Alcohols II

CHAPTER 15
ALCOHOLS, ETHERS AND AMINES II: SYNTHESIS, REDOX REACTIONS AND ELIMINATION 15.1 SYNTHESIS OF ALCOHOLS, ETHERS AND AMINES
Alcohols are important industrial chemicals as well as being useful intermediates in the research 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 starting materials, 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 may be 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 a new carbon-carbon bond is the Grignard synthesis and its analogs. In this reaction, as you may recall, a carbonyl compound reacts with an organometallic reagent (typically a Grignard reagent or an alkyllithium) to give an intermediate alkoxide from which the alcohol is then liberated by mineral acid. Primary alcohols are formed from formaldehyde, secondary alcohols from other aldehydes, and tertiary alcohols from ketones.
CHO 1) CH2=CH-MgBr 2) H3O+ OH
O 1) CH3MgBr 2) KOH/H2O OCOCH3 OH HO
Another major method for the synthesis of alcohols especially 1,3-diols and polyols is the aldol addition reaction, which we discussed at considerable length in Chapter 10.6. Since its resurgence as a method for the stereocontrolled formation of new carbon-carbon bonds, the aldol addition reaction has been widely applied to the synthesis of polyhydric alcohols. In the examples below, the relatively bulky group at the position in the ketone ensures that the Z enolate is formed, and that the anti aldol predominates in the product mixture.
O O 1) LDA/THF/-78C 2) CHO OH
O 1) LDA/THF/-78C 2) CHO
OH
The third major method for the formation of alcohols by formation of a carbon-carbon bond is the pinacol reaction, in which two carbonyl groups are coupled under the influence of a metal.
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This reaction, which gives the 1,2-diol, is usually used only for to intramolecular coupling, or for the synthesis of symmetrical 1,2-diols.
O Mg/Et2O OH HO
Sample Problem 15.1. Write a reaction or sequence of reactions which may be used to prepare 4,5-dimethylhexane-2,4-diol from acetone and any other organic or inorganic compounds needed. Ignore stereochemistry unless it is explicitly specified. Answer:
O 1) LDA/THF/-78C 2) CH3CHO O OH 1) (CH3)2MgBr (excess) 2) H3O+ OH OH
Note that at least two equivalents of isopropylmagnesium bromide are required in the second step. The first equivalent of the Grignard reagent will react with the hydroxyl group of the alcohol in an acid-base reaction to give the magnesium alkoxide and propane; the second equivalent reacts much more slowly, and gives the magnesium alkoxide of the tertiary alcohol. The reaction between Grignard reagents and alkoxides like those formed in the first step often require heating to give adequate yields of product. 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 other organic or inorganic compounds needed. Ignore stereochemistry unless it is explicitly specified. (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 O R R-M R R R OH
M:
Mg (Grignard reagent); Li; Zn (with aldehydes); etc.
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SYNTHESIS, REDOX REACTIONS & ELIMINATION
569
Aldol Addition:
O R1 R2 1) base 2) R3 CHO R1 R2 O OH R3
Base: LDA (or LICA or LHMDS or NaHMDS, etc.)/THF/-78C
Pinacol Synthesis of 1,2-Diols:

R O R [H] R HO R R OH R
[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 of carboxylic acids, provides another important method for the synthesis of alcohols from carbonyl compounds. As discussed in Chapter 10, the most useful reagents for carrying out this transformation are the complex metal hydrides, lithium aluminum hydride (LiAlH4, or LAH) and sodium borohydride (NaBH4). Sodium borohydride is the less reactive reagent; it will not react with 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 most widely-used reagent. Because sodium borohydride and lithium aluminum hydride are also bases that 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.
NaBH4/CH3OH OH O O C OCH2CH3 1) DIBAL-H/hexane 2) HCl/H2O OH H
Hydration of alkenes The conversion of alkenes to alcohols is carried out by adding water across the double bond, a reaction known as hydration which we discussed at length in Section 7.6. The antiMarkovnikov 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 alkenes can be carried out either by simple acid-catalyzed addition of water across the double bond, or by the oxymercuration-demercuration reaction discussed in Section 9.5. Of the two, the acidcatalyzed hydration reaction is the more prone to give rearranged products.
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1) BH3THF CH3 CH3 CH3 2) H2O2/OH/H2O CH3 CH3
OH H
1) Hg(OCOCH3)2/THF/H2O 2) NaBH4/NaOH/H2O/THF OH H2SO4/H2O
(mixture of stereoisomers) CH3
CH3
CH3 OH
Sample Problem 15.2. Write a reaction or sequence of reactions which may be used to prepare the following alcohols from the designated starting material. Where more than one 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:
OH OH OR H+/H2O 1) Hg(OCOCH3)2/THF/H2O 2) NaBH4/NaOH/H2O
(a)
(b)
1) BH3THF 2) H2O2/NaOH/H2O OH
(c)
1) (CH3)2CHMgBr 2) H3O+
OH
CHO
(d)
NaBH4 CH3OH
CH2OH OR
CHO
1) LiAlH4/Et2O 2) H3O
+
CH2OH
Problem 15.2. Write a reaction or sequence of reactions which may be used to prepare the following alcohols from the designated starting material. Where more than one answer 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 at considerable length (Chapter 8). As we saw, the hydroxylation of alkenes can occur with either anti stereochemistry or syn stereochemistry, depending on the reagent. Some typical examples are given here to demonstrate this method for 1,2-diol formation. Note that in six-membered rings, anti hydroxylation occurs by 1,2-diaxial addition.
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571
syn hydroxylation
OsO4/Me3COOH Me3COH/25C OH OH
anti hydroxylation
1) HCO2OH/CH2Cl2 2) NaOH/H2O OH () OH OH 1) HCO2OH/CH2Cl2 2) NaOH/H2O OH but not OH OH
Problem 15.3. Which reagent or sequence of reagents should be used to accomplish the following transformations?
OH OH
(a)
OH
(b)
OH
(c)
HO OH
HO
(d)
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 solvomercurationdemercuration. Acid-catalyzed addition of alcohols to alkenes is especially facile when the alkene is electron-rich (e.g. an enol ether). Perhaps the best example of this is the reaction which we 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, and yet they easily reconverted to the alcohol in dilute aqueous acid. Consequently, THP ethers are often used as protecting groups for alcohols in multistep syntheses.
O (DHP) OH TsOH/CH2Cl2 O OTHP O
In the solvomercuration-demercuration reaction, an alcohol is used as the solvent for the reaction instead of the aqueous THF usually used in the oxymercuration-demercuration, and the mercuric acetate is replaced by mercuric trifluoroacetate (the anion is less nucleophilic, and does not 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 the alkyl groups are tertiary.
Me 1) Hg(OCOCF3)2/EtOH 2) NaBH4/H2O/NaOH Me OEt
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Sample Problem 15.3. Write five different reactions or sequences of reactions involving the formation of at least one carbon-oxygen bond which may be used to prepare tertbutyl methyl ether. Answers:
1) Hg(OCOCF3)2/MeOH 2) NaBH4/NaOH/NaOH H+/MeOH OCH3 OR
OMe
OR
OH
1) Na/ 2) MeI 1) DEAD/(C6H5)3P 2) Me3COH
OMe
OR
Br
MeOH Ag2O
OMe
OR
MeOH
OMe
BUT NOT
Br
MeONa
OMe
(This reaction will give the alkene by E2 elimination instead of SN2 substitution)
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 the following ethers: (a) 1-methoxy-1-ethylcyclopentane. (c) isobutyl cyclohexyl ether. Formation of cyclic acetals and ketals Alcohols with a single hydroxyl group are called monohydric alcohols, while those with two or more hydroxyl groups are called polyhydric alcohols. A special case of the formation of ethers is the formation of cyclic acetals and ketals from 1,2- and 1,3-diols. We have already been introduced to acetals and ketals as intermediates in synthesis for the protection of carbonyl groups during reactions to which they are normally susceptible. The same functional group can also be used to protect diols. Thus, the reaction between a 1,2-diol or a 1,3-diol and an aldehyde or ketone usually leads to the rapid formation of the cyclic acetal or ketal. The reaction itself is carried out under conditions identical to those already discussed in Section 11.3. As illustrated in the second example below, the use of alternative acid catalysts to form cyclic ketals has become very popular in recent years: in the example given, anhydrous copper (II) sulfate serves both as a mild acid catalyst and as a dehydrating agent to drive the equilibrium reaction to completion.
HO H OH OH O R R OH OH Me2C=O/CuSO4/ [R = CO2CH3] R O R Et2C=O THF/TsOH HO H O O O O (74%)
(b) 3-ethoxy-3-methylhexane.
(90%)
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-diol substructure, 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 is formed as 10% of the product mixture. Explain.
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573
SYNTHESIS OF EPOXIDES Despite the strain inherent in the three-membered ring, epoxides are remarkably simple to make. Three-membered rings can be formed by forming one bond a three-atom acyclic compound 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 in an addition to an alkene to give the three-membered ring.
R X R R R O H base R R O R R "O" R R R R
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 close the three-membered ring need not be part of the starting material, but it can be formed by the reaction between a carbon nucleophile and a carbonyl compound if the nucleophile also carries a leaving 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 the aldol, which undergoes a rapid intramolecular SN2 displacement of the halogen to give the epoxide. This reaction is known as the Darzens condensation.
O H R Z X base O R X Z R O R Z O R X R R Z R O O O R R
O (83-95%) CO2C2H5
+
Cl
CO2C2H5
KOCMe3 Me3COH
A more recent variant of the Darzens condensation relies on using a sulfur ylide as the nucleophile. The intermediate alkoxide formed by addition of the carbanion to the carbonyl group undergoes intramolecular SN2 displacement of a dialkyl sulfide to give the epoxide.
CH2 O O CH2 SMe2 SMe2 O O (89%)
(80%)
Georges Auguste Darzens (1867-1954). Darzens was born in Moscow, but was educated and spent his entire career in France. From 1886-1888 he was a student at the cole Polytechnique of the Universit de Paris, where he was appointed as Assistant Professor of Physical Science in 1895. In 1913, he was appointed Professor of Chemistry at the cole Polytechnique, a position he held until his retirement in 1937, 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 glycidic ester synthesis and the acylation of alkenes by acid chlorides. He served the French government in several advisory capacities during his lifetime, and won every major prize conferred by the French scientific societies.
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Sample Problem 15.2. Draw the structure of the major organic product that should be obtained from each of the following reactions:
OH
(a)
Br O
K 2CO3/EtOH
(b)
CH2
SMe2
DMSO-THF/-78C
(c) Answers:
H O H
BrCH2CO2Me KOCMe3
(d)
BrCH2
CN
KOCMe3/Me2SO
(a)
()
(b)
()
(c)
CO2CH3
(d)
O CN
(); mixture of E and Zisomers
(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 remained unchanged. (b) The presence of the double bond in conjugation with the carbonyl group does not alter the course of the reaction. The ylide reacts with the conjugated enone to give the corresponding 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 of the following reactions.
OH
(a)
Br CHO
K 2CO3/EtOH
(b)
CH2
SMe2
DMSO-THF/-78C
(c)
BrCH2CO2Me KOCMe3
(d)
BrCH2 O
CN
KOCMe3/Me2SO
CHO
(e)
CH2
SMe2
DMSO-THF/-78C
(f)
CH2
SMe2
DMSO-THF/-78C
Epoxidation of alkenes The epoxidation of alkenes is a reaction which we have already studied in considerable depth in Chapter 10.2, and there are numerous reagents which can be used to form epoxides from alkenes. The most common method for forming epoxides is by oxidation of alkenes with organic peroxyacids (or peracids). The reaction occurs readily in non-hydroxylic solvents and gives the epoxide 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 by peracids is facilitated by electron-withdrawing groups on the peracid, and by electron-releasing groups on the alkene. This is consistent with a frontier orbital overlap between the peracid LUMO, whose energy would be lowered by electron-withdrawing substituents, and the alkene
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575
HOMO, whose energy would be raised by electron-donating substituents. Epoxidation by peracids is also facilitated by non-polar solvents, and retarded by solvents which can form hydrogen bonds to the peracid.
m-CPBA/CH2Cl2
O O
(77%) O
Epoxidation of allyl alcohols The functional group of an allylic alcohol affects both the regiochemistry and the stereochemistry of the epoxidation reaction due to its ability to form hydrogen bonds to the reagent. The hydroxyl group affects regiochemistry by directing direct the epoxidizing agent to the double bond nearest to itself whether the oxidizing agent is a peracid or a metal-based reagent. The effects of the hydroxyl group on the stereochemistry of epoxidation is nicely illustrated by cyclic allylic alcohols: peracids oxidize cyclic allylic alcohols to the epoxide where the epoxide oxygen is cis to the hydroxyl group. When the hydroxyl group is esterified the stereochemistry 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 acid to give predominantly (90:10) the epoxide where the epoxide oxygen is cis to the hydroxyl group. Its acetate ester, on the other hand, gives a 57:43 mixture of products in which the major isomer is the one with the epoxide oxygen trans to the ester group.
OH C6H5CO2OH C6H6/5C H O H OH (78%) OH H O H
(8%)
OCOCH3 C6H5CO2OH C6H6/5C H O H
OCOCH3 (16%)
OCOCH3
H O H
(22%)
These observations have been rationalized on the basis of a transition state in which the peracid is hydrogen bonded to the alcohol hydroxyl group. According to this model, the peracid forms a hydrogen bond with one of the peroxy oxygens of the peracid, resulting in the peracid being directed to the same face of the double bond.
O R O O H H O
Perhaps the most important reaction of allylic alcohols to have emerged in the last thirty years is the Sharpless asymmetric epoxidation. This reaction, which we studied in some detail in Chapter 10, is certainly worth reviewing here. In the Sharpless epoxidation an allylic alcohol is epoxidized with tert-butyl hydroperoxide and a titanium alkoxide in the presence of a chiral dialkyl tartrate ester (which is also a chiral diol). The real importance of this reaction lies in its power of prediction: based on a simple model, shown below in Figure 15.6, one can predict with a high level of confidence just what the absolute configuration of the final epoxide will be.
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"O" D-(-)-diethyl tartrate ["unnatural isomer"] Ti(Oi-Pr)4/Me3COOH OH L-(+)-diethyl tartrate ["natural isomer"] "O" CH2Cl2/-20C (+)-DET O OH (-)-DET O
OH
