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Introduction to Carbonyl Chemistry; Organometallic Reagents; Oxidation and Reduction

Two broad classes of compounds contain the carbonyl group:

Introduction

[1] Compounds that have only carbon and hydrogen atoms bonded to the carbonyl

[2] Compounds that contain an electronegative atom bonded to the carbonyl

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• The presence or absence of a leaving group on the carbonyl determines the type of reactions the carbonyl compound will undergo.

• Carbonyl carbons are sp2 hybridized, trigonal planar, and have bond angles that are ~1200. In these ways, the carbonyl group resembles the trigonal planar sp2 hybridized carbons of a C=C.

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• In one important way, the C=O and C=C are very different.

• The electronegative oxygen atom in the carbonyl group means that the bond is polarized, making the carbonyl carbon electron deficient.

• Using a resonance description, the carbonyl group is represented by two resonance structures.

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Carbonyls react with nucleophiles.

General Reactions of Carbonyl Compounds

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Aldehydes and ketones react with nucleophiles to form addition products by a two-step process: nucleophilic attack followed by protonation.

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• The net result is that the bond is broken, two new bonds are formed, and the elements of H and Nu are added across the bond.

• Aldehydes are more reactive than ketones towards nucleophilic attack for both steric and electronic reasons.

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Carbonyl compounds with leaving groups react with nucleophiles to form substitution products by a two-step process: nucleophilic attack, followed by loss of the leaving group.

The net result is that Nu replaces Z, a nucleophilic substitution reaction. This reaction is often called nucleophilic acyl substitution.

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• Nucleophilic addition and nucleophilic acyl substitution involve the same first step—nucleophilic attack on the electrophilic carbonyl carbon to form a tetrahedral intermediate.

• The difference between the two reactions is what then happens to the intermediate.

• Aldehydes and ketones cannot undergo substitution because they do not have a good leaving group bonded to the newly formed sp3 hybridized carbon.

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• Carbonyl compounds are either reactants or products in oxidation-reduction reactions.

Preview of Oxidation and Reduction

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The three most useful oxidation and reduction reactions of carbonyl starting materials can be summarized as follows:

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• The most useful reagents for reducing aldehydes and ketones are the metal hydride reagents.

Reduction of Aldehydes and Ketones

• Treating an aldehyde or ketone with NaBH4 or LiAlH4, followed by H2O or some other proton source affords an alcohol.

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• The net result of adding H:¯ (from NaBH4 or LiAlH4) and H+ (from H2O) is the addition of the elements of H2 to the carbonyl bond.

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• Catalytic hydrogenation also reduces aldehydes and ketones to 1° and 2° alcohols respectively, using H2 and a catalyst.

• When a compound contains both a carbonyl group and a carbon—carbon double bond, selective reduction of one functional group can be achieved by proper choice of the reagent.

A C=C is reduced faster than a C=O with H2 (Pd-C).

A C=O is readily reduced with NaBH4 and LiAlH4, but a C=C is inert.

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• Thus, 2-cyclohexenone, which contains both a C=C and a C=O, can be reduced to three different compounds depending upon the reagent used.

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• Hydride converts a planar sp2 hybridized carbonyl carbon to a tetrahedral sp3 hybridized carbon.

The Stereochemistry of Carbonyl Reduction

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• Selective formation of one enantiomer over another can occur if a chiral reducing agent is used.

• A reduction that forms one enantiomer predominantly or exclusively is an enantioselective or asymmetric reduction.

• An example of chiral reducing agents are the enantiomeric CBS reagents.

Enantioselective Carbonyl Reductions

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• CBS refers to Corey, Bakshi and Shibata, the chemists who developed these versatile reagents.

• One B—H bond serves as the source of hydride in this reduction.• The (S)-CBS reagent delivers H:- from the front side of the C=O. This

generally affords the R alcohol as the major product.• The (R)-CBS reagent delivers H:- from the back side of the C=O.

This generally affords the S alcohol as the major product.

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• These reagents are highly enantioselective. For example, treatment of propiophenone with the (S)-CBS reagent forms the R alcohol in 97% ee.

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• LiAlH4 is a strong reducing agent that reacts with all carboxylic acid derivatives.

