Alcohols II

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CHAPTER 15

ALCOHOLS, ETHERS AND AMINES II: SYNTHESIS, REDOX REACTIONSAND ELIMINATION

15.1 SYNTHESIS OF ALCOHOLS, ETHERS AND AMINES

Alcohols are important industrial chemicals as well as being useful intermediates in theresearch laboratory, so their preparation has been the subject of relatively intense study.Numerous methods are now available for the synthesis of alcohols from a wide variety of startingmaterials, many of which (e.g. the Grignard synthesis and the hydroboration-oxidation of alkenes)we have already studied as part of the chemistry of other functional groups. These methods maybe divided into two broad classes: those based on the formation of new carbon-carbon bonds,and those based on the interconversion of functional groups.

SYNTHESIS OF ALCOHOLS BASED ON CARBON-CARBON BOND FORMATION

By far the most widely used method for the synthesis of alcohols based on the formation of anew carbon-carbon bond is the Grignard synthesis and its analogs. In this reaction, as you mayrecall, a carbonyl compound reacts with an organometallic reagent (typically a Grignard reagentor an alkyllithium) to give an intermediate alkoxide from which the alcohol is then liberated bymineral acid. Primary alcohols are formed from formaldehyde, secondary alcohols from otheraldehydes, and tertiary alcohols from ketones.

1) CH2=CH-MgBr

2) H3O+

CHO

OH

2) KOH/H2O

1) CH3MgBr

OH

HO

O

OCOCH3

Another major method for the synthesis of alcohols especially 1,3-diols and polyols is thealdol addition reaction, which we discussed at considerable length in Chapter 10.6. Since itsresurgence as a method for the stereocontrolled formation of new carbon-carbon bonds, the aldoladdition reaction has been widely applied to the synthesis of polyhydric alcohols. In the examplesbelow, the relatively bulky group at the position in the ketone ensures that the Z enolate isformed, and that the anti aldol predominates in the product mixture.

1) LDA/THF/-78C

2)

O

O OH

CHO

1) LDA/THF/-78C

2)

O OH

CHO

O

The third major method for the formation of alcohols by formation of a carbon-carbon bondis the pinacol reaction, in which two carbonyl groups are coupled under the influence of a metal.


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ALCOHOLS, ETHERS & AMINES II Chapter 15 568

This reaction, which gives the 1,2-diol, is usually used only for to intramolecular coupling, or forthe synthesis of symmetrical 1,2-diols.

Mg/Et2OOH

HO

O

Sample Problem 15.1. Write a reaction or sequence of reactions which may be used toprepare 4,5-dimethylhexane-2,4-diol from acetone and any other organic or inorganiccompounds needed. Ignore stereochemistry unless it is explicitly specified.

Answer:1) LDA/THF/-78C

2) CH3CHO

1) (CH3)2MgBr (excess)

2) H3O+

O OHOOHOH

O OOO

Note that at least two equivalents of isopropylmagnesium bromide are required in thesecond step. The first equivalent of the Grignard reagent will react with the hydroxylgroup of the alcohol in an acid-base reaction to give the magnesium alkoxide andpropane; the second equivalent reacts much more slowly, and gives the magnesiumalkoxide of the tertiary alcohol. The reaction between Grignard reagents and alkoxideslike those formed in the first step often require heating to give adequate yields ofproduct.

Problem 15.1. Write a reaction or sequence of reactions which may be used to prepare

each of the compounds below from the indicated starting material and any otherorganic or inorganic compounds needed. Ignore stereochemistry unless it is explicitlyspecified.

(a) 4-methylhexane-2,4-diol from 2-butanone.(b) 3,6-dimethylheptane-3,6-diol from 2-butanone.(c) 1-(2-hydroxy-2-methylpropyl)cyclohexanol from a ketone with six carbon

atoms or less.(d) 3,4-dimethylhexane-3,4-diol from 2-butanone.(e) 1-(1-hydroxycyclopentyl)cyclopentanol from cyclopentanone.

Reaction synopsis

Organometallic Synthesis of Alcohols:R-M

R

R

O

R

R

OHR

M: Mg (Grignard reagent); Li; Zn (with aldehydes); etc.


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Chapter 15 SYNTHESIS, REDOX REACTIONS & ELIMINATION 569

Aldol Addition: R1

O

R2R1

O

R2

OH

R31) base

2) R3CHO

Base: LDA (or LICA or LHMDS or NaHMDS, etc.)/THF/-78C

Pinacol Synthesis of 1,2-Diols:[H]

R

R

O

R

R

HO

R

R

OH

[H]: Mg/Et2O; Ti/THF; etc.

SYNTHESIS OF ALCOHOLS BASED ON FUNCTIONAL GROUP INTERCONVERSIONS

Reduction of carbonyl compounds

The reduction of carbonyl compounds, including aldehydes, ketones and derivatives ofcarboxylic acids, provides another important method for the synthesis of alcohols from carbonylcompounds. As discussed in Chapter 10, the most useful reagents for carrying out thistransformation are the complex metal hydrides, lithium aluminum hydride (LiAlH4, or LAH) andsodium borohydride (NaBH4). Sodium borohydride is the less reactive reagent; it will not reactwith most conjugated ketones, and it does not react with esters except under forcing conditions.For the reduction of carboxylic acids and their derivatives, lithium aluminum hydride is the mostwidely-used reagent. Because sodium borohydride and lithium aluminum hydride are also basesthat may promote unwanted side-reactions, diisobutylaluminum hydride ([(CH3)2CHCH2]2AlH,DIBAL-H) has recently become more popular for reducing carbonyl compounds. This reagent,which is a Lewis acid, can be used to reduce aldehydes, ketones, and all carboxylic acid

derivatives except the carboxylic acid itself.NaBH

4/CH

3OH

H

OH

O

1) DIBAL-H/hexane

2) HCl/H2O

OHCOCH2CH3

O

Hydration of alkenes

The conversion of alkenes to alcohols is carried out by adding water across the double bond, areaction known as hydration which we discussed at length in Section 7.6. The anti-Markovnikov hydration of alkenes is accomplished by the hydroboration-oxidation reaction.Hydroboration-oxidation has the added advantage that it occurs with overall syn stereochemistry,so that the stereochemistry of the product is also defined. The Markovnikov hydration of alkenescan be carried out either by simple acid-catalyzed addition of water across the double bond, or bythe oxymercuration-demercuration reaction discussed in Section 9.5. Of the two, the acid-catalyzed hydration reaction is the more prone to give rearranged products.


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1) BH3THF

2) H2O2/OH

/H2O

OH

H

CH3CH3

(mixture of stereoisomers)2) NaBH4/NaOH/H2O/THF

1) Hg(OCOCH3)2/THF/H2O

CH3

CH3

OHCH3

CH3

H2SO

4/H

2O CH3

OHCH3

Sample Problem 15.2. Write a reaction or sequence of reactions which may be used toprepare the following alcohols from the designated starting material. Where more thanone answer is possible, give two alternatives.

(a) 1,4,4-trimethylcyclohexanol from 1,4,4-trimethylcyclohexene.(b)E-2-ethylcyclopentanol from 1-ethylcyclopentene.

(c) 1-isopropylcyclopentanol from cyclopentanone.(d) cyclopentylmethanol from cyclopentanecarboxaldehyde.

Answers:

H+/H2O1) Hg(OCOCH3)2/THF/H2O

2) NaBH4/NaOH/H2OOR(a)

OHOH

1) BH3THF

2) H2O2/NaOH/H2O(b) OH (c) 2) H3O

+

1) (CH3)2CHMgBr OHO

2) H3O+

OR1) LiAlH4/Et2O

(d)NaBH4

CH3OH

CHO CHO CH2OHCH2OH

Problem 15.2. Write a reaction or sequence of reactions which may be used to preparethe following alcohols from the designated starting material. Where more than oneanswer is possible, give two alternatives.(a) 1-ethylcyclohexanol from 1-ethylcyclohexene.(b)E-2-propylcycloheptanol from 1-propylcycloheptene.(c) 2-cyclohexyl-2-propanol from acetone.(d) isobutyl alcohol from 2-methylpropanal.

(e) 1-cyclopentyl-1-propanol from bromoethane.

Hydroxylation of alkenes

The synthesis of 1,2-diols from alkenes is a reaction which we have already discussed atconsiderable length (Chapter 8). As we saw, the hydroxylation of alkenes can occur with eitheranti stereochemistry or syn stereochemistry, depending on the reagent. Some typical examplesare given here to demonstrate this method for 1,2-diol formation. Note that in six-memberedrings, anti hydroxylation occurs by 1,2-diaxial addition.


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syn hydroxylationMe

3COH/25C

OsO4/Me

3COOH

OH

OH

anti hydroxylation2) NaOH/H2O

1) HCO2OH/CH2Cl2

OH

OH

()

2) NaOH/H2O

1) HCO2OH/CH2Cl2

OH

OH

OH

OH

but not

Problem 15.3. Which reagent or sequence of reagents should be used to accomplish thefollowing transformations?

(a)OH

OH

(b)OH

OH

(c)HO

OH

(d)HO

OH

SYNTHESIS OF ETHERS

The synthesis of ethers can also be effected by acid-catalyzed addition of alcohols to alkenes,and by a variation of the oxymercuration-demercuration reaction called solvomercuration-demercuration. Acid-catalyzed addition of alcohols to alkenes is especially facile when thealkene is electron-rich (e.g. an enol ether). Perhaps the best example of this is the reaction whichwe have already discussed between dihydropyran and an alcohol to give a tetrahydropyranyl(THP) ether. Since THP ethers are acetals, they are unreactive towards most nucleophiles, andyet they easily reconverted to the alcohol in dilute aqueous acid. Consequently, THP ethers areoften used as protecting groups for alcohols in multistep syntheses.

OTHP

TsOH/CH2Cl2

(DHP)

OH O

OO

In the solvomercuration-demercuration reaction, an alcohol is used as the solvent for thereaction instead of the aqueous THF usually used in the oxymercuration-demercuration, and themercuric acetate is replaced by mercuric trifluoroacetate (the anion is less nucleophilic, and doesnot compete with the alcohol as the nucleophile opening the three-membered mercurinium ion).Because of steric hindrance, the reaction cannot be used to prepare ethers in which both of thealkyl groups are tertiary.

