1 Chapter 9 Alcohols, Ethers and Epoxides. 2 Alcohols contain a hydroxy group (OH) bonded to an sp 3...

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Chapter 9

Alcohols, Ethers and Epoxides

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• Alcohols contain a hydroxy group (OH) bonded to an sp3 hybridized carbon.

Introduction—Structure and Bonding

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• enols and phenols Compounds having a hydroxy group on a sp2 hybridized carbon undergo different reactions than alcohols.


• Will be discussed in chapter 11, 19

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• Ethers have two alkyl groups bonded to an oxygen atom.

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• Epoxides are ethers having the oxygen atom in a three-membered ring.

Epoxides are also called oxiranes.


• The C—O—C bond angle for an epoxide must be 60°, a considerable deviation from the tetrahedral bond angle of 109.5°. Thus, epoxides have angle strain, making them much more reactive than other ethers.

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• The oxygen atom in alcohols, ethers and epoxides is sp3 hybridized. Alcohols and ethers have a bent shape like that in H2O.

• The bond angle around the O atom in an alcohol or ether is similar to the tetrahedral bond angle of 109.5°.

• Because the O atom is much more electronegative than carbon or hydrogen, the C—O and O—H bonds are all polar.


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Nomenclature of Alcohols : -- ol

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• When an OH group is bonded to a ring, the ring is numbered beginning with the OH group.

• Because the functional group is at C1, the 1 is usually omitted from the name.

• The ring is then numbered in a clockwise or counterclockwise fashion to give the next substituent the lowest number.

For cyclic compounds

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• Common names are often used for simple alcohols.

Name all the carbon atoms of the molecule as a single alkyl group.

Add the word alcohol, separating the words with a space.

Nomenclature of Alcohols

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• Compounds with two hydroxy groups : diols or glycols. • Compounds with three hydroxy groups : triols

and so forth.

Nomenclature of Alcohols

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• Simple ethers are usually assigned common names. To do so:

Name both alkyl groups bonded to the oxygen, arrange these names alphabetically, and add the word ether.

For symmetrical ethers, name the alkyl group and add the prefix “di-”.

Nomenclature of Ethers

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• More complex ethers are named using the IUPAC system.

One alkyl group is named as a hydrocarbon chain, and the other is named as part of a substituent bonded to that chain:

Name the simpler alkyl group as an alkoxy substituent by changing the –yl ending of the alkyl group to –oxy.

Name the remaining alkyl group as an alkane, with the alkoxy group as a substituent bonded to this chain.

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• Cyclic ethers have an O atom in the ring. A common example is tetrahydrofuran (THF).

This name has a different origin

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• Epoxides can be named in three different ways—As epoxyalkanes, oxiranes, or alkene oxides.

• To name an epoxide as an epoxyalkane, first name the alkane chain or ring to which the O atom is attached,

• and use the prefix “epoxy” to name the epoxide as a substituent.

• Use two numbers to designate the location of the atoms to which the O’s are bonded.

Nomenclature of Epoxides

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• Epoxides bonded to a chain of carbon atoms can also be named as derivatives of oxirane, the simplest epoxide having two carbons and one oxygen atom in a ring.

• The oxirane ring is numbered to put the O atom at position one, and the first substituent at position two.

• No number is used for a substituent in a monosubstituted oxirane.


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• Epoxides are also named as alkene oxides, since they are often prepared by adding an O atom to an alkene. To name an epoxide in this way:

Mentally replace the epoxide oxygen with a double bond.

Name the alkene.

Add the word oxide.


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• Alcohols, ethers and epoxides exhibit dipole-dipole interactions because they have a bent structure with two polar bonds.

• Alcohols are capable of intermolecular hydrogen bonding. Thus, alcohols are more polar than ethers and epoxides.

Physical Properties

• Steric factors affect hydrogen bonding.

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Alcohols, Ethers and EpoxidesInteresting Alcohols

glycerol

Sugars, cellulose, starch etc.

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Interesting Ethers

Diethyl ether is the best-known ether, first used as a general anesthetic in the 1830s. Because of its high flammability and side-effects on some patients, its place as an anesthetic has been taken by other substances.

Cyclic polyether : crown ether

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Interesting Ethers• The ability of crown ethers to complex cations can be

exploited in nucleophilic substitution reactions, as shown in Figure 9.5.

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Interesting Ethers : nature’s crown ether

• Brevetoxin B is a naturally occurring polyether that interferes with Na+ ion transport across cell membranes.

“Red Tide”

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Interesting Epoxides : epoxides are reactive!

• Ethylene oxide : precursor of ethylene glycol, polyethylene glycol

O OH

HO

*

OO

n

• Natural epoxides

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Preparation of Alcohols, Ethers, and Epoxides

• Alcohols and ethers are both common products of nucleophilic substitution of alkyl halides.

Williamson ether synthesis.