• Diisobutylaluminum hydride ([(CH3)2CHCH2]2AlH, abbreviated DIBAL-H, has two bulky isobutyl groups which makes this reagent less reactive than LiAlH4.

• Lithium tri-tert-butoxyaluminum hydride, LiAlH[OC(CH3)3]3, has three electronegative O atoms bonded to aluminum, which makes this reagent less nucleophilic than LiAlH4.

Reduction of Carboxylic Acids and Their Derivatives

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• Acid chlorides and esters can be reduced to either aldehydes or 1° alcohols depending on the reagent.

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• In the reduction of an acid chloride, Cl¯ comes off as the leaving group.

• In the reduction of the ester, CH3O¯ comes off as the leaving group, which is then protonated by H2O to form CH3OH.

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• The mechanism illustrates why two different products are possible.

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• Carboxylic acids are reduced to 1° alcohols with LiAlH4.

• LiAlH4 is too strong a reducing agent to stop the reaction at the aldehyde stage, but milder reagents are not strong enough to initiate the reaction in the first place.

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• Unlike the LiAlH4 reduction of all other carboxylic acid derivatives, which affords 1° alcohols, the LiAlH4 reduction of amides forms amines.

• Since ¯NH2 is a very poor leaving group, it is never lost during the reduction, and therefore an amine is formed.

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• A variety of oxidizing agents can be used, including CrO3, Na2Cr2O7, K2Cr2O7, and KMnO4.

• Aldehydes can also be oxidized selectively in the presence of other functional groups using silver(I) oxide in aqueous ammonium hydroxide (Tollen’s reagent). Since ketones have no H on the carbonyl carbon, they do not undergo this oxidation reaction.

Oxidation of Aldehydes

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• Other metals in organometallic reagents are Sn, Si, Tl, Al, Ti, and Hg. General structures of the three common organometallic reagents are shown:

Organometallic Reagents

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• Since both Li and Mg are very electropositive metals, organolithium (RLi) and organomagnesium (RMgX) reagents contain very polar carbon—metal bonds and are therefore very reactive reagents.

• Organomagnesium reagents are called Grignard reagents.

• Organocopper reagents (R2CuLi), also called organocuprates, have a less polar carbon—metal bond and are therefore less reactive. Although they contain two R groups bonded to Cu, only one R group is utilized in the reaction.

• In organometallic reagents, carbon bears a - charge.

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• Organolithium and Grignard reagents are typically prepared by reaction of an alkyl halide with the corresponding metal.

• With lithium, the halogen and metal exchange to form the organolithium reagent. With Mg, the metal inserts in the carbon—halogen bond, forming the Grignard reagent.

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• Grignard reagents are usually prepared in diethyl ether (CH3CH2OCH2CH3) as solvent.

• It is thought that two ether O atoms complex with the Mg atom, stabilizing the reagent.

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• Organocuprates are prepared from organolithium reagents by reaction with a Cu+ salt, often CuI.

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• Acetylide ions are another example of organometallic reagents.

• Acetylide ions can be thought of as “organosodium reagents”.

• Since sodium is even more electropositive than lithium, the C—Na bond of these organosodium compounds is best described as ionic, rather than polar covalent.

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• An acid-base reaction can also be used to prepare sp hybridized organolithium compounds.

• Treatment of a terminal alkyne with CH3Li affords a lithium acetylide.

• The equilibrium favors the products because the sp hybridized C—H bond of the terminal alkyne is more acidic than the sp3 hybridized conjugate acid, CH4, that is formed.

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• Organometallic reagents are strong bases that readily abstract a proton from water to form hydrocarbons.

• Similar reactions occur with the O—H proton of alcohols and carboxylic acids, and the N—H protons of amines.

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• Since organolithium and Grignard reagents are themselves prepared from alkyl halides, a two-step method converts an alkyl halide into an alkane (or other hydrocarbon).

• Organometallic reagents are also strong nucleophiles that react with electrophilic carbon atoms to form new carbon—carbon bonds.

• These reactions are very valuable in forming the carbon skeletons of complex organic molecules.