1) Hg(OCOCF3)2/EtOH

2) NaBH4/H2O/NaOHMe

OEt

Me


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Sample Problem 15.3. Write five different reactions or sequences of reactions involvingthe formation of at least one carbon-oxygen bond which may be used to prepare tert-butyl methyl ether.

Answers:OR

1) Hg(OCOCF3)2/MeOH

2) NaBH4/NaOH/NaOHOCH3

O R O R

H+/MeOH

OMe1) Na/

2) MeIOMeOH

OR

Ag2O

MeOHOMeBr

2) Me3COH

1) DEAD/(C6H5)3PMeOH OMe

BUT NOT

(This reaction will give the alkene by E2elimination instead of SN2 substitution)

MeONaOMeBr

Problem 15.4. Write five different reactions or sequences of reactions involving the

formation of at least one carbon-oxygen bond which may be used to prepare thefollowing ethers:

(a) 1-methoxy-1-ethylcyclopentane. (b) 3-ethoxy-3-methylhexane.(c) isobutyl cyclohexyl ether.

Formation of cyclic acetals and ketals

Alcohols with a single hydroxyl group are called monohydric alcohols, while those with twoor more hydroxyl groups are called polyhydric alcohols. A special case of the formation ofethers is the formation of cyclic acetals and ketals from 1,2- and 1,3-diols. We have already beenintroduced to acetals and ketals as intermediates in synthesis for the protection of carbonylgroups during reactions to which they are normally susceptible. The same functional group canalso be used to protect diols. Thus, the reaction between a 1,2-diol or a 1,3-diol and an aldehydeor ketone usually leads to the rapid formation of the cyclic acetal or ketal. The reaction itself iscarried out under conditions identical to those already discussed in Section 11.3. As illustrated inthe second example below, the use of alternative acid catalysts to form cyclic ketals has becomevery popular in recent years: in the example given, anhydrous copper (II) sulfate serves both as amild acid catalyst and as a dehydrating agent to drive the equilibrium reaction to completion.

Et2C=O

THF/TsOH(90%)

HOOH

OH

HHO

O

HO

Me2C=O/CuSO4/

[R = CO2CH3](74%)R

RO

O

O

R

ROH

OH

O

Problem 15.5. The reaction between R-3,3-dimethyl-1,2,4-butanetriol and 3-pentanone(shown above) gives only the cyclic ketal in which the triol reacts through the 1,2-diolsubstructure, and none of the 1,3-diol derivative. When acetone is used as the ketone,the 1,2-diol derivative is still the major product, but now the 1,3-diol derivative isformed as 10% of the product mixture. Explain.


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SYNTHESIS OF EPOXIDES

Despite the strain inherent in the three-membered ring, epoxides are remarkably simple tomake. Three-membered rings can be formed by forming one bond a three-atom acycliccompound to close the three-membered ring by intramolecular nucleophilic displacement of a

leaving group by an oxyanion or carbanion nucleophile, or by forming two bonds in one step inan addition to an alkene to give the three-membered ring.

base

R

R

R

R

OR

R

RR

"O"

OX

RR

R

R

H

Condensation reactions

In Chapter 14, we discussed the formation of epoxides by the reaction of a halohydrin (-haloalcohol) or a -hydroxysulfonate ester with a base. However, the precursor needed to closethe three-membered ring need not be part of the starting material, but it can be formed by thereaction between a carbon nucleophile and a carbonyl compound if the nucleophile also carries aleaving group. When the nucleophile is the enolate anion of an -haloketone or an -haloester,the initial product formed in the reaction with an aldehyde or ketone is the conjugate base of thealdol, which undergoes a rapid intramolecular SN2 displacement of the halogen to give theepoxide. This reaction is known as the Darzens condensation.

O

R

R

R

O

Z

X

H

O

ZR

base

R

R

O

X

O

ZR

X

R

RO

RO

Z

(83-95%)

O

CO2C2H5Cl

CO2C2H5

+OKOCMe

3

Me3COH

A more recent variant of the Darzens condensation relies on using a sulfur ylide as thenucleophile. The intermediate alkoxide formed by addition of the carbanion to the carbonylgroup undergoes intramolecular SN2 displacement of a dialkyl sulfide to give the epoxide.

OO

(80%)CH2 SMe2

CH2 SMe2

O O

(89%)

Georges Auguste Darzens (1867-1954). Darzens was born in Moscow, but was educated and spenthis entire career in France. From 1886-1888 he was a student at the cole Polytechnique of the Universitde Paris, where he was appointed as Assistant Professor of Physical Science in 1895. In 1913, he wasappointed Professor of Chemistry at the cole Polytechnique, a position he held until his retirement in1937, although he continued to publish original research papers until his death some 17 years later.Darzens made numerous contributions to the methodology of organic synthesis, including the glycidicester synthesis and the acylation of alkenes by acid chlorides. He served the French government in severaladvisory capacities during his lifetime, and won every major prize conferred by the French scientificsocieties.


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Sample Problem 15.2. Draw the structure of the major organic product that should beobtained from each of the following reactions:

(a)K2CO

3/EtOH

OH

Br

CH2

SMe2

(b)DMSO-THF/-78C

O

BrCH

2CO

2Me

KOCMe3

(c)O

O(d)BrCH

2CN

KOCMe3/Me

2SO

Answers:

(a) OH

H

(b) OO

CO2CH

3

(c) (d)O

CN

() () (); mixture of EandZisomers(a) Note that inversion of configuration has occurred at the carbon atom bearing the

bromine. The configuration at the carbon carrying the hydroxyl group has remainedunchanged.

(b) The presence of the double bond in conjugation with the carbonyl group does not alterthe course of the reaction. The ylide reacts with the conjugated enone to give thecorresponding the epoxide.

(c) This is an example of the Darzens condensation.(d) This is another example of the Darzens condensation. Note that there are two new

chiral centers formed in this reaction, so a mixture of diastereoisomers results.

Problem 15.6. Draw the structure of the major organic product obtained from each ofthe following reactions.

OH

Br

(a)K2CO

3/EtOH CH2 SMe2

O(b)DMSO-THF/-78C

BrCH2CO

2Me

KOCMe3

(c)CHO

(d)BrCH

2CN

KOCMe3/Me

2SOO

CH2

SMe2

DMSO-THF/-78C(e)

CHO

(f)DMSO-THF/-78C

CH2

SMe2

O

Epoxidation of alkenes

The epoxidation of alkenes is a reaction which we have already studied in considerable depthin Chapter 10.2, and there are numerous reagents which can be used to form epoxides fromalkenes. The most common method for forming epoxides is by oxidation of alkenes with organicperoxyacids (or peracids). The reaction occurs readily in non-hydroxylic solvents and gives theepoxide in which an oxygen atom is added to the less hindered face of the bond in a suprafacial(syn) manner. In dienes, the more substituted bond is oxidized first. Epoxidation of alkenes byperacids is facilitated by electron-withdrawing groups on the peracid, and by electron-releasinggroups on the alkene. This is consistent with a frontier orbital overlap between the peracidLUMO, whose energy would be lowered by electron-withdrawing substituents, and the alkene


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HOMO, whose energy would be raised by electron-donating substituents. Epoxidation byperacids is also facilitated by non-polar solvents, and retarded by solvents which can formhydrogen bonds to the peracid.

O

O

OO

O

m-CPBA/CH2Cl2(77%)

Epoxidation of allyl alcohols

The functional group of an allylic alcohol affects both the regiochemistry and thestereochemistry of the epoxidation reaction due to its ability to form hydrogen bonds to thereagent. The hydroxyl group affects regiochemistry by directing direct the epoxidizing agent tothe double bond nearest to itself whether the oxidizing agent is a peracid or a metal-basedreagent. The effects of the hydroxyl group on the stereochemistry of epoxidation is nicelyillustrated by cyclic allylic alcohols: peracids oxidize cyclic allylic alcohols to the epoxide wherethe epoxide oxygen is cis to the hydroxyl group. When the hydroxyl group is esterified thestereochemistry of the epoxidation is determined by steric factors, and the reagent approaches

the less hindered face of the molecule. For example, 2-cyclohexenol reacts with perbenzoic acidto give predominantly (90:10) the epoxide where the epoxide oxygen is cis to the hydroxylgroup. Its acetate ester, on the other hand, gives a 57:43 mixture of products in which the majorisomer is the one with the epoxide oxygen trans to the ester group.

OH

C6H5CO2OH

C6H6/5C+

OH

O

H

H

(78%)

OH

O

H

H

(8%)

OCOCH3

C6H5CO2OH

C6H6/5C+

OCOCH3

O

H

H

(16%)

OCOCH3

O

H

H

(22%)

These observations have been rationalized on the basis of a transition state in which theperacid is hydrogen bonded to the alcohol hydroxyl group. According to this model, the peracidforms a hydrogen bond with one of the peroxy oxygens of the peracid, resulting in the peracidbeing directed to the same face of the double bond.

H

O

R

O O

H

O

Perhaps the most important reaction of allylic alcohols to have emerged in the last thirty yearsis the Sharpless asymmetric epoxidation. This reaction, which we studied in some detail inChapter 10, is certainly worth reviewing here. In the Sharpless epoxidation an allylic alcohol isepoxidized with tert-butyl hydroperoxide and a titanium alkoxide in the presence of a chiraldialkyl tartrate ester (which is also a chiral diol). The real importance of this reaction lies in itspower of prediction: based on a simple model, shown below in Figure 15.6, one can predict witha high level of confidence just what the absolute configuration of the final epoxide will be.


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Ti(Oi-Pr)4/Me3COOH

CH2Cl2/-20C

(-)-DET

(+)-DET

D-(-)-diethyl tartrate["unnatural isomer"]

L-(+)-diethyl tartrate

["natural isomer"]

"O"

"O"

OH

OH

O

OHO

Figure 15.6 The model for predicting the absolute configuration of epoxides in the Sharpless asymmetricepoxidation of allylic alcohols.

In the Sharpless epoxidation model, the allylic alcohol is oriented so that the double bond iswritten vertically with the carbinol carbon in the lower right-hand corner. In this orientation,epoxidation in the presence of the natural L-(+)-dialkyl tartrate esters will occur so that theoxygen is delivered to the bottom face of the double bond, and epoxidation in the presence of theunnatural, D-(-)-dialkyl tartrate will occur so that the oxygen atom is delivered to the top face.

