successful when the alkyl halide is one that is reactive toward SN
2 substitution. Methyl halides and primary alkyl halides are the best reactants (least reactive in elimination).


Secondary and tertiary alkyl halides are not suitable reactants, because they tend to react with alkoxide base by E2 elimination
rather by SN
2 substitution. Whether the alkoxide base is primary, secondary, or tertiary is not very important than the nature of the alkyl halide.
Thus benzyl terbutyl ether is prepared in high yield from benzyl chloride, a primary chloride that is incapable of undergoing
elimination, with potassium ter. butoxide (base).


The alternative synthetic route using the sodium salt of benzyl alcohol and an terbutyl halide would be much less effective, because
of increased competition from elimination, as the alkyl halide becomes 3 than it easily undergo elimination.

We take some following example also, always prefer alkyl halide as primary.


















The alternative combination, cyclohexyl bromide and sodium ethoxide, is not correct, because elimination will be the major
product.


(iii) Oximercuration demercuration of alkenes
Addition of ROH according to marknownikoffs rule without any molecular rearrangement occurs.









Alcohol with diazomethane
(iv) Alcohol with diazomethane













(v) Alkyl halide with dry Ag2O











This reaction is not carried out with moist Ag
2
O because moist Ag
2
O is actually AgOH where substitution occurs and formation of alcohols from alkyl halide takes place.

Chemical properties
(i) Oxidation
Ether are less reactive due to absence of polarity, along with an ability to soluble in nonpolar substances like CCl4, that makes
ethers so often used as solvents when carrying out many organic reactions. Nevertheless, most ethers are explosive and hazardous
materials, and precautions must be taken when using them. Diethyl ether is extremely flammable and because of its high volati lity
can form explosive mixtures in air very quickly. Open flames must never be present in laboratories where diethyl ether is being
used regularly.

A second dangerous property of ethers is when they undergo oxidation in presence of air to form explosive peroxides. Where air
oxidation of diethyl ether gives explosive strained peroxide proceeds according to the following equation.


The reaction is a free-radical type, and oxidation occurs at the carbon that contain the ether oxygen to form a hydroperoxide, a










compound of the type ROOH. Hydroperoxides tend to be unstable and shock-sensitive due to molecular strain. On standing, they
form related peroxidic derivatives, which are also. Due to this, one should never use old bottles of dialkyl ethers, and extr eme care
must be taken in their uses.

(ii) Acidcatalyzed fission of ethers
When the carbon-oxygen bond of alcohols is undergo fission on reaction with hydrogen halides, just similar to an ether linkage
undergo breaking with hydrogen halides.


The fission of ethers is generally carried out under conditions like excess hydrogen halide, cold or hot HX, such that the al cohol
formed as one of the original products and by heating converted to an alkyl halide. Thus, the reaction with hot HX finally gives
two alkyl halide molecules :


Cyclic ethers yield one molecule of a dihalide :


The order of hydrogen halide reactivity is HI>HBr >HCl. Hydrogen fluoride is not effective so normally not considered in organic
chemistry.

A mechanism for the cleavage of diethyl ether by hydrogen bromide is given below where the key is an S
N
2-like attack on a dialkyloxonium ion by bromide.
















Overall Reaction :
Overall Reaction :





Mechanism of reaction



Step A :
Ether reacts with proton to give a dialkyloxonium ion (oxonium salt)


Step B :
Halide attack on carbon of the dialkyloxonium ion. This step gives each molecule of an alkyl halide and an alcohol.


Step C :
In last step where an alcohol is converted to an alkyl halide.




(iii) Reaction with HI (fission reaction)
Reaction with HI is an example of fission reaction where cleavage is decided by structure of ether. If there is smaller alkyl group
up to secondary than fission is S
N
2 so back attack of nucleophile occurs while for large alkyl group always fission by S
N
1 mechanism because they prefer carbocation mechanism.











When ethers reacts with cold HI to form one mole of alkyl iodide. This when reacts with silver nitrate to form yellow precipitate of
AgI.

By finding out the weight of AgI we can find out the structure of ether. This method is known as of
zeisals method
for estimation of alkoxy group in the molecule for example.


Problem
0.74 gm of methyl ether forms 2.35 gm of AgI at NTP find out sturcture of methyl ether ?