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Examples of functional group transformations involving organometallic reagents:

[1] Reaction of R—M with aldehydes and ketones to afford alcohols

[2] Reaction of R—M with carboxylic acid derivatives

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[3] Reaction of R—M with other electrophilic functional groups

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Reaction of Organometallic Reagents with Aldehydes and Ketones.

• Treatment of an aldehyde or ketone with either an organolithium or Grignard reagent followed by water forms an alcohol with a new carbon—carbon bond.

• This reaction is an addition because the elements of R’’ and H are added across the bond.

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• This reaction follows the general mechanism for nucleophilic addition—that is, nucleophilic attack by a carbanion followed by protonation.

• Mechanism 20.6 is shown using R’’MgX, but the same steps occur with RLi reagents and acetylide anions.

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Note that these reactions must be carried out under anhydrous conditions to prevent traces of water from reacting with the organometallic reagent.

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• This reaction is used to prepare 1°, 2°, and 3° alcohols.

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Retrosynthetic Analysis of Grignard Products

• To determine what carbonyl and Grignard components are needed to prepare a given compound, follow these two steps:

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• Let us conduct a retrosynthetic analysis of 3-pentanol.

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• Writing the reaction in the synthetic direction—that is, from starting material to product—shows whether the synthesis is feasible and the analysis is correct.

• Note that there is often more than one way to synthesize a 20 alcohol by Grignard addition.

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Protecting Groups

• Addition of organometallic reagents cannot be used with molecules that contain both a carbonyl group and N—H or O—H bonds.

• Carbonyl compounds that also contain N—H or O—H bonds undergo an acid-base reaction with organometallic reagents, not nucleophilic addition.

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Solving this problem requires a three-step strategy:

[1] Convert the OH group into another functional group that does not interfere with the desired reaction. This new blocking group is called a protecting group, and the reaction that creates it is called “protection.”

[2] Carry out the desired reaction.

[3] Remove the protecting group. This reaction is called “deprotection.”

A common OH protecting group is a silyl ether.

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tert-Butyldimethylsilyl ethers are prepared from alcohols by reaction with tert-butyldimethylsilyl chloride and an amine base, usually imidazole.

The silyl ether is typically removed with a fluoride salt such as tetrabutylammonium fluoride (CH3CH2CH2CH2)4N

+F¯.

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The use of tert-butyldimethylsilyl ether as a protecting group makes possible the synthesis of 4-methyl-1,4-pentanediol by a three-step sequence.

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Figure 20.7General strategy for using a

protecting group

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For Friday, 20.17-20.25

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20.17) Write out the rea tions needed to convert CH3CH2Br to each of the following reagents.

a) H3CH2C Li

H3CH2C Br + 2 Li H3CH2C Li + Li Br

b) H3CH2C MgBr

H3CH2C Br + Mg H3CH2C MgBr

c) H3CH2C CuLi

H3CH2C Br + 2 Li H3CH2C Li + Li Br

H3CH2C Li + CuI

CH2CH3

LiCu

+ Li I2

H3CH2C

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20.18) 1-octyne reacts readily with NaH, forming a gas that bubbles out of the reaction mixture. 1-octyne also reacts with CH3MgBr and a different gas is produced. Write out balanced equations for each reaction.

HC CCH2CH2CH2CH2CH2CH3 + NaH

NaC CCH2CH2CH2CH2CH2CH3 + H2

HC CCH2CH2CH2CH2CH2CH3 + CH3MgBr

BrMgC CCH2CH2CH2CH2CH2CH3 + CH4

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20.19) Draw the product of the following reactions.

a) Li

+ H2O + LiOH

b)MgBr + H2O + HOMgBr

c)MgBr + H2O

+ HOMgBr

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d)

LiC CCH2CH3 + H2O HC CCH2CH3+ LiOH

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20.20) Draw the product formed when each compound is treated with C6H5MgBr followed by H2O.

a)

H

O

H

H

OH

H

b)

H3CH2C

O

CH2CH3

CH2CH3

OH

CH2CH3

c)

H3CH2C

O

H

CH2CH3

OH

H

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d)

O

OH

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20.21)Draw the products of each reaction.

a)

O

H3CH2CH2C Li

H2O

HO CH2CH2CH3

+ LiOH

b)