Problem 15.7. Draw the structure of the major organic product expected from each ofthe following reactions.

Ti(Oi-Pr)4/Me3COOH

(+)-DET/CH2Cl2/-20C(a)

OH(b)

OH (+)-DET/CH2Cl2/-20C

Ti(Oi-Pr)4/Me3COOH

(d)OH

(+)-DET/CH2Cl2/-20C

Ti(Oi-Pr)4/Me3COOHTi(Oi-Pr)4/Me3COOH

(+)-DET/CH2Cl2/-20C(c)

OH

SYNTHESIS OF AMINES

Reduction

The reduction of other functional groups is the basis of several of the more versatile methodsfor the synthesis of amines. Among the functional groups which may be reduced to an aminogroup are the cyano group, whose reduction we discussed at length in Section 11.5, the oximinogroup of oximes, and the imine group. In each of these groups there is a carbon-nitrogen bondwhich is reduced. This bond is intermediate in polarity between the carbon-carbon bond,which is non-polar, and the carbonyl group, which is highly polar, and its can be effected eitherby catalytic hydrogenation (which reduces alkenes rapidly and ketones slowly) or by complexmetal hydrides (which reduce carbonyl groups rapidly and alkenes either slowly or not at all).Some typical examples follow.

2) H3O+

1) LiAlH4/Et2O/

CH3

CH2NH2

CH3

CN

N OH

NH2

H2

/Pd-C

EtOH

Nitriles and oximes are reduced to primary amines either by catalytic hydrogenation or bylithium aluminum hydride. The complex metal hydride is usually preferred for the reduction of


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nitriles, and catalytic hydrogenation usually works better with oximes. Oximes are also readilyreduced by active metals in the presence of a proton source (e.g. lithium in liquid ammonia orsodium in ethanol or zinc in hydrochloric acid).

+

NH2

N OH

NH2

Na/EtOH/

Primary amines may also be prepared by the reduction of azides and nitro compounds.Because aromatic nitro compounds are especially easily prepared, the reduction of nitro groups isan especially important method for the synthesis of amines where the amino group is directlybonded to an aromatic ring. The discovery of this reduction by Russian chemist Nikolai Zinin in1842 was pivotal to the development of the aniline dye industry with all the advances in syntheticorganic chemistry that ensued.

Fe/HCl/H

2O/EtOH/

MeO2N

NO2

MeH2N

NH2

N3 CO2CMe3

H2/Pd-C

MeOHH2N CO2CMe3 (75-82%)

Nikolai Nikolaevich Zinin (1812-1880). Zinin, who was orphaned within days of his birth inShusha, near the Persian border, was raised by his uncle. Zinin entered Kazan' University, graduating witha degree in Astronomy and Physics, and in 1833, he was appointed to a junior faculty position in chemistry

despite his lack of any formal training in the subject whatsoever. Few have managed to achieve thedistinction that Zinin did under these circumstances. In 1837 Zinin was sent abroad to study chemistry inpreparation for his teaching career, and it was while in Liebig's laboratory in Giessen that he first carriedout experiments in organic chemistry. On his return to Russia, Zinin was appointed to the chair ofchemical technology at Kazan' (the chemistry chair had been filled by Karl Klaus, the discoverer ofruthenium, in his absence). At Giessen Zinin discovered the cyanide-catalyzed dimerization ofbenzaldehyde to benzoin, but it was his first independent work the reduction of aromatic nitro compoundsto aromatic amines that led no less a chemist than A.W. von Hofmann himself to proclaim that "If Zininhad done nothing more than to convert nitrobenzene to aniline, even then his name should be inscribed ingolden letters in the history of chemistry." In 1848 Zinin moved to St. Petersburg as Professor ofChemistry at the Medical-Surgical Academy. During his career, Zinin served as mentor to two of the mostimportant Russian organic chemists of the next generation, Aleksandr Butlerov and the composer-chemistAleksandr Borodin.

Reductive amination

The condensation reaction between a carbonyl compound and ammonia or primary aminesgives an imine as the major product, and the condensation with a secondary amine gives anenamine. Like the polar bond of the carbonyl compounds, the polar C=N bond of an imineor its conjugate acid, an iminium ion, is susceptible to reduction by complex metal hydrides.When the condensation and reduction are carried out in a single reaction, the reaction is calledreductive amination. In modern variants of the reductive amination, the carbonyl compound istreated with ammonia or an amine in the presence of a hydride reducing agent (sodiumcyanoborohydride, NaBH3CN is probably most widely used) or hydrogen and a palladiumcatalyst. The product of the reductive amination is an amine where the alkyl group is derivedfrom the carbonyl compound.

Historically, the reducing agent has been formic acid, and under these conditions the reductiveamination occurs by a mechanism similar to that of the crossed Cannizzarro reaction. Dependingon the exact conditions used, this reaction has several names: if ammonium formate is thereagent, the product is the primary amine and the reaction is called the Leuckart reaction;extension of the Leuckart reaction to using primary or secondary amines with the formic acid isknown as the Wallach reaction. In its most widely-used form today, the carbonyl compound in


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the Leuckart reaction is formaldehyde, and the product is usually the tertiary amine where all theamine hydrogen have been replaced by methyl groups; this reaction is known as the Eschweiler-Clarke reaction.

H2N

OH

Me2N

OHH2CO/HCO2H/

(63%)

(100%)

OO

H

H

H

H

NH4OCOCH3

NaBH3CN/MeOH

H2NO

H

H

H

H

CHO

EtNH2/MeOH/NaBH3CN

CH3CO2H

NHEt(80%)

Rudolf Leuckart (1854-1889). Leuckart was born in Giessen, the son of the zoologist of the samename. After studying in Heidelberg he took his Ph.D. in Leipzig in 1879 under Kolbe. Following hisgraduation, Leuckart remained at Leipzig for a year as Kolbe's assistant, before moving to Munich to takeup his first professional appointment in 1880, as an assistant to Baeyer. In 1883 he moved to Gttingen as

assistant in the chemistry department and as a privat-dozent, being promoted to professor in 1889. He diedat Gttingen of an apparent stroke a scant month after his thirty-fifth birthday. Leuckart's majorcontribution to the development of organic chemistry was his discovery of the reaction between ammoniumformate and carbonyl compounds that bears his name.

Otto Wallach (1847-1931). Wallach was born in Knigsberg and educated at the University ofGttingen under Whler, where he took his Ph.D. in 1869. Following his graduation, Wallach moved tothe University of Bonn in 1870 to work with Kekul. At Bonn he taught pharmacy, and in 1876 he wasappointed Professor of Pharmacy. In 1889 he returned to his alma mater as Director of the ChemicalInstitute, a post he held until his retirement in 1915. While at Bonn, Wallach became interested in theethereal oils, the essential oils which were (and still are) widely used as medicinal oils. His carefuldistillations allowed him to separate mixtures that Kekul believed to be absolutely resistant to analysis, andon the basis of their structures, which he determined, Wallach was able to formulate the isoprene rule forthe structures of terpenes. Wallach's work was recognized in 1910, when he received the Nobel Prize inChemistry for his work with the ethereal oils.

Wilhelm Eschweiler (1860-1936). Eschweiler was born in Euskirchen and studied at the Universityof Munich. In 1887 he began his studies at the Technische Hochschule in Hannover as Assistant in thechemistry laboratory. This work culminated in his obtaining his Ph.D. from Rostock in 1889 under Kraut.

In 1892 he was promoted to privat-dozent, and rose through the ranks to become Professor of AnalyticalChemistry at the Technische Hochschule. Eschweiler's only major contribution to organic chemistry washis report of the reaction between amines and formaldehyde in the presence of formic acid, the reactionwhich now bears his name.

Hans Thacher Clarke (1887-1972). Clarke was born of American parents in Harrow, England, andhe received all his education in England, taking his B.Sc. (1908) and D.Sc. (1914) degrees from UniversityCollege, London. From 1908-1909 he was a demonstrator in chemistry at University College, beingpromoted to lecturer in stereochemistry in 1910. From 1913-1914, Clarke carried out graduate study at theUniversity of Berlin. In 1914 Clarke moved to the United States, where he took a position as a researchchemist with Eastman Kodak in Rochester, New York. In 1928 he returned to academic ranks as Professorof Biological chemistry at the College of Physicians and Surgeons at Columbia University, a post he helduntil 1956, when he became Professor Emeritus. from 1951-1952 he was science attach of the U.S.Embassy in London. Clarke was a major contributor to the development of biological chemistry, and was aprolific book author: his first book appeared in 1911, his last in 1949. He served as President of theAmerican Society of Biological Chemists from 1947-1949.

Synthesis of amines from alkyl halides

On first examination, the simplest method for the synthesis of amines should be the directnucleophilic displacement of alkyl halides by ammonia or an amine, and alkylation is an importantmethod for the synthesis of amines. However, the reaction does have one major limitation:because the product of the reaction is itself an amine, it can also react further with the alkyl halideto give the product of over-alkylation (Figure 15.1), as we saw in Section 14.6. Over-alkylationis usually difficult to control, so direct alkylation is used most often for the preparation of primaryamines (where a large excess of ammonia can be used) or for the formation of quaternaryammonium salts (where a large excess of alkyl halide is used).


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SN2

SN2

H3N

R

N

H

HN

H

R

HR

N

H

R

R

N

R

R

R

N

R

R

RR

R XN

H

H

H

N

H

H

H R R XN

H

R

H

Figure 15.1 The reaction between ammonia and an alkyl halide proceeds stepwise to form the primaryamine, then the secondary amine, then the tertiary amine, and finally the quaternary ammonium salt. Thecomposition of the product mixture depends on the composition of the starting mixture.

The problem of over-alkylation in the formation of amines by nucleophilic substitution wassolved by German chemist Siegmund Gabriel, and the method is known as the Gabrielsynthesis (Figure 15.2).

C6H4(CO)2N

H2N Rbase SN2

phthalimide N-alkylphthalimide

N

O

O

H N

O

O

RN

O

O

R X

Figure 15.2 The Gabriel synthesis of primary amines.