(iv) Reaction with dil H2SO4











(v) Reaction with CO












































Reaction with Lewis Acids
(vi) Reaction with Lewis Acids when reacts with Lewis acid to form acid base complex (oxonium salt.)















(vii) Oxidation with acidic K2Cr2O7


















Epoxides (cyclic ether)



Preparation



There are two main laboratory methods for the preparation of epoxides :




(1) Epoxidation of alkenes by reaction with peroxy acids






The reaction is easy to carry out, and yields are usually high. Epoxidation is a stereospecific syn addition.







(2) Conversion of vicinal halohydrins to epoxides



The formation of vicinal halohydrins from alkenes was already described in hydrocarbon. Halohydrins are readily converted to
epoxides on treatment with base.







Properties



The chemical property that differ epoxide from normal inert ether is their far greater reactivity toward nucleophilic reagents
compared to simple ethers. This high reactivity results from the ring strain of epoxides.




An example of nucleophilic ring opening of epoxides in Grignard reagent, where Grignard reagents with ethylene oxide is used to
steeping up in alcohol series.







Nucleophiles other than Grignard reagents also responsible for ring opening of epoxides. There are two medium in which these
reactions are carried out.
The first involves anionic nucleophiles in neutral or basic solution.






These reactions are carried out in water or alcohols as solvents, and the alkoxide ion intermediate is rapidly changes in to an
alcohol by proton transfer.




Nucleophilic ring-opening reactions of epoxides may also be catalysed by acidic medium where the nucleophile is not an anion but
rather a solvent molecule.







There is very important difference in the ring-opening chemistry of epoxides depending on the reaction medium.
Unsymmetrically substituted epoxides tend to react with anionic nucleophiles in basic medium at the less hindered carbon of t he
cycle. While under conditions of acid catalysis, the more highly substituted carbon is attacked because partial carbocation character























comes in this condition so molecule tends to prefer more stable intermediate.









Ring?cleavage reactions of epoxides by base catalysed
Ethylene oxide very reactive substance, reacts rapidly and exothermically with anionic nucleophiles to yield 2-substituted
derivatives of ethanol by cleaving the carbon-oxygen bond of the ring for example used for stepping up carbon atom in many
family.




Nucleophilic ring opening of epoxides has many of the features of an SN
2 reaction. Inversion of configuration is observed at the carbon at which substitution occurs.





Unsymmetrical epoxides prefer to attack at the less substituted, less sterically hindered carbon of the ring in basic medium while
opposite in acidic medium.





According to the mechanism the nucleophile attacks the less crowded carbon from the back side of the carbon-oxygen bond. Bond
formation with the nucleophile followed by carbon-oxygen bond cleavage, and the strain in the three-membered ring is gone as it
follows the opening of this ring from transition state. In this reaction initially an alkoxide anion is formed, which finally absorb a
proton from the solvent to give a

alcohol as final product.




Epoxides reduction takes place by lithium aluminum hydride or NaBH4
these are hydride donar so hydride is transferred to the less crowded carbon.





Remember here that epoxidation of an alkene, followed by lithium aluminum hydride reduction of epoxide, gives the same alcohol
that would be given by same alkene by acid-catalyzed hydration or oxymercuration-demercuration.




(ii) Ringcleavage reaction of epoxides by acid-catalyzed



Here we discuss the preparation of ethylene glycol (HOCH2CH2
OH) by hydrolysis of ethylene oxide in dilute sulfuric acid. There is a significant difference between the ring openings of epoxides
the acid-catalyzed. Under conditions of acid catalysis, the species that is attacked by the nucleophile is not the epoxide itself, but
rather its conjugated acid. The transition state for ring opening has a fair amount of carbocation character so the total system
undergo strain. Breaking of the ring carbon-oxygen bond is more advanced than formation of the bond to the nucleophile.





Because carbocation character develops at the transition state, substitution is prefer at the carbon that can better support a
developing positive charge or stabilises intermediate. Thus, in comparison to the reaction epoxides with relatively basic medium, in
which SN
2- like attack is faster at the less crowded carbon of the epoxide ring, acid catalysis promotes just opposite at the position that bears
the more number of alkyl groups for example.





























Here substitution proceeds with inversion of configuration for example back attack of nucleophile takes place so trans product are
formed in these reactions.s





Deoxygenation of oxiranes



Although there is no general way to de oxygenate ethers, but oxiranes can be deoxygenated
(reduced) to alkenes by certain trivalent phosphorous compounds for example.