Figure 15.6 The model for predicting the absolute configuration of epoxides in the Sharpless asymmetric epoxidation of allylic alcohols. In the Sharpless epoxidation model, the allylic alcohol is oriented so that the double bond is written 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 the oxygen is delivered to the bottom face of the double bond, and epoxidation in the presence of the unnatural, 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 of the following reactions. (a)
Ti(Oi-Pr)4/Me3COOH OH (+)-DET/CH2Cl2/-20C
(b)
Ti(Oi-Pr)4/Me3COOH OH (+)-DET/CH2Cl2/-20C
OH
(c)
Ti(Oi-Pr)4/Me3COOH (+)-DET/CH2Cl2/-20C
(d)
OH
Ti(Oi-Pr)4/Me3COOH (+)-DET/CH2Cl2/-20C
SYNTHESIS OF AMINES Reduction The reduction of other functional groups is the basis of several of the more versatile methods for the synthesis of amines. Among the functional groups which may be reduced to an amino group are the cyano group, whose reduction we discussed at length in Section 11.5, the oximino group of oximes, and the imine group. In each of these groups there is a carbon-nitrogen bond which 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 either by catalytic hydrogenation (which reduces alkenes rapidly and ketones slowly) or by complex metal hydrides (which reduce carbonyl groups rapidly and alkenes either slowly or not at all). Some typical examples follow.
CN 1) LiAlH4/Et2O/ CH3 2) H3O+ CH2NH2 CH3
H2/Pd-C EtOH N OH NH2
Nitriles and oximes are reduced to primary amines either by catalytic hydrogenation or by lithium aluminum hydride. The complex metal hydride is usually preferred for the reduction of
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577
nitriles, and catalytic hydrogenation usually works better with oximes. Oximes are also readily reduced by active metals in the presence of a proton source (e.g. lithium in liquid ammonia or sodium in ethanol or zinc in hydrochloric acid).
Na/EtOH/ N OH NH2
+
NH2
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 is an especially important method for the synthesis of amines where the amino group is directly bonded to an aromatic ring. The discovery of this reduction by Russian chemist Nikolai Zinin in 1842 was pivotal to the development of the aniline dye industry with all the advances in synthetic organic chemistry that ensued.
NO2 O 2N Me Fe/HCl/H2O/EtOH/ H2N NH2 Me
N3
CO2CMe3
H2/Pd-C MeOH
H2N
CO2CMe3
(75-82%)
Nikolai Nikolaevich Zinin (1812-1880). Zinin, who was orphaned within days of his birth in Shusha, near the Persian border, was raised by his uncle. Zinin entered Kazan' University, graduating with a 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 the distinction that Zinin did under these circumstances. In 1837 Zinin was sent abroad to study chemistry in preparation for his teaching career, and it was while in Liebig's laboratory in Giessen that he first carried out experiments in organic chemistry. On his return to Russia, Zinin was appointed to the chair of chemical technology at Kazan' (the chemistry chair had been filled by Karl Klaus, the discoverer of ruthenium, in his absence). At Giessen Zinin discovered the cyanide-catalyzed dimerization of benzaldehyde to benzoin, but it was his first independent work the reduction of aromatic nitro compounds to aromatic amines that led no less a chemist than A.W. von Hofmann himself to proclaim that "If Zinin had done nothing more than to convert nitrobenzene to aniline, even then his name should be inscribed in golden letters in the history of chemistry." In 1848 Zinin moved to St. Petersburg as Professor of Chemistry at the Medical-Surgical Academy. During his career, Zinin served as mentor to two of the most important Russian organic chemists of the next generation, Aleksandr Butlerov and the composer-chemist Aleksandr Borodin.
Reductive amination The condensation reaction between a carbonyl compound and ammonia or primary amines gives an imine as the major product, and the condensation with a secondary amine gives an enamine. Like the polar bond of the carbonyl compounds, the polar C=N bond of an imine or 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 called reductive amination. In modern variants of the reductive amination, the carbonyl compound is treated with ammonia or an amine in the presence of a hydride reducing agent (sodium cyanoborohydride, NaBH3CN is probably most widely used) or hydrogen and a palladium catalyst. The product of the reductive amination is an amine where the alkyl group is derived from the carbonyl compound. Historically, the reducing agent has been formic acid, and under these conditions the reductive amination occurs by a mechanism similar to that of the crossed Cannizzarro reaction. Depending on the exact conditions used, this reaction has several names: if ammonium formate is the reagent, 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 is known as the Wallach reaction. In its most widely-used form today, the carbonyl compound in
Chapter 15 578
the Leuckart reaction is formaldehyde, and the product is usually the tertiary amine where all the amine hydrogen have been replaced by methyl groups; this reaction is known as the EschweilerClarke reaction.
OH H2N H2CO/HCO2H/ Me2N OH (63%)
O H H
H H
NH4OCOCH3 NaBH3CN/MeOH
H2N H H
H H NHEt
O (100%)
CHO
EtNH2/MeOH/NaBH3CN CH3CO2H
(80%)
Rudolf Leuckart (1854-1889). Leuckart was born in Giessen, the son of the zoologist of the same name. After studying in Heidelberg he took his Ph.D. in Leipzig in 1879 under Kolbe. Following his graduation, Leuckart remained at Leipzig for a year as Kolbe's assistant, before moving to Munich to take up 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 died at Gttingen of an apparent stroke a scant month after his thirty-fifth birthday. Leuckart's major contribution to the development of organic chemistry was his discovery of the reaction between ammonium formate and carbonyl compounds that bears his name. Otto Wallach (1847-1931). Wallach was born in Knigsberg and educated at the University of Gttingen under Whler, where he took his Ph.D. in 1869. Following his graduation, Wallach moved to the University of Bonn in 1870 to work with Kekul. At Bonn he taught pharmacy, and in 1876 he was appointed Professor of Pharmacy. In 1889 he returned to his alma mater as Director of the Chemical Institute, a post he held until his retirement in 1915. While at Bonn, Wallach became interested in the ethereal oils, the essential oils which were (and still are) widely used as medicinal oils. His careful distillations allowed him to separate mixtures that Kekul believed to be absolutely resistant to analysis, and on the basis of their structures, which he determined, Wallach was able to formulate the isoprene rule for the structures of terpenes. Wallach's work was recognized in 1910, when he received the Nobel Prize in Chemistry for his work with the ethereal oils. Wilhelm Eschweiler (1860-1936). Eschweiler was born in Euskirchen and studied at the University of Munich. In 1887 he began his studies at the Technische Hochschule in Hannover as Assistant in the chemistry 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 Analytical Chemistry at the Technische Hochschule. Eschweiler's only major contribution to organic chemistry was his report of the reaction between amines and formaldehyde in the presence of formic acid, the reaction which now bears his name. Hans Thacher Clarke (1887-1972). Clarke was born of American parents in Harrow, England, and he received all his education in England, taking his B.Sc. (1908) and D.Sc. (1914) degrees from University College, London. From 1908-1909 he was a demonstrator in chemistry at University College, being promoted to lecturer in stereochemistry in 1910. From 1913-1914, Clarke carried out graduate study at the University of Berlin. In 1914 Clarke moved to the United States, where he took a position as a research chemist with Eastman Kodak in Rochester, New York. In 1928 he returned to academic ranks as Professor of Biological chemistry at the College of Physicians and Surgeons at Columbia University, a post he held until 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 a prolific book author: his first book appeared in 1911, his last in 1949. He served as President of the American 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 direct nucleophilic displacement of alkyl halides by ammonia or an amine, and alkylation is an important method 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 halide to give the product of over-alkylation (Figure 15.1), as we saw in Section 14.6. Over-alkylation is usually difficult to control, so direct alkylation is used most often for the preparation of primary amines (where a large excess of ammonia can be used) or for the formation of quaternary ammonium salts (where a large excess of alkyl halide is used).
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579
H H H R R N R R N R X
S N2
H H3N H H R N R R N H R R N R H
H N R R S N2 R R N H H N H R H X
Figure 15.1 The reaction between ammonia and an alkyl halide proceeds stepwise to form the primary amine, then the secondary amine, then the tertiary amine, and finally the quaternary ammonium salt. The composition 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 was solved by German chemist Siegmund Gabriel, and the method is known as the Gabriel synthesis (Figure 15.2).
O N H O phthalimide base O N O C6H4(CO)2N R X S N2 O N R O H2N R
N-alkylphthalimide
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 an amine, which can generate a new nucleophile, but is instead the (usually potassium) salt of phthalimide (a derivative of phthalic acid). The product of the initial SN2 reaction is an Nalkylphthalimide; this is not a nucleophile, so over-alkylation cannot occur. The desired amine is then liberated from the N-alkylphthalimide by warming it with hydrazine. The Gabriel synthesis is still one of the most widely used methods for the formation of primary amines from alkyl halides.
Br MeO2C Br CO2Me 1) C6H4(CO)2NK + 2) N2H4/ NH2 HO2C NH2 CO2H (80%)
The reduction of azides has also been used for the synthesis of primary amines from alkyl halides. Like the phthalimide anion, azide anion is a useful nucleophile for SN2 reactions; this permits the introduction of a primary amine group by a two-step process involving initial displacement of the halide by azide ion and subsequent reduction of the azide. In cases where the conditions required to liberate the amine from the N-alkylphthalimide make the Gabriel synthesis unsuitable for use, azide reduction offers an attractive alternative method for the formation of primary amines.
O H O O H MsO H O O H NaN3/DMF O O H O H N3 H O O H H2/Pd-C MeOH O H O O H H2N H O O H
Sample Problem 15.4. Write equations for the formation (free from contamination by the secondary amine) of 2-amino-4-methylpentane from each of the following types of compounds.
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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:
Br
(a)
1) C6H4(CO)2N 2) N2H4/ (Gabriel synthesis)
NH2
Br OR
1) NaN3/DMF/ 2) H2/Pd-C/MeOH (azide reduction)
NH2
(b)
1) NH2OH 2) H2/Pd-C (Oxime Reduction)
NH2 OR
NH3/H2/Pd-C
NH2
(Reductive amination)
(c)
NH3/NaBH3CN MeOH
NH2
(Reductive amination)
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 given in each case. (a) isopropylamine from acetone (three different sets of reagents). (b) cyclopentylamine from an alkyl halide (two different sets of reagents) and from a carbonyl 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 in Berlin, and he began his chemical studies at the University of Berlin under A.W. von Hofmann. In 1872 he 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, becoming extraordinary professor of chemistry at the University in 1896. On Hofmann's death in 1892, he continued in the same position under Emil Fischer. Gabriel's own research was clearly influenced by his association with Hofmann from the very beginning he worked with cyclic nitrogen compounds. In 1887 he reported the alkylation of phthalimide salts the reaction which now bears his name. Gabriel developed syntheses of many cyclic nitrogen compounds, including the isoquinolines (in 1886 he reported the first synthesis of an isoquinoline derivative), phthalazines, pyridazines, pyrimidines and many substituted amines. In 1913 he was appointed to an honorary professorship at the University of Berlin.
Reaction synopsis Preparation of Alcohols by Reduction:

R O R [H] R OH R
[H]:
LiAlH4/Et2O; NaBH4/EtOH; DIBAL-H/hexane; etc.
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581
Hydration of Alkenes:
R R R H R R R R OH R
Reagents: 1) BH3THF; 2) H2O2/NaOH/H2O; other hydroborations; anti-Markovnikov; syn. or H2SO4/H2O (H3O+ ); Markovnikov; stereorandom. or 1) Hg(OAc)2/THF/H2O, 2) NaBH4/NaOH/H2O; Markovnikov; first step anti, second step stereorandom.
Hydroxylation of Alkenes:
R R R HO R R R R OH R
Reagents: or
1) HCO3H; 2) OH (anti addition) OsO4/Me3COOH/Me3C-OH; KMnO4/KOH/H2O (syn addition);
Solvomercuration-Demercuration:
R R R H R R R R OR R
Reagents: 1) Hg(OCOCF3)2/THF/ROH; 2) NaBH4/NaOH/H2O Regiochemistry: Markovnikov
The Darzens glycidic ester condensation

Br R R COX R O R COX
X = OR, NR2 Reagents: KOBut/R2CO
Sharpless Asymmetric Epoxidation of Allylic Alcohols:

O Ti(O-i-Pr)4/Me3COOH OH (-)-DET/CH2Cl2/-20C OH Ti(O-i-Pr)4/Me3COOH (+)-DET/CH2Cl2/-20C O
OH
Proceeds with high levels of stereoselectivity to give enantiomer shown.
Preparation of Amines by Reduction:

R R R C N [H] [H] [H] R R R CH2NH2 NH2 NH2
NO2 N3
Reagents: or or or
LiAlH4/Et2O; etc. (nitriles); Sn/HCl/H2O/; other metals may be Fe, Zn, Mg, etc.; Na/EtOH; Li/NH3/ROH; or other variant of Birch reduction; H2/Pd-C/EtOH
Reductive Amination:
Chapter 15 582
R O R
NH2
[H] R
R NHR
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 be used for this reaction.
Gabriel Synthesis:
R X 1) C6H4(CO)2NM+ 2) N2H4 R NH2
Restricted to those alkyl halides and sulfonates that will participate in SN2 reactions. Hydrazinolysis is preferred 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 alcohols to alkenes can be effected using a variety of reagents protic acids, phosphorus oxychloride in pyridine, 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 of alkenes 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 E2 mechanism, all other alcohols by the E1 mechanism. Like the E1 reactions of alkyl halides, the acid-catalyzed dehydration of alcohols shows a marked preference for Zaitsev orientation in the product alkene. It is worth noting that one of the simplest methods for the formation of a carbocation is the reaction between an alcohol and a strong acid.
OH H3PO4/ (51%)
(13%)
H3PO4/ OH
(80%)
The dehydration of secondary and tertiary alcohols by protic acids has, to a large degree, been superseded by dehydration using phosphorus oxychloride or thionyl chloride in pyridine. Both these reagents react with secondary and tertiary alcohols to give the alkene formed by Zaitsev elimination of water from the alcohol. The first step of the elimination is the same as the first step of the substitution reactions with these reagents: the formation of the chlorophosphate or chlorosulfite ester. In the presence of the excess base, however, the decomposition of this intermediate occurs by the E2 mechanism rather than the SN1, SN2 or SNi mechanism.
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583
O O OH SOCl2/py
O O
OH POCl3/py
+
O O
Problem 15.9. What will be the major organic product formed by treating each of the alcohols in the list below with the reagents in the list that follows it? Alcohols: (a) 1-methylcyclohexanol. (c) E-2-methylcyclohexanol. (e) 2,2-diethylcyclopentanol. (g) isobutyl alcohol. (i) R-2-octanol. Reagents: (i) H2SO4/NaBr/H2O/. (iii) SOCl2/. (v) (C6H5)3P/Br2/DMF. (vii) H3PO4/. (ix) PBr3/Et2O. (xi) SOCl2/py. Amines In 1851 the great German chemist A.W. von Hofmann noted that bases react with quaternary ammonium salts to give predominantly the least substituted alkene. This orientation for elimination, which we discussed in Chapter 6 as the Hofmann orientation, is typical of molecules 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 charge accumulates at the carbon of activated complex (Figure 15.3) the reaction has a certain amount of E1cb character. It is this accumulation of negative charge that accounts for the orientation of the elimination: since alkyl groups are electron-releasing, they tend to destabilize the activated complex, and the proton is removed from the least substituted available carbon atom.
R R H NR3 R R H NR3 R R H B B
(b) Z-2-methylcyclohexanol. (d) 3,3-dimethyl-2-butanol. (f) 3-ethyl-2-pentanol. (h) Z-bicyclo[3.3.0]octan-1-ol. (j) S-2-methyl-1-butanol. (ii) 1) TsCl/py; 2) KOH/EtOH/. (iv) POCl3/py. (vi) 1) MsCl/py; 2) LiI/DMF. (viii) (C6H5)3P/CCl4/. (x) HCl/ZnCl2/. (xii) H2SO4/.
R R R R
NR3
R R
Figure 15.3 The Hofmann elimination proceeds by an E2 mechanism through an activated complex where there is substantial partial negative charge accumulation at the carbon. The Hofmann elimination has been used as the basis of a method for removing the nitrogen from an amine. This method, known as the Hofmann exhaustive methylation, involves by
Chapter 15 584
converting the amine to the quaternary ammonium salt with methyl iodide, carrying out the Hofmann elimination, and repeating these two steps in order until the nitrogen atom is lost as trimethylamine. Its use is illustrated by applying it to to the tropine nucleus (the basis of the atropine and cocaine-type alkaloids), below, a process used by Nobel Prize-winning German chemist Richard Willsttter to complete the first synthesis of 1,3,5-cycloheptatriene.
N Me Me MeI/ (excess) N Me Ag2O/H2O (forms AgOH; AgI is formed) MeI/ NMe2
Ag2O/H2O (forms AgOH; AgI is formed)
NMe3
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 for determining the structures of many amines. The Hofmann elimination is an E2 elimination reaction, and it is subject to all the limitations of the E2 mechanism, including the strong preference for anti elimination. Pyrolytic elimination reactions: the Ei mechanism To this point, the elimination reactions which we have discussed at length occur by either the E1 or the E2 mechanism. However, certain compounds selenoxides, sulfoxides, xanthate esters and amine N-oxides to name four undergo elimination simply by heating. These pyrolytic eliminations (Greek , pyr, fire) all occur by an intramolecular mechanism denoted as the Ei (Elimination, intramolecular) mechanism. We briefly discussed the elimination of sulfoxides and selenoxides in Section 8.1.
R O R R R H O R R R O S S R R H R R R S O R R H R R Se R O R R H R R N O R R R R H
ester
xanthate
sulfoxide
selenoxide
amine-N-oxide
Ei eliminations can be divided into two major types: those proceeding through six-membered cyclic transition states (ester pyrolysis, xanthate pyrolysis), and those proceeding through fivemembered cyclic transition states (selenoxide pyrolysis, sulfoxide pyrolysis, amine-N-oxide pyrolysis) as illustrated in Figure 15.4. In both cases, the geometric constraints of the transition state ensure that the elimination occurs with syn stereochemistry. Thus, pyrolytic elimination reactions provide a stereochemical contrast with the E2 elimination, which preferentially gives anti elimination if the hydrogen and the leaving group can achieve coplanarity. In most Ei eliminations, the Zaitsev alkene predominates where both the Zaitsev and Hofmann alkenes may be formed. The ease of pyrolysis depends on the compound undergoing the reaction. The pyrolytic elimination of esters, which has been known for over a century (in 1883, the German chemist Krafft described the formation of alkenes by heating esters of fatty acids), occurs between 400C and 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 after Lev Chugaev, the Russian chemist who first described it in 1899. The pyrolytic elimination of
Chapter 15
585
sulfoxides occurs at temperatures between 60C and 150C; the related elimination of selenoxides occurs below 0C, which is why selenoxides are now so widely used for the formation of alkenes. The pyrolytic elimination of amine-N-oxides, which is known as the Cope elimination after American chemist Arthur C. Cope who first described it, typically occurs at temperatures between 100C and 150C.
X X Z R R R Y H R Z R X Y H R R R Y Y X R H R X R Y H R R R Y H
+
R R
X=CR; Y=Z=O: ester X=CSR; Y=S; Z=O: xanthate
+
R R
X=SR; Y=O: sulfoxide X=SeR; Y=O: selenoxide X=NR 2 ; Y=O: amine-N -oxide
transition state.
Figure 15.4 The Ei elimination reaction proceeds through either a five-membered or a six-membered cyclic
The pyrolysis of esters and xanthates provide the basis for methods for the indirect dehydration 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 we discussed briefly in Section 15.6.
H R R OH R R O + R C Cl Me O py R R H R O C R O R Me
Me OH
(C6H5)3P/DEAD CH3CO2H
O Me
450C
Xanthate esters (Greek , xanthos, yellow a reference to the bright yellow color of copper xanthate salts) are prepared from alcohols by nucleophilic addition of the alkoxide to the carbon-sulfur bond of carbon disulfide to give the xanthate salt, and the SN2 reaction of the xanthate with an alkyl halide almost always methyl iodide to give the S-alkyl xanthate.
S C S
H R R
O R
H R R
S O C R S R O
CH3
I H R R S CH3 O C R S R
OH 1) KH/C6H5Me 2) CS2 3) MeI
C S
SMe 150C
Amine-N-oxides are prepared from tertiary mines by oxidation with a peracid such as mchloroperbenzoic acid, a reagent which we have seen used for the oxidation of alkenes to
Chapter 15 586
epoxides (Section 8.2) and for the Baeyer-Villiger oxidation of ketones (Section 10.9). Primary and secondary amines are not oxidized to N-oxides.
R N R R O N Me Me
m-CPBA/CH2Cl2
R
O N R R
160C
Lev Aleksandrovich Chugaev (1873-1922). Chugaev was born in Moscow and educated at the University of Moscow where he studied under Zelinsky. His development of the xanthate elimination reaction which bears his name was an extension of his research into camphor and its derivatives, which he presented as his master's thesis. In 1904 he was appointed professor of chemistry at Moscow Technical College, 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 later research was devoted to inorganic chemistry and the formation of metal complexes, especially of the platinum metals. It was Chugaev who, in 1905, introduced dimethylglyoxime as an analytical reagent for nickel (II). Arthur C. Cope (1909-1966). See Chapter 10.
Sample Problem 15.5. Give the major organic product expected from each of the following reaction sequences. Where appropriate, specify product stereochemistry. (a)
H NMe2 H 1) CH3I/ 2) KOH/EtOH/
(b)
H
NMe2 H
1) m-CBPA/CH2Cl2 2)
Answers:
H H
(a)
(b)
The Hofmann elimination in part (a) occurs by an E2 mechanism, so the reaction occurs with anti stereochemistry to give the Ealkene as the major product. The Cope elimination in part (b) occurs by an Ei mechanism so the reaction occurs with syn stereochemistry to give the Z alkene as the major product Problem 15.10. Give the major organic product expected from each of the following sequences of reactions. Where appropriate, specify the stereochemistry of the product.
NMe2
(a)
CH3 NMe2
1) CH3I/ 2) KOH/EtOH/
NMe2
(b)
CH3 NMe2
1) m-CBPA/CH2Cl2 2)
(c)
Et HO H Me H
1) CH3I/ 2) KOH/EtOH/
(d)
Et OH H Me H
1) m-CBPA/CH2Cl2 2)
(e)
1) CS2/KOH 2) MeI 3)
(f)
1) (C6H5)3P/DEAD 2) CH3CO2H 3)
[CAREFUL!]
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587
Reaction synopsis Dehydration of Alcohols:

R H R R OH R R R R R
Reagents: H2SO4/, H3PO4/ (E1 preferred; strongly Zaitsev) or POCl3/py; SOCl2/py (probable E2 through chlorophosphate or chlorosulfite esters)
Hofmann Exhaustive Methylation:

R H R R NR2 R 1) MeI 2) base/ R R R R
Base: Ag2O/H2O (Effectively AgOH); KOH/EtOH/; KOCMe3 Regiochemistry: Hofmann (mainly least substituted alkene). Stereochemistry: mainly anti. [Some syn elimination can occur in Hofmann eliminations.]
Pyrolytic Eliminations:
R H R R R X R R R R
X: OCOR; OCSSR; R2N+ O; SOR; SeOR Stereochemistry: Reaction proceeds by syn elimination.
15.3 OXIDATION OF ALCOHOLS

The oxidation of alcohols is a particularly important reaction for many of the same reasons that the elimination reaction is important the product has a reactive bond. We have already discussed 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 structure of the alcohol, and on the oxidant. Primary alcohols may be oxidized to the aldehyde or the carboxylic acid, depending on the reagent used, while oxidation of secondary alcohols gives only ketones. 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 are compounds of chromium in the +6 oxidation state chromic acid and its derivatives; the most commonly 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, while oxidation of primary alcohols by aqueous chromic acid usually results in oxidation to the corresponding carboxylic acid.
Me Me OH Me MeO OH PCC/CH2Cl2/25C MeO Me Me CH=O Me OH (80%)
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OH
Na2Cr2O7/H2SO4/H2O CO2H
(60%)
Potassium permanganate is one of the most powerful of the common oxidizing agents, and oxidations with this reagent are usually much less selective. Potassium permanganate oxidizes primary alcohols to carboxylic acids.
KMnO4/Na2CO3/H2O/4-5C OH CO2H (76%)
Tetrapropylammonium perruthenate (TPAP, [(CH3CH2CH2)4N+ RuO4]) rapidly and selectively oxidizes primary alcohols to aldehydes. It can be used catalytically with a co-oxidant such as N-methylmorpholine N-oxide (NMMO), so that the amount of the relatively expensive ruthenium reagent needed is minimized. TPAP oxidation frequently gives higher yields of product than the Swern oxidation.
O OH TPAP (5 mol %)/NMMO CH2Cl2/r.t./30 min O (73%) O
Oxidations based on dimethyl sulfoxide As discussed in Section 10.1, many functional groups other than the hydroxyl group of the alcohol (especially sulfides and certain alkenes and polyhydroxy compounds) are susceptible to oxidation by metal-based oxidizing agents. For the oxidation of such alcohols, alternative oxidation 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 to aldehydes.
H OH (COCl)2/Me2SO/CH2Cl2 H (64%) CHO
i-Pr2NEt/-78C
Allylic and benzylic alcohols the most easily oxidized alcohols As we discussed in Chapter 7, allyl halides are unusually reactive towards many reagents. You are probably not be surprised, therefore, to learn that allyl alcohols can be oxidized under very mild conditions. Manganese dioxide selectively oxidizes allyl and benzyl alcohols to the conjugated aldehydes and ketones. Since this reagent does not oxidize saturated alcohols or unsaturated alcohols which are not allylic or benzylic, it can be used to oxidize allyl or benzyl hydroxyl groups in the presence of saturated primary and secondary hydroxyl groups. Note the dramatic contrast in reactivity between this reagent, which is based on Mn(IV), and potassium permanganate, which is based on Mn(VII).
OH MnO2/pentane 25C/12 h OH H H HO H MnO2/CHCl3/25C/10 h O H H H (90%) OH O (72%)
Chapter 15
589
The currently accepted mechanism of chromium (VI) oxidation of alcohols involves the E2 elimination of a chromium (IV) species from an intermediate chromate ester, as we discussed in Section 12.2. Saturated tertiary alcohols lack the hydrogen atom required for this elimination, so they are resistant to oxidation. Saturated tertiary alcohols are oxidized only under forcing conditions. 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 actually oxidized. 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 be smoothly oxidized by these reagents on prolonged exposure. In these reactions, the oxidation occurs with an allylic rearrangement: during the reaction, the oxygen atom becomes bonded to the other end of the allylic system. The rearrangement step probably occurs at the chromate ester stage of the reaction (Section 12.2); the mechanism of the rearrangement has not yet been unambiguously determined, and it may involve the carbocation formed by heterolysis of the carbon-oxygen bond or it may be a [3.3] sigmatropic rearrangement of the chromate ester.
OH Me PCC/CH2Cl2 O Me
OH CrO32py CH2Cl2 H
Sample Problem 15.6. What is the major organic product obtained from the oxidation of the alcohol below with each of the following reagents? Where appropriate, give your reasons.
OH OH
OH
(a) PCC/CH2Cl2/25C/30 min. (c) CrO3/H2SO4/H2O/acetone/25C. (e) TPAP/NMMO/CH2Cl2/25C. (g) PCC/CH2Cl2/25C/24 h. Answers:
OH OH
(b) MnO2/CH3(CH2)3CH3/25C. (d) KMnO4/H2O. (f) (COCl)2/(CH3CH2)3N/CH2Cl2/-78C.
OH
(a)
O OH CHO
(b)
OH OH CHO
(c)
O OH CO2H
(d)
O CO2H
(e)
O CHO
(f)
O CHO
(g)
O O CO2H
Note that in (a) the total time for the reaction is only 25 minutes not long enough for the tertiary allylic alcohol to undergo appreciable oxidation. In part (g), the reaction
Chapter 15 590
time is now 24 hours plenty of time for the slow oxidation of the tertiary alcohol. In part (b) the reagent used, manganese dioxide, can oxidize only the primary allylic alcohol. Problem 15.11. What is the major organic product obtained from the oxidation of reach of the alcohols below with the reagents listed in Sample Problem 15.6? Where appropriate, give reasons for your answer.
OH HO HO OH OH
(a)
(b)
OH
(c)
OH
(d)
OH
Oxidative cleavage of vicinal diols In contrast to their monohydric counterparts, the vicinal diols (the 1,2-diols) are susceptible to oxidative 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 cyclic periodate ester is formed in the first step, and in which the cleavage of the carbon-carbon bond occurs in the second step during the decomposition of the ester. Overall, the diol is oxidized to the two carbonyl compounds, while the periodate (iodine in the +7 oxidation state) is reduced to iodate (iodine in the +5 oxidation state).
R R R OH OH R HIO4 R R R R OO I O OH OH OH R O
+
R O R
H3IO4
Figure 15.5 The accepted mechanism for periodate cleavage of vicinal diols involves the formation of a fivemembered, cyclic periodate ester which subsequently decomposes to the two carbonyl compounds and iodate. Evidence supporting this mechanism comes from kinetic studies of periodate cleavage of related 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 cyclic periodate ester) cleaves only very slowly.
OH OH O O IO(OH)3 CHO CHO
OH OH
O IO(OH)3 O CHO CHO
Like the periodate cleavage, the lead tetraacetate cleavage of diols requires a cyclic intermediate in most cases. However, there is also evidence that the cleavage may occur by an acyclic 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 oxidation because it was developed by Rudolf Criegee (who also proposed the currently accepted
Chapter 15
591
mechanism for ozonolysis), is frequently preferred to the periodate method. In this reaction, the lead is reduced from the +4 oxidation state to the +2 oxidation state.
OH OH Pb(OAc)4/CH3CO2H 50C CHO (64%)
Problem 15.12. The oxidative cleavage of meso-2,3-butanediol by lead tetraacetate and periodic 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