In this method, the nucleophile used to displace the halide ion from the alkyl halide is not anamine, which can generate a new nucleophile, but is instead the (usually potassium) salt ofphthalimide (a derivative of phthalic acid). The product of the initial SN2 reaction is an N-alkylphthalimide; this is not a nucleophile, so over-alkylation cannot occur. The desired amine isthen liberated from theN-alkylphthalimide by warming it with hydrazine. The Gabriel synthesisis still one of the most widely used methods for the formation of primary amines from alkyl

halides. MeO2C

CO2Me

Br

Br

2) N2H4/

1) C6H4(CO)2N

K+

HO2CCO2H

NH2

NH2

(80%)

The reduction of azides has also been used for the synthesis of primary amines from alkylhalides. Like the phthalimide anion, azide anion is a useful nucleophile for SN2 reactions; thispermits the introduction of a primary amine group by a two-step process involving initialdisplacement of the halide by azide ion and subsequent reduction of the azide. In cases where theconditions required to liberate the amine from the N-alkylphthalimide make the Gabriel synthesisunsuitable for use, azide reduction offers an attractive alternative method for the formation of

primary amines.O

O

OO

O

H

H

H

H

MsO

O

O

OO

O

H

H

H

H

N3

H2/Pd-C

MeOH

O

O

OO

O

H

H

H

H

H2N

NaN3/DMF

Sample Problem 15.4. Write equations for the formation (free from contamination by thesecondary amine) of 2-amino-4-methylpentane from each of the following types ofcompounds.


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(a) an alkyl halide. (b) a ketone (three different procedures).(c) ammonia (a set of reagents not used to answer part b).

Answers:

OR2) H2/Pd-C/MeOH1) NaN3/DMF/

NH2

Br

(azide reduction)

(a)2) N2H4/1) C6H4(CO)2N

NH2

Br

(Gabriel synthesis)

(Oxime Reduction) (Reductive amination)

OR(b)1) NH2OH

2) H2/Pd-C

O NH2 NH3/H2/Pd-CO NH2

NH3/NaBH3CN(Reductive amination)(c)

MeOH

O NH2

Problem 15.8. Write equations for the formation of each of the following primary amines(free from contamination by the secondary amines) from the types of compounds givenin each case.(a) isopropylamine from acetone (three different sets of reagents).(b) cyclopentylamine from an alkyl halide (two different sets of reagents) and from acarbonyl compound.(c) 8-methyl-1-aminononane from a carbonyl compound and a nitrile.(d) 1-aminopentane from 1-bromobutane [Hint: see part (c) of this question].

Siegmund Gabriel (1851-1924). During his career, Gabriel had the good fortune to study under

three of the greatest organic chemists of the nineteenth and early twentieth centuries. He was born inBerlin, and he began his chemical studies at the University of Berlin under A.W. von Hofmann. In 1872he moved to the University of Heidelberg, where he took his Ph.D. in 1874 under the direction of R.W.Bunsen. Upon graduation he returned to Berlin where he became assistant Hofmann, becomingextraordinary professor of chemistry at the University in 1896. On Hofmann's death in 1892, he continuedin the same position under Emil Fischer. Gabriel's own research was clearly influenced by his associationwith Hofmann from the very beginning he worked with cyclic nitrogen compounds. In 1887 he reportedthe alkylation of phthalimide salts the reaction which now bears his name. Gabriel developed synthesesof many cyclic nitrogen compounds, including the isoquinolines (in 1886 he reported the first synthesis ofan isoquinoline derivative), phthalazines, pyridazines, pyrimidines and many substituted amines. In 1913he was appointed to an honorary professorship at the University of Berlin.

Reaction synopsis

Preparation of Alcohols by Reduction:

[H]

R

R

O

R

R

OH

[H]: LiAlH4/Et2O; NaBH4/EtOH; DIBAL-H/hexane; etc.


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Hydration of Alkenes: R

R R

R R

R R

OH

R

H

Reagents: 1) BH3THF; 2) H2O2/NaOH/H2O; other hydroborations; anti-Markovnikov; syn.or H

2SO

4/H

2O (H

3O+); Markovnikov; stereorandom.

or 1) Hg(OAc)2/THF/H2O, 2) NaBH4/NaOH/H2O; Markovnikov; first step anti, secondstep stereorandom.

Hydroxylation of Alkenes: R

R R

R R

R R

OH

R

HO

Reagents: 1) HCO3H; 2) OH (anti addition)or OsO4/Me3COOH/Me3C-OH; KMnO4/KOH/H2O (syn addition);

Solvomercuration-Demercuration:

R

R R

R R

R R

OR

R

H

Reagents: 1) Hg(OCOCF3)2/THF/ROH; 2) NaBH4/NaOH/H2ORegiochemistry: Markovnikov

The Darzens glycidic ester condensationCOXR

Br

COX

R

R

OR

X = OR, NR2Reagents: KOBut/R2CO

Sharpless Asymmetric Epoxidation of Allylic Alcohols:OHOH

O(+)-DET/CH2Cl2/-20C

OOH

Ti(O-i-Pr)4/Me3COOHTi(O-i-Pr)4/Me3COOH

(-)-DET/CH2Cl2/-20C

Proceeds with high levels of stereoselectivity to give enantiomer shown.

Preparation of Amines by Reduction:R C N

[H]

R CH2NH2

[H]R NO2 R NH2

[H]R N3 R NH2

Reagents: LiAlH4/Et2O; etc. (nitriles);or Sn/HCl/H2O/; other metals may be Fe, Zn, Mg, etc.;or Na/EtOH; Li/NH3/ROH; or other variant of Birch reduction;or H2/Pd-C/EtOH

Reductive Amination:


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[H]

R

R

O

R

R

NHRR NH2+

Reagents: RNH2/H2/Pd-C/EtOH; other catalysts may also be used;or RNH2/NaBH3CN/MeOH;

or HCO2H/NH3 (Leuckart Reaction); HCO2H/RNH2 (Wallach Reaction);or H2CO/HCO2H (Eschweiler-Clarke Reaction)The intermediate imine may or may not be isolated. Ammonia or primary or secondary amines may beused for this reaction.

Gabriel Synthesis: 1) C6H4(CO)2N

M

+

2) N2H4R NH2R X

Restricted to those alkyl halides and sulfonates that will participate in SN2 reactions. Hydrazinolysis ispreferred for obtaining the primary amine from the product.

15.2 ELIMINATION

Alcohols

The elimination of water from an alcohol is known as dehydration. Dehydration of alcoholsto alkenes can be effected using a variety of reagents protic acids, phosphorus oxychloride inpyridine, thionyl chloride in pyridine, and iodine in boiling benzene to name just a few.Depending on the reaction conditions, the dehydration of alcohols can lead to the formation ofalkenes or ethers or both.

Unlike the reaction between an alcohol and a hydrogen halide, the reaction between an

alcohol and an oxyacid (e.g. phosphoric or sulfuric acid) seldom leads to substitution products,but to the alkene through the oxonium ion intermediate. Primary alcohols eliminate by the E2mechanism, all other alcohols by the E1 mechanism. Like the E1 reactions of alkyl halides, theacid-catalyzed dehydration of alcohols shows a marked preference for Zaitsev orientation in theproduct alkene. It is worth noting that one of the simplest methods for the formation of acarbocation is the reaction between an alcohol and a strong acid.

H3PO4/OH

+(51%) (13%)

(80%)

H3PO4/

OH

The dehydration of secondary and tertiary alcohols by protic acids has, to a large degree, beensuperseded by dehydration using phosphorus oxychloride or thionyl chloride in pyridine. Boththese reagents react with secondary and tertiary alcohols to give the alkene formed by Zaitsevelimination of water from the alcohol. The first step of the elimination is the same as the first stepof the substitution reactions with these reagents: the formation of the chlorophosphate orchlorosulfite ester. In the presence of the excess base, however, the decomposition of thisintermediate occurs by the E2 mechanism rather than the SN1, SN2 or SNi mechanism.


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SOCl2/py O

O

OHO

O

O

OH

POCl3/py

O O

+

Problem 15.9. What will be the major organic product formed by treating each of thealcohols in the list below with the reagents in the list that follows it?

Alcohols:(a) 1-methylcyclohexanol. (b)Z-2-methylcyclohexanol.(c)E-2-methylcyclohexanol. (d) 3,3-dimethyl-2-butanol.(e) 2,2-diethylcyclopentanol. (f) 3-ethyl-2-pentanol.(g) isobutyl alcohol. (h)Z-bicyclo[3.3.0]octan-1-ol.(i)R-2-octanol. (j) S-2-methyl-1-butanol.

Reagents:(i) H2SO4/NaBr/H2O/. (ii) 1) TsCl/py; 2) KOH/EtOH/.(iii) SOCl2/. (iv) POCl3/py.(v) (C6H5)3P/Br2/DMF. (vi) 1) MsCl/py; 2) LiI/DMF.(vii) H3PO4/. (viii) (C6H5)3P/CCl4/.(ix) PBr3/Et2O. (x) HCl/ZnCl2/.(xi) SOCl2/py. (xii) H2SO4/.

Amines

In 1851 the great German chemist A.W. von Hofmann noted that bases react with quaternaryammonium salts to give predominantly the least substituted alkene. This orientation forelimination, which we discussed in Chapter 6 as the Hofmann orientation, is typical ofmolecules in which the leaving group is strongly bound to carbon (ammonium ions and fluorine).The Hofmann elimination occurs by an E2 mechanism, but a substantial partial negative chargeaccumulates at the carbon of activated complex (Figure 15.3) the reaction has a certainamount of E1cb character. It is this accumulation of negative charge that accounts for theorientation of the elimination: since alkyl groups are electron-releasing, they tend to destabilizethe activated complex, and the proton is removed from the least substituted available carbonatom.

NR3

H

RR

RR

B

NR3

H

R

R

RR

B

R

RR

R

NR3

B

H

Figure 15.3 The Hofmann elimination proceeds by an E2 mechanism through an activated complex wherethere is substantial partial negative charge accumulation at the carbon.

The Hofmann elimination has been used as the basis of a method for removing the nitrogenfrom an amine. This method, known as the Hofmann exhaustive methylation, involves by


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converting the amine to the quaternary ammonium salt with methyl iodide, carrying out theHofmann elimination, and repeating these two steps in order until the nitrogen atom is lost astrimethylamine. Its use is illustrated by applying it to to the tropine nucleus (the basis of theatropine and cocaine-type alkaloids), below, a process used by Nobel Prize-winning Germanchemist Richard Willsttter to complete the first synthesis of 1,3,5-cycloheptatriene.