H

O

H

Li

H2OH

HO

H

+ LiOH

c)O

C6H5Li

H2O

OH

+ LiOH

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d)

CNaH2C O

H2OC

H2C

OH

+ NaOH

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20.22) Draw the products (including stereochemistry) of the following reactions.

a)

H3C

O

H

H3CH2C MgBr

H2O

H OH H OH

+

b)OH3CH2C Li

H2OOH

CH2CH3

OH

CH2CH3+

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20.23) What Grignard and carbonyl are needed to prepare each alcohol?

a)OH O

H

+ H3C MgBr

b) OHO

H H

+

MgBr

c)

OHO

+ H3CH2C MgBr

orO

|+

MgBr

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d)OH

O

+ H3C Br

or

MgBr+

O

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20.24) Tertiary alcohols with three different R groups on the carbon attached to the OH can be prepared in three different ways using the Grignard reagent. Show them.

a)H3C

OH

CH2CH3

CH2CH2CH3

O

CH2CH3

H3CH2CH2C

H3C

O

CH2CH2CH3

H3C

O

CH2CH3

+ H3C MgBr

H3CH2C MgBr+

+ H3CH2CH2C MgBr

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b) OH

O

+ H3C MgBr

O+

MgBr

O

+

MgBr

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c) OH

O

O

O

+ MgBr

+

MgBr

+ H3CH2C MgBr

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20.25) Show the steps for the following reaction.

HO O HO

OH

CH2CH2CH2CH3

HO OTBDMS-Cl

N

HN

TBDMSO O

BrMg CH2CH2CH2CH3

H2O

TBDMSO

OH

CH2CH2CH2CH3FN(CH2CH2CH2CH3)4

H2O

HO

OH

CH2CH2CH2CH3

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Reaction of Organometallic Reagents with Carboxylic Acid Derivatives.

• Both esters and acid chlorides form 3° alcohols when treated with two equivalents of either Grignard or organolithium reagents.

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• To form a ketone from a carboxylic acid derivative, a less reactive organometallic reagent—namely an organocuprate—is needed.

• Acid chlorides, which have the best leaving group (Cl¯) of the carboxylic acid derivatives, react with R’2CuLi to give a ketone as the product.

• Esters, which contain a poorer leaving group (¯OR), do not react with R’2CuLi.

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Reaction of Organometallic Reagents with Other Compounds

• Grignards react with CO2 to give carboxylic acids after protonation with aqueous acid.

• This reaction is called carboxylation.• The carboxylic acid formed has one more carbon atom than the

Grignard reagent from which it was prepared.

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• The mechanism resembles earlier reactions of nucleophilic Grignard reagents with carbonyl groups.

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• Like other strong nucleophiles, organometallic reagents—RLi, RMgX, and R2CuLi—open epoxide rings to form alcohols.

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• The reaction follows the same two-step process as opening of epoxide rings with other negatively charged nucleophiles—that is, nucleophilic attack from the back side of the epoxide, followed by protonation of the resulting alkoxide.

• In unsymmetrical epoxides, nucleophilic attack occurs at the less substituted carbon atom.

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,-Unsaturated Carbonyl Compounds

,-Unsaturated carbonyl compounds are conjugated molecules containing a carbonyl group and a C=C separated by a single bond.

• Resonance shows that the carbonyl carbon and the carbon bear a partial positive charge.

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• This means that ,-unsaturated carbonyl compounds can react with nucleophiles at two different sites.

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• The steps for the mechanism of 1,2-addition are exactly the same as those for the nucleophilic addition of an aldehyde or a ketone—that is, nucleophilic attack, followed by protonation.

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• Consider the conversion of a general enol A to the carbonyl compound B. A and B are tautomers: A is the enol form and B is the keto form of the tautomer.

• Equilibrium favors the keto form largely because the C=O is much stronger than a C=C. Tautomerization, the process of converting one tautomer into another, is catalyzed by both acid and base.

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Summary of the Reactions of Organometallic Reagents

[1] Organometallic reagents (R—M) attack electrophilic atoms, especially the carbonyl carbon.

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[2] After an organometallic reagent adds to the carbonyl group, the fate of the intermediate depends on the presence or absence of a leaving group.