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Preparation of Alcohols, Ethers, and Epoxides

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• SN2 reaction

Strong Nucleophile (An alkoxide salt) is needed to make an ether.

Williamson ether synthesis.

• Cyclic ethers are formed through intramolecular reaction.

nHO

BrNaH

O

n

When n= -2, epoxides

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Preparation of Epoxides

• Organic compounds that contain both a hydroxy group and a halogen atom on adjacent carbons are called halohydrins.

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Reactions of Alcohols

Substitution, elimination, oxidation

• The OH group in alcohols is a very poor leaving group.

• For an alcohol to undergo nucleophilic substitution, OH must be converted into a better leaving group (activated).

• By using acid, ¯OH can be converted into H2O, a good leaving group.

• By converting to sulfonates, ¯OH can be converted into ¯OSO2R, a good leaving group.

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Reactions of Alcohols

OH OH2

+HBr (for SN)or H2SO4

(for E) SN

E

Br

Halide

Alkene

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Reactions of Ethers and Epoxides

Ethers do not have a good leaving group and are difficult to activate.

Epoxides are highly reactive due to high angle strain.

O

C C

Nu:_

C

O

C

Nu

_relief of strainRing-opening results in

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Reactions of Alcohols—Dehydration

• Dehydration, like dehydrohalogenation, is a elimination reaction in which the elements of OH and H are removed from the and carbon atoms respectively.

• Dehydration is typically carried out using H2SO4 and other strong acids, or phosphorus oxychloride (POCl3) in the presence of an amine base.

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• Typical acids used for alcohol dehydration : H2SO4 or p-toluenesulfonic acid (TsOH).

• More substituted alcohols dehydrate more easily, giving rise to the following order of reactivity.

strong organic acid

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Reactions of Alcohols—Dehydration• Dehydration follows the Zaitsev rule.

The more substituted alkene is the major product when a mixture of constitutional isomers is possible.

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Reactions of Alcohols—Dehydration• Secondary and 3° alcohols react by an E1 mechanism

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Reactions of Alcohols—Dehydration• The E1 dehydration of 20 and 30 alcohols with acid gives clean elimination

products without any by-products formed from an SN1 reaction.

• Clean elimination takes place because the reaction mixture contains no good nucleophile to react with the intermediate carbocation, so no competing SN1 reaction occurs.

• This makes the E1 dehydration of alcohols much more synthetically useful than the E1 dehydrohalogenation of alkyl halides.

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Reactions of Alcohols—Dehydration• 1° alcohols undergo dehydration following an E2 mechanism.• 1° carbocations are highly unstable, their dehydration cannot occur

by an E1 mechanism involving a carbocation intermediate.

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While dehydrations have favorable entropy changes, the position of equilibrium favors reactants.

Operation of the Principle of Le Châtelier in Alcohol Dehydrations

• removing a product from a reaction mixture as it is formed drives the equilibrium to the right, forming more product.

• Thus, the alkene, which usually has a lower boiling point than the starting alcohol, can be removed by distillation as it is formed, thus driving the equilibrium to the right to favor production of more product.

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Carbocation Rearrangements

CH3

H3C

CH3

H

OH

CH3

H2SO4

CH3

H3C

CH3

H

CH2

CH3

H3C

CH3

CH3

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Carbocation Rearrangements• Often, when carbocations are intermediates, a less stable

carbocation will be converted into a more stable carbocation by a shift of a hydrogen or an alkyl group. This is called a rearrangement.

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Carbocation Rearrangements• A 1,2-shift can convert a less stable carbocation into a

more stable carbocation.• Rearrangements can occur whenever a carbocation is

formed as a reactive intermediate.

1,2-hydride shift

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Dehydration of Alcohols Using POCl3 and Pyridine

• Dehydration under basic condition• A common method uses phosphorus oxychloride (POCl3) and

pyridine (an amine base) in place of H2SO4 or TsOH.

Dehydration proceeds by an E2 mechanism.

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Dehydration of Alcohols Using POCl3 and Pyridine

Mechanism : E2 mechanism

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Dehydration of Alcohols in the natural product synthesis

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Conversion of Alcohols to Alkyl Halides with HX

• Substitution reactions do not occur with alcohols unless ¯OH is converted into a good leaving group.

• The reaction of alcohols with HX (X = Cl, Br, I) is a general method to prepare 1°, 2°, and 3° alkyl halides.

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• More substituted alcohols usually react more rapidly with HX:

• The mechanism depends on the structure of the R group.