MeI/

(forms AgOH;AgI is formed)

Ag2O/H2ONMe3

(forms AgOH;AgI is formed)

Ag2O/H2O

(excess)

MeI/N

Me NMe

Me

NMe2

Coupled with ozonolysis as a method for determining the structure of the alkenes produced,the Hofmann exhaustive methylation (or Hofmann degradation) was a powerful tool fordetermining the structures of many amines. The Hofmann elimination is an E2 eliminationreaction, and it is subject to all the limitations of the E2 mechanism, including the strongpreference for anti elimination.

Pyrolytic elimination reactions: the Ei mechanism

To this point, the elimination reactions which we have discussed at length occur by either theE1 or the E2 mechanism. However, certain compounds selenoxides, sulfoxides, xanthate estersand amine N-oxides to name four undergo elimination simply by heating. These pyrolyticeliminations (Greek ,pyr, fire) all occur by an intramolecular mechanism denoted as the Ei(Elimination, intramolecular) mechanism. We briefly discussed the elimination of sulfoxidesand selenoxides in Section 8.1.

N O

R

R

H

R

R

R

R

Se O

R

R

H

R

R

R

S O

R

H

R

R

R

R

O

O

R

R

H

R

R

O

S

SR

H

RR

R R

ester xanthate sulfoxide selenoxide amine-N-oxide

Ei eliminations can be divided into two major types: those proceeding through six-memberedcyclic transition states (ester pyrolysis, xanthate pyrolysis), and those proceeding through five-membered cyclic transition states (selenoxide pyrolysis, sulfoxide pyrolysis, amine-N-oxidepyrolysis) as illustrated in Figure 15.4. In both cases, the geometric constraints of the transitionstate ensure that the elimination occurs with syn stereochemistry. Thus, pyrolytic elimination

reactions provide a stereochemical contrast with the E2 elimination, which preferentially givesanti elimination if the hydrogen and the leaving group can achieve coplanarity. In most Eieliminations, the Zaitsev alkene predominates where both the Zaitsev and Hofmann alkenes maybe formed.

The ease of pyrolysis depends on the compound undergoing the reaction. The pyrolyticelimination of esters, which has been known for over a century (in 1883, the German chemistKrafft described the formation of alkenes by heating esters of fatty acids), occurs between 400Cand 600C. The related pyrolytic elimination of xanthates occurs at much lower temperatures(typically 100C to 250C). The pyrolysis of xanthates is known as the Chugaev reaction afterLev Chugaev, the Russian chemist who first described it in 1899. The pyrolytic elimination of


19/38


sulfoxides occurs at temperatures between 60C and 150C; the related elimination ofselenoxides occurs below 0C, which is why selenoxides are now so widely used for theformation of alkenes. The pyrolytic elimination of amine-N-oxides, which is known as the Copeelimination after American chemist Arthur C. Cope who first described it, typically occurs attemperatures between 100C and 150C.

X

Z H

R

Y

RRR

H

Y

Z

X

R

R R

R

+

X

Z H

R

Y

RRR

X=CR; Y=Z=O: esterX=CSR; Y=S; Z=O: xanthate

X=SR; Y=O: sulfoxideX=SeR; Y=O: selenoxideX=NR2; Y=O: amine-N-oxide

X

Y

R R

R R

H

Y

X

R RRR

H

R

R R

R

Y

X H

+

Figure 15.4 The Ei elimination reaction proceeds through either a five-membered or a six-membered cyclictransition state.

The pyrolysis of esters and xanthates provide the basis for methods for the indirectdehydration of alcohols that do not depend on the formation of a sulfonate ester intermediate,which is invariably more reactive than these esters. Esters are prepared from alcohols as wediscussed briefly in Section 15.6.

OH

R R

R R

C

O

ROHH

R R

R Rpy

+ R C

O

Cl

450C(C6H5)3P/DEAD

CH3CO2HOH

Me Me

O

Me

Me

O

Xanthate esters (Greek ,xanthos, yellow a reference to the bright yellow color ofcopper xanthate salts) are prepared from alcohols by nucleophilic addition of the alkoxide to thecarbon-sulfur bond of carbon disulfide to give the xanthate salt, and the SN2 reaction of thexanthate with an alkyl halide almost always methyl iodide to give the S-alkyl xanthate.

OH

R R

R R

C

S

S CH3

OH

R R

R R

S

C

S OH

R R

R R

C

S

S

CH3 I

150C1) KH/C6H5Me

2) CS23) MeI

OH OC

SMe

S

Amine-N-oxides are prepared from tertiary mines by oxidation with a peracid such as m-chloroperbenzoic acid, a reagent which we have seen used for the oxidation of alkenes to


20/38


epoxides (Section 8.2) and for the Baeyer-Villiger oxidation of ketones (Section 10.9). Primaryand secondary amines are not oxidized toN-oxides.

m-CPBA/CH2

Cl2

NR R

R

O

NR R

R

N

O

MeMe

160C

Lev Aleksandrovich Chugaev (1873-1922). Chugaev was born in Moscow and educated at theUniversity of Moscow where he studied under Zelinsky. His development of the xanthate eliminationreaction which bears his name was an extension of his research into camphor and its derivatives, which hepresented as his master's thesis. In 1904 he was appointed professor of chemistry at Moscow TechnicalCollege, and from 1908 to his death he was professor of inorganic chemistry at the University o St.Petersburg and professor of organic chemistry at St. Petersburg Institute of Technology. Most of his laterresearch was devoted to inorganic chemistry and the formation of metal complexes, especially of theplatinum metals. It was Chugaev who, in 1905, introduced dimethylglyoxime as an analytical reagent fornickel (II).

Arthur C. Cope (1909-1966). See Chapter 10.

Sample Problem 15.5. Give the major organic product expected from each of thefollowing reaction sequences. Where appropriate, specify product stereochemistry.

1) CH3I/ ?

HH

NMe2

2) KOH/EtOH/(a)

2)

1) m-CBPA/CH2Cl2?

HH

NMe2(b)

Answers:H

(a)

H

(b)

The Hofmann elimination in part (a) occurs by an E2 mechanism, so the reaction

occurs with anti stereochemistry to give theEalkene as the major product. The Copeelimination in part (b) occurs by an Ei mechanism so the reaction occurs with synstereochemistry to give theZalkene as the major product

Problem 15.10. Give the major organic product expected from each of the followingsequences of reactions. Where appropriate, specify the stereochemistry of the product.

CH3

NMe21) CH3I/

2) KOH/EtOH/(a) ? (b)

2)

1) m-CBPA/CH2Cl2?

CH3

NMe2

Et

NMe21) CH3I/

2) KOH/EtOH/ ?(c) 2)

1) m-CBPA/CH2Cl2

?Et

NMe2

(d)

(e)1) CS2/KOH

2) MeI3)

?MeHO

H H (f) 2) CH3CO2H3)

1) (C6H5)3P/DEAD?

MeOH

HH

[CAREFUL!]


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Reaction synopsis

Dehydration of Alcohols: R

R R

RR

R R

OH

R

H

Reagents: H2SO4/, H3PO4/ (E1 preferred; strongly Zaitsev)or POCl3/py; SOCl2/py (probable E2 through chlorophosphate or chlorosulfite esters)

Hofmann Exhaustive Methylation:1) MeI

2) base/R

R R

RR

R R

NR2

R

H

Base: Ag2O/H2O (Effectively AgOH); KOH/EtOH/; KOCMe3Regiochemistry: Hofmann (mainly least substituted alkene). Stereochemistry: mainly anti.

[Some syn elimination can occur in Hofmann eliminations.]

Pyrolytic Eliminations:

R

R R

RR

R R

X

R

H

X: OCOR; OCSSR; R2N+O; SOR; SeORStereochemistry: Reaction proceeds by syn elimination.

15.3 OXIDATION OF ALCOHOLS

The oxidation of alcohols is a particularly important reaction for many of the same reasonsthat the elimination reaction is important the product has a reactive bond. We have alreadydiscussed the oxidation of alcohols as a method for the synthesis of aldehydes and ketones(Section 12.2). The products obtained by the oxidation of alcohols depend on both the structureof the alcohol, and on the oxidant. Primary alcohols may be oxidized to the aldehyde or thecarboxylic acid, depending on the reagent used, while oxidation of secondary alcohols gives onlyketones. Let us first review briefly the oxidations which we have already studied in some depth.

Oxidations with metal-based reagents

The most common reagents used by organic chemists for the oxidation of alcohols arecompounds of chromium in the +6 oxidation state chromic acid and its derivatives; the mostcommonly used chromium (VI)-based reagents are given in Table 10.1. Chromium (VI)compounds can be used to oxidize primary alcohols to aldehydes in the absence of water, whileoxidation of primary alcohols by aqueous chromic acid usually results in oxidation to thecorresponding carboxylic acid.

OH

Me

OH

Me Me

MeO

CH=OMe

OH

Me Me

MeO

PCC/CH2Cl2/25C(80%)


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Na2Cr2O7/H2SO4/H2O

(60%)CO2HOH

Potassium permanganate is one of the most powerful of the common oxidizing agents, andoxidations with this reagent are usually much less selective. Potassium permanganate oxidizesprimary alcohols to carboxylic acids.

KMnO4/Na2CO3/H2O/4-5C(76%)

CO2HOH

Tetrapropylammonium perruthenate (TPAP, [(CH3CH2CH2)4N+ RuO4]) rapidly andselectively oxidizes primary alcohols to aldehydes. It can be used catalytically with a co-oxidantsuch asN-methylmorpholineN-oxide (NMMO), so that the amount of the relatively expensiveruthenium reagent needed is minimized. TPAP oxidation frequently gives higher yields ofproduct than the Swern oxidation.

TPAP (5 mol %)/NMMO

CH2Cl2/r.t./30 min(73%)

O

O

O

OH

Oxidations based on dimethyl sulfoxide

As discussed in Section 10.1, many functional groups other than the hydroxyl group of thealcohol (especially sulfides and certain alkenes and polyhydroxy compounds) are susceptible tooxidation by metal-based oxidizing agents. For the oxidation of such alcohols, alternativeoxidation methods based on dimethyl sulfoxide have been developed. One of these reactions the Swern oxidation has become a method of choice for converting primary alcohols toaldehydes.