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

R CH2OH [O] R CO2H
Reagents: Cr (VI) K2Cr2O7/H2SO4/H2O, etc. Mn (VII) KMnO4/H2O.
Oxidative Cleavage of 1,2-Diols:

R HO R R OH R [O] R O R R
O 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 systems cis-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 than their 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 a carbon-heteroatom bond, as well as to -substituted carbonyl compounds. All these compounds are susceptible to reactions in which the allylic carbon-heteroatom bond is replaced by a carbonhydrogen 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 in ethanol, or zinc in acetic acid is called hydrogenolysis ("lysis by hydrogen").
R R R R X R X R R R O X R R O R R H R R [H] R R R R H R H R [H]: H2/Pd-C, Li/NH3/ROH, Na/ROH, Zn/CH3CO2H, Zn/HCl/H2O, etc.
X: halogen, OH, OR, NH2, NHR, NR2, O-CO-R, NH-CO-R, NR-CO-R, OTs, OP(O)(OR)2, 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 and hydrogenolysis can be carried out under neutral conditions. For these reasons benzyl ethers prepared using the Williamson ether synthesis have become popular functional groups for the protection of alcohol hydroxyl groups in organic synthesis. Likewise, benzyl groups have been used as protecting groups for amines.
OH H2/Ra-Ni/EtOH H
N CH3
H2/Pd-C/EtOH O
CH3 N O
(62%)
O Me3CSiMe2O O O
H2/Pd-C
O Me3CSiMe2O HO O
Problem 15.13. The molecule below has three ether groups. Write the sequence of reagents needed to cleave all but the methoxy group. Draw the structure of the product obtained after each step. [Hint alcohols are generally more reactive than ethers.]
OCH3 C6H5CH2O OTHP
How will this sequence of reactions need to be modified if all three ether groups must be 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, so considerable 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 Figure 15.7; they typically involve an alkene (reduced by hydrogenation) or a carbonyl compound (reduced by the Wolff-Kishner reaction) as an intermediate.
R O R
R OTs R R OH R R Br R R R R R
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 to complete all the transformations shown in Figure 15.7. Where more than one reagent may 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-based derivatives such as xanthates have been developed, and these reactions are rapidly gaining popularity. When a compound containing a CS bond is treated with the reducing agent tri-nbutyltin hydride (tri-n-butylstannane) under ultraviolet light (h) or a free-radical initiator such as a peroxide (ROOR) or azobisisobutyronitrile (AIBN), the free-radical reaction whose mechanism 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 rather than an alkane. The reaction may be carried out as a reductive elimination of exactly the same type as we discussed in Section 8.8, where the two hydroxyl groups are first converted to suitable leaving groups and then treated with a metal. In fact, such deoxygenation reactions are also important reactions of other difunctional hydroxy compounds, especially those in which there is a good leaving group (e.g. a halogen) at the carbon of the alcohol (such a deoxygenation is a dominant side-reaction in cases where one attempts to prepare a Grignard reagent from ethers such as 2-bromo-1-methoxyethane). These deoxygenations proceed, as we discussed discussed earlier, with anti stereochemistry. The treatment of the xanthate esters of 1,2-diols also leads to alkenes by a free-radical mechanism.
Chapter 15 594
R S SnBu3
S CH3 R O S CH 3 S Sn(C4H9)3 CH3S Bu3Sn H R + O S S CH3 Sn(C4H9)3 LUMO C RO S Sn HOMO (SOMO)
Figure 15.8 The mechanism of the tri-n-butylstannane reduction of an alkyl methyl xanthate involves an initial addition of the tri-n-butylstannyl radical to the carbon-sulfur bond of the xanthate ester. The frontier orbitals for this reaction are the carbon-sulfur * orbital (the LUMO) and the sp3 hybrid orbital on the tin (the HOMO or SOMO) which contains the unpaired electron. Problem 15.15. Design two distinct methods for the protection of an alkene double bond as a cyclic ketal and for its regeneration with its original stereochemistry. Reaction synopsis Deoxygenation of Alcohols:
R R R OH [H] R R R H
Reagents: or or or
1) PCC/CH2Cl2, 2) H2NNH2/KOH/HOCH2CH2OH/; (if 1 or 2 ROH) 1) TsCl/py, 2) KOCMe3/, 3) H2/Pd-C; 1) TsCl/py, 2) LiAlH4/Et2O/ (if 1 or 2 ROH); 1) KOH/CS2, 2) Bu3SnH/AIBN/h
Hydrogenolysis:
R R R R X R [H] R R R R H R
OH, OR, OCOR, NH2, NHR, NR2, NR3+ , NHCOR, NRCOR, SH, SR, halogen, etc. Reagents: H2/Pd-C; Li/NH3/ROH; Na/EtOH; etc. X:
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 and SN2 reactions. The reaction between an amine and a nitrosating agent is actually a reaction between the amine and the nitrosonium ion obtained from the nitrosating agent.
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O HO N
H H2O N
O N O N O
nitrosonium ion
The diazonium group leaves as nitrogen gas (a particularly stable species consider the earth's atmosphere!), so that it is a very effective leaving group. Moreover, the cleavage of the carbonnitrogen bond of an alkyldiazonium ion is a highly exothermic reaction with a very low activation energy, so the loss of nitrogen from a diazonium ion (known as deamination) occurs extremely readily. Deamination of a primary amine is one of the most efficient methods for the formation of carbocations. Carbocations generated by this reaction tend to be highly reactive because the cleavage of the carbon-nitrogen bond of the diazonium ion occurs more rapidly than solvent reorganization to help stabilize the carbocation as it forms. Such cations are often termed "hot" carbocations.
R NH2 NO (NaNO2/HCl) R
N2
diazonium ion
As expected for a reaction involving a carbocation intermediate, deamination reactions are extremely prone to rearrangements. One of the more useful applications of the deamination reaction is the Demyanov rearrangement, a typical example of which is shown below. The Demyanov rearrangement has been widely used for ring expansion and ring contraction in cyclic compounds, especially small-ring compounds.
CH2NH2 NO H2O CH2OH
OH
Problem 15.16. The Demyanov rearrangement involves the migration of an alkyl group to an electron-deficient carbon. The Baeyer-Villiger, Beckmann, and Schmidt rearrangements (Chapter 13.4) involve migration of an alkyl group to an electrondeficient heteroatom. Based on your knowledge of the migratory aptitudes of alkyl groups in the Baeyer-Villiger rearrangement, predict the major rearranged product which will be formed when each of the following amines is treated with nitrous acid.
NH2 NH2 NH2
(a)
(b)
(c)
H
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 (and frequently does) also exhibit unique reactivity that is solely due to the close spatial relationship between the two functional groups. As we saw in Chapters 7 and 8, this is certainly true for dienes. It is also true for polyhydroxy compounds and aminoalcohols, especially if the two functional 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 lead to mixtures of alkenes in which the Zaitsev alkene predominates. However, when a 1,2-diol is treated with a protic acid or a Lewis acid, the product is not the alkene or diene, but is, rather, a carbonyl compound. This reaction, which is known as the pinacol rearrangement, was first reported 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 by strictly analogous mechanisms (Figure 15.9). In the top sequence of steps in Figure 15.9, the reaction 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 is lost. 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 the rearrangement and the loss of water or nitrogen are usually concerted as shown in the bottom sequence of reactions in Figure 15.9, and that the free carbocation intermediate never actually exists.
X=OH, NH2
R R R X OH
Y=OH2+ , N2+
R R R Y OH R R R Y OH R R R OH R R R R OH R R R R OH R R R R O
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 is similar to the migratory aptitude of alkyl groups in the Baeyer-Villiger reaction. When the two hydroxyl groups of a 1,2-diol are not equivalent, the carbon-oxygen bond which breaks in the pinacol rearrangement is the one which will lead to the more stable cation.
HO OH H2SO4/ O (70%)
OH HO Me Me
H2SO4/ O=CH
H Me Me (100%)
The pinacol and Tiffeneau-Demyanov rearrangements have been used quite widely and quite successfully in synthesis, especially for carrying out such transformations as ring expansions and ring contractions. The ready availability of the -aminoalcohols by the reduction of cyanohydrins has made the Tiffeneau-Demyanov rearrangement especially popular for ring expansion of ketones.
OH conc. H2SO4 0C OH OH OH OH NH2 O (100%)
70% HClO4/-20C O
(81%)
HCN
OH CN
LiAlH4
HONO
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Sample Problem 15.7. Draw the structure of the final organic product expected from the following reactions or reaction sequences. Where appropriate, specify stereochemistry. If more than one regioisomeric product may be formed, give reasons for your choice.
O 1) Me3SiCN/CH2Cl2 2) LiAlH4/Et2O 3) NaNO2/HCl/H2O H OH NH2 HONO
(a)
(b)
H
Answers:
O NH2 NC OSiMe3 1) 2) OSiMe3 3) O H CHO
(a)
(b)
H
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 the following reactions or reaction sequences. Where appropriate, specify stereochemistry. If more than one regioisomeric product may be formed, give reasons for your choice.
(a)
1) Me3SiCN/CH2Cl2 2) LiAlH4/Et2O 3) NaNO2/HCl/H2O
(b)
1) Me3SiCN/CH2Cl2 O 2) LiAlH4/Et2O 3) NaNO2/HCl/H2O
(c)
CH2
1) OsO4/NMMO/CH2Cl2 2) H2SO4/0C
(d)
1) OsO4/NMMO/CH2Cl2 CH2 2) H2SO4/0C
Nikolai Yakovlevich Demyanov (1861-1938). Demyanov was born in the city of Tver, northwest of Moscow, and he studied under Markovnikov at the University of Moscow. Following his graduation, he was appointed to the faculty of the Petrine Forestry and Agricultural Academy (later Moscow Agricultural University), where he became professor in 1894. From 1935 until his death, he was laboratory head of the Institute of Organic Chemistry of the USSR Academy of Science. Much of Demyanov's fame derives from the reactions between nitrosating agents and amines. His first research on the reaction between nitrous acid and amines was part of the work for his master's degree in 1895; six years later he began research into the rearrangement which bears his name. He also carried out research into small ring compounds: he was the first to prepare methylenecyclopropane, methylenecyclobutane and vinylcyclopropane. He wrote textbooks in plant chemistry and organic chemistry. In 1924, he was awarded the Butlerov Prize of the Russian Academy of Science. Marc Emile Pierre Adolphe Tiffeneau (1873-1945). Tiffeneau was one of eight children born to a second-generation milliner just north of Paris. He graduated with the gold medal (which he promptly pawned to get the money for a trip to the Wagner Theatre in Bayreuth) from the Facult de Pharmacie of the University of Paris in 1900. For the next decade, he worked as a pharmacist in several hospitals and carried out research that led to his D.Sc. in 1907 and his M.D. in 1910 from the University of Paris. From 1924 until his death, he was associated with the University of Paris, first as Professor of chemistry in the Faculty of Science, then in the Faculty of Medicine, serving as Dean of Medicine from 1939-1940. Nearly half of his published work appeared in medical, biological and pharmaceutical journals, applying chemistry to medical problems. He was one the small group of chemists that helped the Socit Chimique de France survive World War I. Tiffeneau held the major office of every French learned society to which he belonged, 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 carbonyl compound isomeric with the epoxide. This same rearrangement is catalyzed by acids, especially when both carbon atoms of the epoxide ring are substituted and when there is no nucleophile present 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 oxirane carbons are substituted) is treated with magnesium bromide (a weak Lewis acid) in diethyl ether, the major organic product is cyclopentanecarboxaldehyde.
O MgBr2 Et2O CH=O
This particular reaction can cause complications in the reactions between epoxides and Grignard 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 the rearrangement first, and the major organic products then arise from the reaction between the carbonyl compound and the Grignard reagent. Because the lithium- and copper-based organometallic reagents avoid this problem, they are usually preferred for ring opening reactions of epoxides.
O MeMgBr Et2O OH OH
+
CH3 OH CH3
CH2OH
MeMgBr Et2O
OH
The mechanism of the rearrangement reaction may be rationalized as illustrated in Figure 15.7. This mechanism relies on the fact that the strain inherent in the three-membered ring provides the driving force for a rearrangement that would not otherwise occur. The oxonium ion 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 nucleophilic substitution, the "normal" substitution product is obtained. However, if the nucleophile does not react rapidly with the oxonium ion (and remember that secondary alkyl halides and oxonium ions do not react rapidly by the SN2 mechanism), the rate of the rearrangement reaction becomes competitive with the substitution.
O R R R R R R R A O R R R R A O R R R O A R R
A = H+, MgX2, AlR3, BX3, etc. O R R R R A O 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 carbocation canonical form of the oxonium ion. If you examine this carbocation closely, you will note that it is 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 same as 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 a way that one can predict the major product on the basis of the more stable carbocation canonical form. Where more than one group may migrate, the migratory aptitude is the same as for the Baeyer-Villiger rearrangement (Chapter 11.4).
Problem 15.18. Write a mechanism that could be used to account for the formation of the products in the reaction between methylmagnesium bromide and 2,3dimethyloxirane. Do the same for the formation of the first two products shown in the reaction between methylmagnesium bromide and cyclohexene oxide. Reaction synopsis Deamination.
R R R NH2 NO R R R N2 R R R
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 HNO2 OH
OH
A special case of deamination which involves the rearrangement of a primary cation to give an equilibrium mixture of products.
Pinacol Rearrangement:
HO R R OH R R R R R R O
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:
H2N R R OH R R NO R R R R O
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 of organometallic or enolate anion nucleophiles, or by reduction. The addition of a Grignard reagent to formaldehyde produces a primary alcohol with one carbon more than the Grignard reagent; addition to other aldehydes produces secondary alcohols; Grignard addition to ketones produces tertiary alcohols. The reaction between a Grignard reagent and an epoxide is best carried out in the presence of a copper catalyst; the product is the alcohol formed by ring opening 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 the absence of a proton source gives vicinal 1,2-diols, also known as pinacols. Reduction of aldehydes with complex metal hydrides gives primary alcohols; reduction of ketones gives secondary alcohols. Alcohols may be formed by hydration or hydroxylation of alkenes. Acid-catalyzed addition of water or oxymercuration-demercuration of alkenes gives the Markovnikov alcohol. Acidcatalyzed hydration may lead to rearrangements; oxymercuration-demercuration usually does not. 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-Markovnikov regiochemistry is accomplished by hydroboration-oxidation; the reaction gives stereospecific syn addition. Hydroxylation of alkenes gives 1,2-diols; osmium tetroxide or alkaline potassium permanganate give the syn hydroxylation product; epoxidation and ring-opening of the epoxide give the anti hydroxylation product. Ethers are formed by the Williamson ether synthesis: SN2 substitution of an alkyl halide by an alkoxide anion or by the Mitsunobu reaction between two alcohols in the presence of triphenylphosphine and an azodicarboxylate ester. Solvomercuration-demercuration of alkenes gives ethers with Markovnikov regiochemistry. Epoxides are formed by direct epoxidation of alkene double bonds with peracids or with tert-butyl hydroperoxide and a transition metal catalyst. Sharpless asymmetric epoxidation is a titanium-catalyzed epoxidation of allylic alcohols using 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 nucleophilic substitution of alkyl halides as in the Gabriel synthesis, or by reductive amination of carbonyl compounds or reduction of amides or imines with complex metal hydrides. Tertiary amines are synthesized 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 they may be converted to esters or xanthates which undergo pyrolytic Ei elimination. Amine Noxides 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 acid or water, or by dimethylsulfoxide-based sulfonium reagents as in the Swern and Moffatt-Pfitzner reactions. Recently, tetrapropylammonium perruthenate has been discovered as a useful oxidizing agent for alcohols. Potassium permanganate or cromic acid oxidize primary alcohols to carboxylic acids. Vicinal diols are cleaved to carbonyl compounds by periodic acid or by lead tetraacetate. 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 pinacol rearrangement. The migratory aptitude of the alkyl groups is similar to that for the BaeyerVilliger rearrangement. Amines rearrange in the presence of a nitrosating agent such as nitrous acid or nitrosyl chloride; the reaction is known as the Demyanov rearrangement. Aminoalcohols rearrange to ketones under similar conditions; this rearrangement is known as the Tiffeneau-Demyanov rearrangement.
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Allylic and benzylic alcohols, ethers and amines may be reduced to the hydrocarbon by hydrogenation 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. The reaction proceeds by the Ei mechanism. Cope elimination pyrolytic syn elimination of an amine N-oxide to give an alkene. The reaction occurs by an Ei mechanism. Darzens condensation formation of an epoxide by condensation of an -halocarbonyl compound with an aldehyde or ketone in the presence of a strong base. Deamination a reaction of primary amines in which the NH2 group is replaced by another functional group (usually a hydroxyl group). Demyanov Rearrangement A rearrangement of amines which occurs during deamination reactions. The reaction may be used for ring expansion and ring contraction of cyclic compounds. Diazonium ion an ion bearing the NN+ group (one of the best leaving groups known). Eschweiler-Clarke reaction methylation of an amine with formaldehyde and formic acid. Gabriel synthesis a method for the preparation of primary amines uncontaminated by secondary or higher amines by the sequential SN2 substitution of an alkyl halide with potassium phthalimide and the hydrazinolysis of the resultant N-alkylphthalimide. Hofmann elimination the E2 elimination of a tertiary amine from a quaternary ammonium ion. The product is the less substituted alkene where two or more alkenes might be formed. Hofmann exhaustive methylation a method for the removal of the nitrogen from an amine by repeated quaternization with methyl iodide and Hofmann elimination of the quaternary salt. Hydrogenolysis the replacement of a carbon-heteroatom bond by a carbon-hydrogen bond. This reaction is used for the cleavage of allyl and benzyl compounds. Leuckart reaction reaction between an aldehyde or ketone and ammonium formate; the product is a primary amine. Nitrosating agent a derivative of nitrous acid capable of forming the nitrosonium ion, NO+. The most widely used nitrosating agents are nitrous acid, HONO, and nitrosyl chloride, NOCl. Pinacol rearrangement the rearrangement of a 1,2-diol under acidic conditions to give a carbonyl compound and water. Very similar to the Tiffeneau-Demyanov rearrangement. Reductive amination the synthesis of amines from carbonyl compounds and ammonia or simpler amines in the presence of a reducing agent. Sharpless asymmetric epoxidation the epoxidation of allylic alcohols with a tert-butyl hydroperoxide in the presence of a titanium catalyst formed from titanium isopropoxide and a dialkyl tartrate. Solvomercuration-Demercuration the addition of an alcohol across an alkene bond in a reaction analogous to oxymercuration-demercuration. The product is the ether derived by Markovnikov addition to the alkene. Swern oxidation oxidation of an alcohol by dimethyl sulfoxide in the presence of oxalyl chloride and triethylamine at low temperature. Tiffeneau-Demyanov rearrangement a deamination reaction of a 2-aminoalcohol to give a carbonyl compound with a rearranged carbon skeleton and nitrogen gas on treatment with a nitrosating agent. Very similar to the pinacol rearrangement. Wallach reaction reaction between an aldehyde or ketone and a primary or secondary amine in the presence of formic acid; the product is a secondary or tertiary amine.
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15.8 ADDITIONAL PROBLEMS