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1o alcohols and methanol react via an SN2 mechanism

C

D

OHCH3

HHX

1. Protonation

Primary alcohol

(S)

2. SN2 with inversion of configuration

+C

D

CH3H

OH2

+C

D

CH3H

OH2X_

+ OH2CCH3

H

X

D+

(R)

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2o and 3o alcohols react via an SN1 mechanism

CPh

OH

CH3CH3CH2

1. Protonation

2. SN1 reaction with racemization

CPh

CH3CH3CH2

OH2

HX+ X

_+

+C

Ph

CH3CH3CH2

OH2

Tertiary alcohol

C

CH3CH2CH3

Ph

+ OH2+

Carbocation (planar)

(R)

(a) Dissociation

(b) Attack of nucleophile

+C

CH3CH2CH3

Ph

CPh

CH3CH3CH2

X

Attack fromright

X_

Attack from left

X_

Racemate

CCH2CH3

CH3

PhX

(R) (S)

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• The reactivity of hydrogen halides increases with increasing acidity.

HIRCH2 OH RCH2 I

HClRCH2 OH too slow to detect products

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• 2o alcohols

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Conversion of Alcohols to Alkyl Halides

HIRCH2 OH RCH2 I

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Conversion of Alcohols to Alkyl Halides with SOCl2 and PBr3

• For primary and 2° alcohols• SOCl2 (thionyl chloride) converts alcohols into alkyl chlorides.

• PBr3 (phosphorus tribromide) converts alcohols into alkyl bromides.

via an SN2 reaction

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• For primary and 2° alcohols• SOCl2 (thionyl chloride) converts alcohols into alkyl chlorides.

• PBr3 (phosphorus tribromide) converts alcohols into alkyl bromides.

via an SN2 reaction

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Tosylate—Another Good Leaving Group

• An alkyl tosylate is composed of two parts: the alkyl group R, derived from an alcohol; and the tosylate (short for p-toluenesulfonate), which is a good leaving group.

• A tosyl group, CH3C6H4SO2¯, is abbreviated Ts, so an alkyl tosylate becomes ROTs.

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Tosylate—Another Good Leaving Group

• This process converts a poor leaving group (¯OH) into a good one (¯OTs).

• Tosylate is a good leaving group because its conjugate acid, p-toluenesulfonic acid (CH3C6H4SO3H, TsOH) is a strong acid (pKa = -7).

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Tosylate—Another Good Leaving Group• Because alkyl tosylates have good leaving groups, they

undergo both nucleophilic substitution and elimination, exactly as alkyl halides do.

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Tosylate—Another Good Leaving Group• Substitution occurs via an SN2 mechanism.

• Tosylates are equivalent to halides.

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Example:

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Reaction of Ethers with Strong Acid

cleavage occurs either side of the ether oxygen atom to give two alkyl halide products, so ethers are not generally as useful as alcohols in synthesis.

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Mechanism of

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Mechanism of

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Reactions of Epoxides

• Nucleophilic attack opens the strained three-membered ring, making it a favorable process even with a poor leaving group.

Reactions occur with strong nucleophiles (such as OH-, CH3S-, CH3O- or CN-), in the absence of acid and with weaker nucleophiles (such as Cl-) in the presence of strong acid (such as HCl).

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• Common nucleophiles that open the epoxide ring include ¯OH, ¯OR, ¯CN, ¯SR and NH3. With these strong nucleophiles.

• The reaction occurs by an SN2 mechanism.

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Reactions of Epoxides : stereochemical consequences

Nucleophilic attack of ¯OCH3 occurs from the backside at either C—O bond, because both ends are similarly substituted. Since attack at either side occurs with equal probability, an equal amount of the two enantiomers (i.e., a racemic mixture) is formed.

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Optically inactive starting materials give optically inactive products!

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Alcohols, Ethers and EpoxidesReactions of Epoxides• Acids HZ that contain a nucleophile Z also open epoxide rings by

a two-step sequence.• HCl, HBr and HI, as well as H2O and ROH in the presence of acid,

all open an epoxide ring in this manner.

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Leukotriene Synthesis and Asthma Drugs

Leukotriene C4Leukotriene A4

CO2H

C5H11

Arachidonic acid

C5H11

CO2H

OOH

Lipoxygenase

5-HPETE

CO2HO

C5H11

Sulfur nucleophile,RSH (glutathione)

CO2H

C5H11

OH

SR

..

..

Zileuton blocksthis step

S

N CONH2

HO

Zileuton

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Alcohols, Ethers and EpoxidesImportant Epoxide Ring Opening Reactions

9.48, 9.49, 9.50, 9.52, 9.56, 9.58, 9.66, 9.67, 9.70, 9.71,

9.76

Homework

Write mechanisms for following reactions.

HIRCH2 OH RCH2 I

Preview of Chapter 10

Alkenes

Reactions of alkenes

Addition reaction --- What is Markovnikov’s rule?

- Which reactions follow markovnikov’s rule?Hydrohalogenation reaction, Hydration reactionHalogenation reaction, Halohydrin formationHydroboration reaction

1 Chapter 9 Alcohols, Ethers and Epoxides. 2 Alcohols contain a hydroxy group (OH) bonded to an sp 3...

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