(COCl)2/Me2SO/CH2Cl2

i-Pr2NEt/-78C

(64%)

H

CHO

H

OH

Allylic and benzylic alcohols the most easily oxidized alcohols

As we discussed in Chapter 7, allyl halides are unusually reactive towards many reagents. Youare probably not be surprised, therefore, to learn that allyl alcohols can be oxidized under verymild conditions. Manganese dioxide selectively oxidizes allyl and benzyl alcohols to theconjugated aldehydes and ketones. Since this reagent does not oxidize saturated alcohols orunsaturated alcohols which are not allylic or benzylic, it can be used to oxidize allyl or benzylhydroxyl groups in the presence of saturated primary and secondary hydroxyl groups. Note thedramatic contrast in reactivity between this reagent, which is based on Mn(IV), and potassium

permanganate, which is based on Mn(VII).MnO2/pentane

25C/12 h(72%)

OOH

MnO2/CHCl3/25C/10 h(90%)

OH

H H

H

O

OH

H H

H

HO


23/38


The currently accepted mechanism of chromium (VI) oxidation of alcohols involves the E2elimination of a chromium (IV) species from an intermediate chromate ester, as we discussed inSection 12.2. Saturated tertiary alcohols lack the hydrogen atom required for this elimination, sothey are resistant to oxidation. Saturated tertiary alcohols are oxidized only under forcingconditions. In fact, it has been recognized since the early 1860's that the oxidation of tertiary

alcohols by chromic acid is preceded by dehydration, and the alkene is the compound actuallyoxidized.Although saturated tertiary alcohols are not oxidized by chromium (VI) reagents, tertiary

allylic alcohols with at least one hydrogen atom at the far end of the double bond can besmoothly oxidized by these reagents on prolonged exposure. In these reactions, the oxidationoccurs with an allylic rearrangement: during the reaction, the oxygen atom becomes bonded tothe other end of the allylic system. The rearrangement step probably occurs at the chromateester stage of the reaction (Section 12.2); the mechanism of the rearrangement has not yet beenunambiguously determined, and it may involve the carbocation formed by heterolysis of thecarbon-oxygen bond or it may be a [3.3] sigmatropic rearrangement of the chromate ester.

PCC/CH2Cl

2MeO

Me

OH

CrO32py

CH2Cl2

O

H

OH

H

Sample Problem 15.6. What is the major organic product obtained from the oxidation ofthe alcohol below with each of the following reagents? Where appropriate, give yourreasons.

OH

OH

OH

(a) PCC/CH2Cl2/25C/30 min. (b) MnO2/CH3(CH2)3CH3/25C.(c) CrO3/H2SO4/H2O/acetone/25C. (d) KMnO4/H2O.(e) TPAP/NMMO/CH2Cl2/25C. (f) (COCl)2/(CH3CH2)3N/CH2Cl2/-78C.(g) PCC/CH2Cl2/25C/24 h.

Answers:

(a)

CHOO

OH

(b)

CHOOH

OH

(c)

O

OH

CO2H

(d)

CO2HO

OH

(e)

CHOO

OH

(f)

O

OH

CHO

(g)

CO2HO

O

Note that in (a) the total time for the reaction is only 25 minutes not long enough forthe tertiary allylic alcohol to undergo appreciable oxidation. In part (g), the reaction


24/38


time is now 24 hours plenty of time for the slow oxidation of the tertiary alcohol. Inpart (b) the reagent used, manganese dioxide, can oxidize only the primary allylicalcohol.

Problem 15.11. What is the major organic product obtained from the oxidation of reachof the alcohols below with the reagents listed in Sample Problem 15.6? Where

appropriate, give reasons for your answer.

(a)HO

OH (b)

HOOH

(c)

OH

OH

(d)

OH

OH

Oxidative cleavage of vicinal diols

In contrast to their monohydric counterparts, the vicinal diols (the 1,2-diols) are susceptible tooxidative cleavage by reagents such as potassium periodate, as we saw in Chapters 7, 8 and 10.In addition, lead tetraacetate, Pb(OCOCH3)4 or Pb(OAc)4, has also been found to be useful for

carrying out the cleavage of these compounds.The periodate cleavage of vicinal diols has been quite extensively studied, and there is good

evidence to support the overall mechanism shown in Figure 15.5, where a five-membered cyclicperiodate ester is formed in the first step, and in which the cleavage of the carbon-carbon bondoccurs in the second step during the decomposition of the ester. Overall, the diol is oxidized tothe two carbonyl compounds, while the periodate (iodine in the +7 oxidation state) is reduced toiodate (iodine in the +5 oxidation state).

I

O

O

O

OHOH

R

R

R

R

OHOH

OH

R

R

R

R

HIO4

H3IO

4

R

R

O

R

R

O

+ +

Figure 15.5 The accepted mechanism for periodate cleavage of vicinal diols involves the formation of a five-membered, cyclic periodate ester which subsequently decomposes to the two carbonyl compounds and iodate.

Evidence supporting this mechanism comes from kinetic studies of periodate cleavage ofrelated diols: although Z-1,2-cyclohexanediol (which can readily from a cyclic periodate ester)undergoes rapid cleavage with periodate, the E isomer (which does not readily from a cyclicperiodate ester) cleaves only very slowly.

CHO

CHOO IO(OH)3

OOHOH

CHO

CHO

O

OIO(OH)3

OH

OH

Like the periodate cleavage, the lead tetraacetate cleavage of diols requires a cyclicintermediate in most cases. However, there is also evidence that the cleavage may occur by anacyclic mechanism where a cyclic intermediate cannot form for steric reasons. For this reason,the lead tetraacetate cleavage of diols, which is also sometimes called the Criegee oxidationbecause it was developed by Rudolf Criegee (who also proposed the currently accepted


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mechanism for ozonolysis), is frequently preferred to the periodate method. In this reaction, thelead is reduced from the +4 oxidation state to the +2 oxidation state.

Pb(OAc)4/CH3CO2H

50C(64%)

CHOOH

OH

Problem 15.12. The oxidative cleavage ofmeso-2,3-butanediol by lead tetraacetate andperiodic acid both occur much more slowly than the oxidative cleavage of the ()-isomer under the same reaction conditions. Suggest a reason why this should be so.[It will help to use models here.]

Rudolf Criegee (1902-1975). See Chapter 8.

Reaction synopsis

Oxidation of Alcohols:

(a) To aldehydes and ketones [O]

R

R

O

R

R

OH

Reagents: Cr (VI) PCC/CH2Cl2, PDC/CH2Cl2, CrO32py/CH2Cl2, etc.or Me2SO (COCl)2/Me2SO/CH2Cl2/Et3N/-60C (Swern), etc.or TPAP/NMMO/CH2Cl2/r.t.or Mn (IV) MnO2/C6H6/ (allylic and benzylic alcohols only)

(b) To carboxylic acids [O]

R CO2HR CH2OH

Reagents: Cr (VI) K2Cr2O7/H2SO4/H2O, etc.Mn (VII) KMnO4/H2O.

Oxidative Cleavage of 1,2-Diols:RR

RR

HO OH[O]

O

R

R

O

R

R

+

Reagents: HIO4; Pb(OAc)4/CH3CO2H; CrO3; etc.

Cyclic esters may be intermediates in the cleavage of 1,2-diols by these oxidants; in cyclic systemscis-diols react faster than their corresponding trans isomers.

15.4 REDUCTIONS OF ALCOHOLS, ETHERS AND AMINES

Hydrogenolysis

Bonds located adjacent to a bond or an aromatic ring tend to be much more reactive thantheir saturated counterparts, as we have already seen with allyl and benzyl halides and alcohols.


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In fact, this extraordinary reactivity applies to most allyl and benzyl functional groups based on acarbon-heteroatom bond, as well as to -substituted carbonyl compounds. All these compoundsare susceptible to reactions in which the allylic carbon-heteroatom bond is replaced by a carbon-hydrogen bond. This reaction, which can be effected with a variety of reducing agents hydrogen and a catalyst, or a dissolving metal such as lithium in liquid ammonia, sodium inethanol, or zinc in acetic acid is called hydrogenolysis ("lysis by hydrogen").

[H]

R

X

R

O R

R X

R

R

R

X

R

R

R

R

H

R

O R

R H

R

R

R

H

R

R

R X: halogen, OH, OR, NH2, NHR, NR2,

O-CO-R, NH-CO-R, NR-CO-R, OTs,OP(O)(OR)2, etc.

[H]: H2/Pd-C, Li/NH3/ROH, Na/ROH,

Zn/CH3CO2H, Zn/HCl/H2O, etc.

The carbon-heteroatom bond affects the ease of hydrogenolysis so that the relative rates

follow the order:

NR3+ > OR > NR2

The cleavage of allyl and benzyl ethers generates only an alcohol and a hydrocarbon andhydrogenolysis can be carried out under neutral conditions. For these reasons benzyl ethers prepared using the Williamson ether synthesis have become popular functional groups for theprotection of alcohol hydroxyl groups in organic synthesis. Likewise, benzyl groups have beenused as protecting groups for amines.

H2/Ra-Ni/EtOH

HOH

(62%)

H2/Pd-C/EtOHCH3

N OOCH3

N

H2/Pd-C O

OMe3CSiMe2O

HO

O

OMe3CSiMe2O

O

Problem 15.13. The molecule below has three ether groups. Write the sequence ofreagents needed to cleave all but the methoxy group. Draw the structure of theproduct obtained after each step. [Hint alcohols are generally more reactive thanethers.]

OCH3

OTHPC6H5CH2O

How will this sequence of reactions need to be modified if all three ether groups mustbe cleaved to leave the triol? Why?


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Deoxygenation of Alcohols

It is sometimes important to be able to replace the hydroxyl group of an alcohol, soconsiderable effort has gone into developing methods for the removal of this functional group.Based on the reactions which we have already studied, one can devise a number of indirect ways

to accomplish this transformation. Some of these pathways are summarized below in Figure15.7; they typically involve an alkene (reduced by hydrogenation) or a carbonyl compound(reduced by the Wolff-Kishner reaction) as an intermediate.

R

R

R

R

R

R

Br

R

R

OTs

R

R

O

R

R

OH

Figure 15.7 Different pathways that may be used to remove the functional group from an alcohol.