In this reaction oxirane derivatives which are originally cis end up trans in the alkene product
and vice versa so this reaction could be quite valuable. While per acids epoxidation preserves
the stereochemistry of the alkene, deoxygenation of the alkene, deoxygenation by the above
path create inversion of configuration




Mechanism



A nucleophilic ring opening of the oxirane at its less hindered carbon, formation of dipolar
ion that undergoes bond rotation followed by ring closure to the strained oxaprosphetane
(unstable) ultimately gives final product.




Problems
Find the products of following reaction and give stereochemistry where appropriate.





Answers:



(a) PhOH + ICH
2
Ph, S
N

2 cleavage at the alkyl, as opposed to aryl, carbon of the protonated ether.




(b) (H
3
C)
2
CHOH + BrC(CH
3
)
3
, S
N

1 cleavage at the more Su.




























Ring?cleavage reactions of epoxides by base catalysed
Ethylene oxide very reactive substance, reacts rapidly and exothermically with anionic nucleophiles to yield 2-substituted
derivatives of ethanol by cleaving the carbon-oxygen bond of the ring for example used for stepping up carbon atom in many
family.




Nucleophilic ring opening of epoxides has many of the features of an SN
2 reaction. Inversion of configuration is observed at the carbon at which substitution occurs.





Unsymmetrical epoxides prefer to attack at the less substituted, less sterically hindered carbon of the ring in basic medium while
opposite in acidic medium.





According to the mechanism the nucleophile attacks the less crowded carbon from the back side of the carbon-oxygen bond. Bond
formation with the nucleophile followed by carbon-oxygen bond cleavage, and the strain in the three-membered ring is gone as it
follows the opening of this ring from transition state. In this reaction initially an alkoxide anion is formed, which finally absorb a
proton from the solvent to give a

alcohol as final product.




Epoxides reduction takes place by lithium aluminum hydride or NaBH4
these are hydride donar so hydride is transferred to the less crowded carbon.





Remember here that epoxidation of an alkene, followed by lithium aluminum hydride reduction of epoxide, gives the same alcohol
that would be given by same alkene by acid-catalyzed hydration or oxymercuration-demercuration.




(ii) Ringcleavage reaction of epoxides by acid-catalyzed



Here we discuss the preparation of ethylene glycol (HOCH2CH2
OH) by hydrolysis of ethylene oxide in dilute sulfuric acid. There is a significant difference between the ring openings of epoxides
the acid-catalyzed. Under conditions of acid catalysis, the species that is attacked by the nucleophile is not the epoxide itself, but
rather its conjugated acid. The transition state for ring opening has a fair amount of carbocation character so the total system
undergo strain. Breaking of the ring carbon-oxygen bond is more advanced than formation of the bond to the nucleophile.





Because carbocation character develops at the transition state, substitution is prefer at the carbon that can better support a
developing positive charge or stabilises intermediate. Thus, in comparison to the reaction epoxides with relatively basic medium, in
which SN
2- like attack is faster at the less crowded carbon of the epoxide ring, acid catalysis promotes just opposite at the position that bears
the more number of alkyl groups for example.





























Here substitution proceeds with inversion of configuration for example back attack of nucleophile takes place so trans product are
formed in these reactions.s





Deoxygenation of oxiranes
Deoxygenation of oxiranes



Although there is no general way to de oxygenate ethers, but oxiranes can be deoxygenated (reduced) to alkenes by certain
trivalent phosphorous compounds for example.




In this reaction oxirane derivatives which are originally cis end up trans in the alkene product and vice versa so this reaction could
be quite valuable. While per acids epoxidation preserves the stereochemistry of the alkene, deoxygenation of the alkene,
deoxygenation by the above path create inversion of configuration




Mechanism



A nucleophilic ring opening of the oxirane at its less hindered carbon, formation of dipolar ion that undergoes bond rotation
followed by ring closure to the strained oxaprosphetane (unstable) ultimately gives final product.




Problems
Find the products of following reaction and give stereochemistry where appropriate.






Answers:



(a) PhOH + ICH2Ph, SN
2 cleavage at the alkyl, as opposed to aryl, carbon of the protonated ether.




(b) (H3C)2CHOH + BrC(CH3)3, SN
1 cleavage at the more Su.