[3] The polarity of the R—M bond determines the reactivity of the reagents:

—RLi and RMgX are very reactive reagents.

—R2CuLi is much less reactive.

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Synthesis

Figure 20.8Conversion of 2–hexanol into

other compounds

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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 are H2SO4 or p-toluenesulfonic acid (TsOH).

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

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• When an alcohol has two or three carbons, dehydration is regioselective and follows the Zaitsev rule.

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

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• Secondary and 3° alcohols react by an E1 mechanism, whereas 1° alcohols react by an E2 mechanism.

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• Since 1° carbocations are highly unstable, their dehydration cannot occur by an E1 mechanism involving a carbocation intermediate. Therefore, 1° alcohols undergo dehydration following an E2 mechanism.

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Dehydration of Alcohols Using POCl3 and Pyridine

• Some organic compounds decompose in the presence of strong acid, so other methods have been developed to convert alcohols to alkenes.

• A common method uses phosphorus oxychloride (POCl3) and pyridine (an amine base) in place of H2SO4 or TsOH.

• POCl3 serves much the same role as a strong acid does in acid-catalyzed dehydration. It converts a poor leaving group (¯OH) into a good leaving group.

• Dehydration then proceeds by an E2 mechanism.

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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:

• This order of reactivity can be rationalized by considering the reaction mechanisms involved. The mechanism depends on the structure of the R group.

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• The reactivity of hydrogen halides increases with increasing acidity.

• Because Cl¯ is a poorer nucleophile than Br¯ or I¯, the reaction of 10 alcohols with HCl occurs only when an additional Lewis acid catalyst, usually ZnCl2, is added. Complexation of ZnCl2 with the O atom of the alcohol makes a very good leaving group that facilitates the SN2 reaction.

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Conversion of Alcohols to Alkyl Halides with SOCl2 and PBr3

• Primary and 2° alcohols can be converted to alkyl halides using SOCl2 and PBr3.

• SOCl2 (thionyl chloride) converts alcohols into alkyl chlorides.

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

• Both reagents convert ¯OH into a good leaving group in situ—that is, directly in the reaction mixture—as well as provide the nucleophile, either Cl¯ or Br¯, to displace the leaving group.

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• When a 1° or 2° alcohol is treated with SOCl2 and pyridine, an alkyl chloride is formed, with HCl and SO2 as byproducts.

• The mechanism of this reaction consists of two parts: conversion of the OH group into a better leaving group, and nucleophilic cleavage by Cl¯ via an SN2 reaction.

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• Treatment of a 10 or 20 alcohol with PBr3 forms an alkyl halide.

• The mechanism of this reaction also consists of two parts: conversion of the OH group into a better leaving group, and nucleophilic cleavage by Br¯ via an SN2 reaction.

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Tosylate—Another Good Leaving Group

• Alcohols can be converted into alkyl tosylates.

• 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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• Alcohols are converted to tosylates by treatment with p-toluenesulfonyl chloride (TsCl) in the presence of pyridine.

• 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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• (S)-2-Butanol is converted to its tosylate with retention of configuration at the stereogenic center. Thus, the C—O bond of the alcohol is not broken when tosylate is formed.

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• Because alkyl tosylates have good leaving groups, they undergo both nucleophilic substitution and elimination, exactly as alkyl halides do.

• Generally, alkyl tosylates are treated with strong nucleophiles and bases, so the mechanism of substitution is SN2, and the mechanism of elimination is E2.

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• Because substitution occurs via an SN2 mechanism, inversion of configuration results when the leaving group is bonded to a stereogenic center.

• We now have another two-step method to convert an alcohol to a substitution product: reaction of an alcohol with TsCl and pyridine to form a tosylate (step 1), followed by nucleophilic attack on the tosylate (step 2).

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• Step 1, formation of the tosylate, proceeds with retention of configuration at a stereogenic center.

• Step 2 is an SN2 reaction, so it proceeds with inversion of configuration because the nucleophile attacks from the backside.

• Overall there is a net inversion of configuration at a stereogenic center.

Example:

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Figure 9.8Summary: Nucleophilic

substitution and β eliminationreactions of alcohols

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For Monday, 20.26-20.36