Problem 15.14. Supply reagents or sequences of reagents which may be used tocomplete all the transformations shown in Figure 15.7. Where more than one reagentmay be used to effect a given transformation, give at least two alternatives.

More recently, new free-radical reductions of alcohols based on the reduction of sulfur-basedderivatives such as xanthates have been developed, and these reactions are rapidly gainingpopularity. When a compound containing a CS bond is treated with the reducing agent tri-n-butyltin hydride (tri-n-butylstannane) under ultraviolet light (h) or a free-radical initiatorsuch as a peroxide (ROOR) or azobisisobutyronitrile (AIBN), the free-radical reaction whosemechanism is shown in Figure 15.8 occurs. Just like other free-radical additions to bonds,which we briefly discussed in Chapter 8, the addition occurs through the alkene LUMO.

The reduction of 1,2-diols is most often carried out with a view to forming an alkene ratherthan an alkane. The reaction may be carried out as a reductive elimination of exactly the sametype as we discussed in Section 8.8, where the two hydroxyl groups are first converted tosuitable leaving groups and then treated with a metal. In fact, such deoxygenation reactions arealso important reactions of other difunctional hydroxy compounds, especially those in whichthere is a good leaving group (e.g. a halogen) at the carbon of the alcohol (such adeoxygenation is a dominant side-reaction in cases where one attempts to prepare a Grignardreagent from ethers such as 2-bromo-1-methoxyethane). These deoxygenations proceed, as wediscussed discussed earlier, with anti stereochemistry. The treatment of the xanthate esters of1,2-diols also leads to alkenes by a free-radical mechanism.


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SnBu3

+HR

Bu3Sn H

RO

Sn(C4H9)3S

SCH3

OR

S

SCH3

Sn(C4H9)3

OR

S

SCH3

LUMO

HOMO(SOMO)

Sn

C

RO

CH3S

S

Figure 15.8 The mechanism of the tri-n-butylstannane reduction of an alkyl methyl xanthate involves aninitial addition of the tri-n-butylstannyl radical to the carbon-sulfur bond of the xanthate ester. The frontierorbitals for this reaction are the carbon-sulfur * orbital (the LUMO) and the sp3 hybrid orbital on the tin (theHOMO or SOMO) which contains the unpaired electron.

Problem 15.15. Design two distinct methods for the protection of an alkene double bondas a cyclic ketal and for its regeneration with its original stereochemistry.

Reaction synopsis

Deoxygenation of Alcohols: [H]

R

R

HR

R

R

OHR

Reagents: 1) PCC/CH2Cl2, 2) H2NNH2/KOH/HOCH2CH2OH/;(if 1 or 2 ROH)

or 1) TsCl/py, 2) KOCMe3/, 3) H2/Pd-C;or 1) TsCl/py, 2) LiAlH4/Et2O/ (if 1 or 2 ROH);

or 1) KOH/CS2, 2) Bu3SnH/AIBN/h

Hydrogenolysis: [H] R

RR

R

H

RR

R

R

X

R

R

X: OH, OR, OCOR, NH2, NHR, NR2, NR3+, NHCOR, NRCOR, SH, SR,halogen, etc.

Reagents: H2/Pd-C; Li/NH3/ROH; Na/EtOH; etc.

15.5 REARRANGEMENT REACTIONS

Primary amines react with reagents such nitrous acid (HONO) or nitrosyl chloride (NOCl) reagents known as nitrosating agents to form diazonium ions, ions which contain the N2+

group. Unlike many other amine derivatives, alkyldiazonium ions readily enter into SN1 andSN2 reactions. The reaction between an amine and a nitrosating agent is actually a reactionbetween the amine and the nitrosonium ion obtained from the nitrosating agent.


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N

O

HO N O

N O

H

N

O

H2O

nitrosonium ion

The diazonium group leaves as nitrogen gas (a particularly stable species consider the earth'satmosphere!), so that it is a very effective leaving group. Moreover, the cleavage of the carbon-

nitrogen bond of an alkyldiazonium ion is a highly exothermic reaction with a very low activationenergy, so the loss of nitrogen from a diazonium ion (known as deamination) occurs extremelyreadily. Deamination of a primary amine is one of the most efficient methods for the formationof carbocations. Carbocations generated by this reaction tend to be highly reactive because thecleavage of the carbon-nitrogen bond of the diazonium ion occurs more rapidly than solventreorganization to help stabilize the carbocation as it forms. Such cations are often termed "hot"carbocations.

NO

(NaNO2/HCl)RR NH2 + N2R N N

R N N

diazonium ion

As expected for a reaction involving a carbocation intermediate, deamination reactions areextremely prone to rearrangements. One of the more useful applications of the deaminationreaction is the Demyanov rearrangement, a typical example of which is shown below. TheDemyanov rearrangement has been widely used for ring expansion and ring contraction in cycliccompounds, especially small-ring compounds.

OHCH2OHCH2NH2NO

+H2O

Problem 15.16. The Demyanov rearrangement involves the migration of an alkyl groupto an electron-deficient carbon. The Baeyer-Villiger, Beckmann, and Schmidtrearrangements (Chapter 13.4) involve migration of an alkyl group to an electron-

deficient heteroatom. Based on your knowledge of the migratory aptitudes of alkylgroups in the Baeyer-Villiger rearrangement, predict the major rearranged productwhich will be formed when each of the following amines is treated with nitrous acid.

(b)

NH2

(c)

NH2

H

H

NH2(a)

Pinacol and Tiffeneau-Demyanov rearrangements

When a molecule contains two functional groups in close proximity to each other, the

chemistry typical of each individual functional group occurs, but the molecule may (andfrequently does) also exhibit unique reactivity that is solely due to the close spatial relationshipbetween the two functional groups. As we saw in Chapters 7 and 8, this is certainly true fordienes. It is also true for polyhydroxy compounds and aminoalcohols, especially if the twofunctional groups are involved in a 1,2- or a 1,3- relationship relative to each other.

The acid-catalyzed dehydration of alcohols and the diazotization of primary amines both leadto mixtures of alkenes in which the Zaitsev alkene predominates. However, when a 1,2-diol istreated with a protic acid or a Lewis acid, the product is not the alkene or diene, but is, rather, acarbonyl compound. This reaction, which is known as the pinacol rearrangement, was firstreported by German chemist Rudolf Fittig in 1860 one year after he reported the discovery of


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the pinacol reaction. A related rearrangement, developed by French chemist Marc Tiffeneau,results when a -aminoalcohol is treated with a nitrosating agent. Both reactions proceed bystrictly analogous mechanisms (Figure 15.9). In the top sequence of steps in Figure 15.9, thereaction is shown as proceeding by an E1-like mechanism for clarity: the leaving group departs,and the intermediate cation rearranges to a resonance-stabilized oxonium ion before the proton islost. However, in most cases the rearrangement occurs so that the group anti to the leaving

group migrates wherever possible. From this observation it has been deduced that therearrangement and the loss of water or nitrogen are usually concerted as shown in the bottomsequence of reactions in Figure 15.9, and that the free carbocation intermediate never actuallyexists.

X=OH, NH2 Y=OH2+, N2+

R

R OH

YR

R

R

RX

OHR

RR

R O

R

RR

R OH

YR

R

R

R OHR

RR

R OH

R

R

R

R OH

R

R

Figure 15.9 The accepted mechanism of the pinacol and Tiffeneau-Demyanov rearrangements.

In more conformationally flexible systems where more than one of the groups at the carbon to the leaving group can be anti to the leaving group, the migratory aptitude of the groups issimilar to the migratory aptitude of alkyl groups in the Baeyer-Villiger reaction. When the twohydroxyl groups of a 1,2-diol are not equivalent, the carbon-oxygen bond which breaks in thepinacol rearrangement is the one which will lead to the more stable cation.

H2SO4/(70%)

OHO OH

(100%)

H2SO4/

O=CH

H

MeMe

Me

HOMe

OH

The pinacol and Tiffeneau-Demyanov rearrangements have been used quite widely and quitesuccessfully in synthesis, especially for carrying out such transformations as ring expansions andring contractions. The ready availability of the -aminoalcohols by the reduction of cyanohydrinshas made the Tiffeneau-Demyanov rearrangement especially popular for ring expansion ofketones.

conc. H2SO4

0C(100%)

OOH

OH

70% HClO4/-20C

(81%)O

OH

OH

HCN LiAlH4 HONO

O

NH2

OHOH

CNO


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Sample Problem 15.7. Draw the structure of the final organic product expected from thefollowing reactions or reaction sequences. Where appropriate, specify stereochemistry.If more than one regioisomeric product may be formed, give reasons for your choice.

1) Me3SiCN/CH2Cl2

2) LiAlH4/Et2O3) NaNO2/HCl/H2O

(a)

O

(b)HONO

NH2H

OH

H

Answers:

(b)

H CHO

H

(a)

O OSiMe3NC

2) 3)1)

OOSiMe3

NH2

In (b), either the alkyl group or the hydrogen atom to the hydroxyl group may migrate.Because the alkyl group is anti to the nitrogen (and, therefore, the leaving group), it is

the alkyl group which migrates, and the major product should be the aldehyde.

Problem 15.17. Draw the structure of the final organic product expected from thefollowing reactions or reaction sequences. Where appropriate, specify stereochemistry.If more than one regioisomeric product may be formed, give reasons for your choice.

(a)2) LiAlH4/Et2O

3) NaNO2/HCl/H2O

1) Me3SiCN/CH2Cl2O (b) O

1) Me3SiCN/CH2Cl2

2) LiAlH4/Et2O

3) NaNO2/HCl/H2O

(c) CH22) H2SO4/0C

1) OsO4/NMMO/CH2Cl2(d)

CH2 2) H2SO4/0C

1) OsO4/NMMO/CH2Cl2

Nikolai Yakovlevich Demyanov (1861-1938). Demyanov was born in the city of Tver, northwest ofMoscow, and he studied under Markovnikov at the University of Moscow. Following his graduation, hewas appointed to the faculty of the Petrine Forestry and Agricultural Academy (later Moscow AgriculturalUniversity), where he became professor in 1894. From 1935 until his death, he was laboratory head of theInstitute of Organic Chemistry of the USSR Academy of Science. Much of Demyanov's fame derivesfrom the reactions between nitrosating agents and amines. His first research on the reaction betweennitrous acid and amines was part of the work for his master's degree in 1895; six years later he beganresearch into the rearrangement which bears his name. He also carried out research into small ringcompounds: he was the first to prepare methylenecyclopropane, methylenecyclobutane andvinylcyclopropane. He wrote textbooks in plant chemistry and organic chemistry. In 1924, he wasawarded the Butlerov Prize of the Russian Academy of Science.

