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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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