Marc Emile Pierre Adolphe Tiffeneau (1873-1945). Tiffeneau was one of eight children born to asecond-generation milliner just north of Paris. He graduated with the gold medal (which he promptlypawned to get the money for a trip to the Wagner Theatre in Bayreuth) from the Facult de Pharmacie ofthe University of Paris in 1900. For the next decade, he worked as a pharmacist in several hospitals andcarried out research that led to his D.Sc. in 1907 and his M.D. in 1910 from the University of Paris. From1924 until his death, he was associated with the University of Paris, first as Professor of chemistry in theFaculty of Science, then in the Faculty of Medicine, serving as Dean of Medicine from 1939-1940. Nearlyhalf of his published work appeared in medical, biological and pharmaceutical journals, applying chemistryto medical problems. He was one the small group of chemists that helped the Socit Chimique de Francesurvive World War I. Tiffeneau held the major office of every French learned society to which hebelonged, being made Chevalier (1922) and Officier (1938) of the Legion d'Honneur.


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Acid-catalyzed rearrangements of epoxides

When an epoxide is heated to 200C or so, the ring opens and the product is a carbonylcompound isomeric with the epoxide. This same rearrangement is catalyzed by acids, especiallywhen both carbon atoms of the epoxide ring are substituted and when there is no nucleophilepresent to react with the oxonium ion or when the reaction conditions reduce the rate of the

nucleophilic ring-opening reaction. For example, when cyclohexene oxide (where both oxiranecarbons are substituted) is treated with magnesium bromide (a weak Lewis acid) in diethyl ether,the major organic product is cyclopentanecarboxaldehyde.

OMgBr2

Et2OCH=O

This particular reaction can cause complications in the reactions between epoxides andGrignard reagents due to the following equilibrium:

2 RMgX MgX2 + R2Mg

The dialkylmagnesium formed in this reaction reacts with epoxides in the "normal" manner to

give the ring-opened product, but the magnesium halide produced reacts to cause therearrangement first, and the major organic products then arise from the reaction between thecarbonyl compound and the Grignard reagent. Because the lithium- and copper-basedorganometallic reagents avoid this problem, they are usually preferred for ring opening reactionsof epoxides.

OMeMgBr

Et2OCH2OH

OH

CH3

OH

CH3

+ +

OH

+OHO MeMgBr

Et2O

The mechanism of the rearrangement reaction may be rationalized as illustrated in Figure15.7. This mechanism relies on the fact that the strain inherent in the three-membered ringprovides the driving force for a rearrangement that would not otherwise occur. The oxoniumion intermediate can be represented as the resonance hybrid of the two canonical forms shown.In the presence of a nucleophile that can rapidly trap the oxonium ion by nucleophilicsubstitution, the "normal" substitution product is obtained. However, if the nucleophile does notreact rapidly with the oxonium ion (and remember that secondary alkyl halides and oxonium ionsdo not react rapidly by the SN2 mechanism), the rate of the rearrangement reaction becomescompetitive with the substitution.

A = H+, MgX2, AlR3,

BX3, etc.

O

R

R R

RO

R

R R

R

A

O

R

R R

R

A A

O

R

R

R

R

A

O

R

R

R

RO

R

R

R

R

Figure 15.7 Proposed mechanism for the acid-catalyzed rearrangement of epoxides to carbonyl


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compounds.

The rearrangement reaction can be easily rationalized on the basis of the carbocationcanonical form of the oxonium ion. If you examine this carbocation closely, you will note that itis the same cation which we proposed as the intermediate in the pinacol rearrangement

and the Tiffeneau-Demyanov rearrangements. So, the key step of this reaction is the sameas that of these two rearrangement reactions which we have already studied, and the product is

the same. It is reassuring to know, also, that the rearrangement of the epoxide occurs in such away that one can predict the major product on the basis of the more stable carbocation canonicalform. Where more than one group may migrate, the migratory aptitude is the same as for theBaeyer-Villiger rearrangement (Chapter 11.4).

Problem 15.18. Write a mechanism that could be used to account for the formation ofthe products in the reaction between methylmagnesium bromide and 2,3-dimethyloxirane. Do the same for the formation of the first two products shown in thereaction between methylmagnesium bromide and cyclohexene oxide.

Reaction synopsis

Deamination. NO

R

R

NH2R

R

R

R

R

R

N2R

Reagents: HNO2, NaNO2/HCl/H2O; NOCl; RONO.

Reaction involves intermediate diazonium ion which rapidly decomposes by loss of nitrogen to"hot" carbocation; products may be substitution or elimination products by SN1 or E1 pathways.

Demyanov Rearrangement.NH2 OH OH

HNO2+

A special case of deamination which involves the rearrangement of a primary cation to give anequilibrium mixture of products.

Pinacol Rearrangement: RR

HO OH

RR R R

OR

R

Reagents: H2SO4; TsOH/C6H6; etc.Migratory aptitude of groups same as Baeyer-Villiger rearrangement; in geometrically fixed systems,group anti to leaving group migrates. Unsymmetrical diols lose OH group which would give most

stable carbocation as intermediate.

Tiffeneau-Demyanov Rearrangement:RR

H2

N OH

RR R R

OR

RNO

Reagents: HONO, NOCl/py, etc.Rearrangement strictly analogous to pinacol rearrangement.


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15.6 SUMMARY

Alcohols are most often prepared from carbonyl compounds by nucleophilic addition oforganometallic or enolate anion nucleophiles, or by reduction. The addition of a Grignardreagent to formaldehyde produces a primary alcohol with one carbon more than the Grignard

reagent; addition to other aldehydes produces secondary alcohols; Grignard addition to ketonesproduces tertiary alcohols. The reaction between a Grignard reagent and an epoxide is bestcarried out in the presence of a copper catalyst; the product is the alcohol formed by ringopening of the epoxide at the lesws substituted carbon. The aldol addition reaction produces -ketoalcohols. Reduction of carbonyl compounds with a divalent metal such as magnesium in theabsence of a proton source gives vicinal 1,2-diols, also known as pinacols. Reduction ofaldehydes with complex metal hydrides gives primary alcohols; reduction of ketones givessecondary alcohols.

Alcohols may be formed by hydration or hydroxylation of alkenes. Acid-catalyzed additionof water or oxymercuration-demercuration of alkenes gives the Markovnikov alcohol. Acid-catalyzed hydration may lead to rearrangements; oxymercuration-demercuration usually doesnot. The first step of the oxymercuration-demercuration is an anti addition to the alkene, but the

second step is stereorandom. Addition of water to alkenes with anti-Markovnikovregiochemistry is accomplished by hydroboration-oxidation; the reaction gives stereospecific synaddition. Hydroxylation of alkenes gives 1,2-diols; osmium tetroxide or alkaline potassiumpermanganate give the syn hydroxylation product; epoxidation and ring-opening of the epoxidegive the anti hydroxylation product.

Ethers are formed by the Williamson ether synthesis: SN2 substitution of an alkyl halide by analkoxide anion or by the Mitsunobu reaction between two alcohols in the presence oftriphenylphosphine and an azodicarboxylate ester. Solvomercuration-demercuration of alkenesgives ethers with Markovnikov regiochemistry. Epoxides are formed by direct epoxidation ofalkene double bonds with peracids or with tert-butyl hydroperoxide and a transition metalcatalyst. Sharpless asymmetric epoxidation is a titanium-catalyzed epoxidation of allylic alcoholsusing tert-butyl hydroperoxide and a dialkyl tartrate ester as a chiral adjuvant; the absolute

configuration of the epoxide can be predicted based on the chirality of the tartrate ester.Amines are formed by reduction of nitro compounds, nitriles or azides, by nucleophilicsubstitution of alkyl halides as in the Gabriel synthesis, or by reductive amination of carbonylcompounds or reduction of amides or imines with complex metal hydrides. Tertiary amines aresynthesized by reductive amination with formaldehyde and formic acid (the Eschweiler-Clarke,Wallach and Leuckart reactions).

Alcohols undergo elimination under acid-catalysis (typically by the E1 mechanism) or theymay be converted to esters or xanthates which undergo pyrolytic Ei elimination. Amine N-oxides also undergo pyrolytic elimination. The stereochemistry of pyrolytic eliminations is syn.Nucleophilic substitution of alcohols is best carried out by the Mitsunobu reaction.

Primary alcohols are oxidized to aldehydes by chromium (VI) reagents in the absence of acidor water, or by dimethylsulfoxide-based sulfonium reagents as in the Swern and Moffatt-Pfitzner

reactions. Recently, tetrapropylammonium perruthenate has been discovered as a usefuloxidizing agent for alcohols. Potassium permanganate or cromic acid oxidize primary alcohols tocarboxylic acids. Vicinal diols are cleaved to carbonyl compounds by periodic acid or by leadtetraacetate. Allylic and benzylic alcohols are selectively oxidized with manganese dioxide.

In the presence of acids, 1,2-diols rearrange to ketones; the reaction is known as the pinacolrearrangement. The migratory aptitude of the alkyl groups is similar to that for the Baeyer-Villiger rearrangement. Amines rearrange in the presence of a nitrosating agent such as nitrousacid or nitrosyl chloride; the reaction is known as the Demyanov rearrangement. -Aminoalcohols rearrange to ketones under similar conditions; this rearrangement is known as theTiffeneau-Demyanov rearrangement.


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Allylic and benzylic alcohols, ethers and amines may be reduced to the hydrocarbon byhydrogenation over palladium or by Birch reduction. The reaction is called hydrogenolysis.

15.7 GLOSSARY OF IMPORTANT TERMS

Chugaev elimination pyrolytic syn elimination of a xanthate ester to give an alkene. Thereaction proceeds by the Ei mechanism.

Cope elimination pyrolytic syn elimination of an amine N-oxide to give an alkene. Thereaction occurs by an Ei mechanism.

Darzens condensation form

Alcohols II

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