15.19. Draw the structure of the major organic product expected from the treatment of each of the alcohols in the list below with each of the reagents in the list that follows it. If no reaction is expected, write "N/R". Alcohols: (a) isobutyl alcohol (c) sec-pentyl alcohol (e) cis-cyclopentane-1,2-diol (g) Z-1,5-cyclooctanediol (i) 1-cyclopentylcyclopentanol (k) ethylvinylcarbinol (m) trans-1,2-cyclohexanediol (o) 1-methyl-2-cyclopentenol Reagents: (a) CrO3.2py/CH2Cl2. (c) MnO2/C6H6/. (e) PCC/CH2Cl2/24 h. (g) 1) KOH/CS2; 2) CH3I; 3) . (i) H3PO4/. (k) Pb(OAc)4/C6H6. (m) TPAP/NMMO/CH2Cl2/25C. (o) 1) KOH/CS2; 2) (C4H9)3SnH/AIBN/h. (b) (E)-3-penten-1-ol (d) 1-dodecanol (f) (1R,2S,4R)-bicyclo[2.2.1]heptan-2-ol (h) 1,3-propylene glycol (j) tripropylcarbinol (l) 3-(methoxymethyl)-1,5-pentanediol (n) trans-cyclohexane-1,2-diol (p) 3-(1-hydroxycyclopentyl)-3-pentanol
(b) HIO4/THF/H2O. (d) POCl3/py. (f) (COCl)2/DMSO/Et3N/CH2Cl2/-60C. (h) KMnO4/H2O. (j) 1) KOH/CS2; 2) CH3I; 3) (C4H9)3SnH/h. (l) K2Cr2O7/H2SO4/H2O. (n) cyclopentanone/TsOH/.
15.20. Draw the structure of the major organic product expected from the treatment of each of the allylic alcohols in the list below with each of the reagents in the list that follows it. If no reaction is expected, write "N/R". Alcohols: (a) 3-methyl-2-buten-1-ol (b) (E)-2-buten-1-ol (c) R-2-cyclopentenol (d) E-2-dodecenol (e) cis-3-cyclopentene-1,4-diol (f) S-2-methyl-2-cyclohexenol (g) ethylvinylcarbinol (h) (2E,4E)-2,4-hexadien-1-ol (i) E-3,7-dimethylocta-2,6-dien-1-ol (j) 2-hydroxymethylbicyclo[2.2.1]hept-2-ene Reagents: (a) MnO2/C6H6/. (b) Li/NH3. (c) H2/Pd-C. (d) CHI/Zn(Cu)/Et2O. (e) Ti(O-i-Pr)4/(CH3)3COOH/CH2Cl2/-20C (open-chain alcohols only). 15.21. Draw the structure of the major product of each of the following reactions: (a)
1) CH3Li CHO 2) H3O+
(b)
Na2Cr2O7/H2SO4 OH H2O/Et2O/25C
(c )
OH
CrO3/H2SO4/H2O Me2CO/20-35C
(d )
CrO32py OH CH2Cl2/25C
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603
HO H
OH O CrO3/py/25C
(e)
O O
? (f)
N C6H5CH2 CO2CH3
CrO3/H2SO4 Me2CO/H2O
(f)
OH
N O SiMe3
TPAP (5 mol %)/NMMO CH3CN/r.t./3h
15.22. Draw the structure of the major organic product of each of the following Sharpless asymmetric epoxidation reactions. Unless otherwise stated, assume that the oxidant is Ti(O-i-Pr)4/Me3COOH in CH2Cl2 at -20C. (a)
(+)-DET OH MeO
(b)
MeO
OH
(+)-DET -78C
(c)
MeO OH
(+)-DET
(d)
OH
(+)-DET -78C
OH
(e)
()-DET
(f)
OH
()-DET -78C
(g)
O CH3O
OH
()-DET
(h)
OH
()-DET -78C
15.23. In principle, at least, each of the following alcohols may be prepared by up to three different combinations of a carbonyl compound and a Grignard reagent. Give all different Grignard reactions which may be used for the synthesis of each. Are there any of these combinations which may not work as well as the alternatives? Why?
OH
(a)
OH
(b)
OH OH
(c)
(d)
OH
OH
(e)
OH
(f)
OH
(g)
OH
(h)
OH
(e)
(f)
OH
(g)
OH
(h)
15.24. What sequence of reagents should be used to convert cyclohexanol to each of the following compounds? Note that there is more than one correct answer possible for most of these questions. (a) Z-1,2-cyclohexanediol. (b) 1-methylcyclohexanol. (c) 1(1-hydroxycyclohexyl)cyclohexanol. (d) E-2-methylcyclohexanol.
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(e) 1-ethylcyclohexene. (g) hexanedial. (i) cyclohexane. (k) cyclohexylmethanol. (m) cyclohexanecarbonitrile.
(f) cyclohexene. (h) 1,6-diaminohexane. (j) Z-1,2-dideuteriocyclohexane. (l) cyclohexylamine. (n) hexanediol.
15.25. What sequence of reactions should be used to convert cyclopentylamine to the following compounds? Note that there is more than one correct answer possible for most of these problems. (a) cyclopentene. (d) cyclopentanone. (b) cyclobutylmethanol. (e) cyclohexanone. (c) cyclopentane.
15.26. What reaction or sequence of reactions should be used to convert menthol to each of the following compounds?
OH menthol NH2 CH2OH
(a)
(b)
(c)
(d)
CH2
HO
NH2
(e)
(f)
(g)
15.27. The following sequence of reactions was used in a synthesis of the antitumor agent descarboxyquadrone. Draw the structures of the missing compounds.
MgBr O Et2O
A
(C10H16O)
CrO32py CH2Cl2/r.t.
B
(C10H14O)
LiAlH4
C
(C10H16O)
15.28. Draw the structures of the missing compounds in the following sequence of reactions, which has been used as part of a synthesis of the naturally-occurring compound alliacolide.
O HO H /hexane/47 h
+
D
(C11H18O2)
1) S
OBH3
E
(C11H20O3) MsCl/Et3N CH2Cl2/1 h
2) H2O2/NaOH/EtOH
H
(C18H34O3) PCC/alumina C6H6/
1) Mg/THF/ 2) CHO
G
(C11H19BrO2)
LiBr/DMF acetone
F
(C12H22O5S)
I
(C18H32O3)
OsO4/Et2O/H2O/NaIO4 r.t./18 h
J
(C17H30O4)
KOH/H2O Et2O/
K
(C17H28O3)
When compound K in this problem is treated with with dilute aqueous acid, the following ketone , 2-[(3-hydroxy-1-methyl)propyl]-4,4-dimethyl-2-cyclopent-2-enone, is obtained.

Alcohols II

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Alcohols II

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CHAPTER 15

O 1) CH3MgBr 2) KOH/H2O OCOCH3 OH HO

ALCOHOLS, ETHERS & AMINES II

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

SYNTHESIS, REDOX REACTIONS & ELIMINATION

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

Pinacol Synthesis of 1,2-Diols:

Mg/Et2O; Ti/THF; etc.

ALCOHOLS, ETHERS & AMINES II

1) BH3THF CH3 CH3 CH3 2) H2O2/OH/H2O CH3 CH3

1) Hg(OCOCH3)2/THF/H2O 2) NaBH4/NaOH/H2O/THF OH H2SO4/H2O

(mixture of stereoisomers) CH3

SYNTHESIS, REDOX REACTIONS & ELIMINATION

ALCOHOLS, ETHERS & AMINES II

1) Na/ 2) MeI 1) DEAD/(C6H5)3P 2) Me3COH

SYNTHESIS, REDOX REACTIONS & ELIMINATION

ALCOHOLS, ETHERS & AMINES II

(); mixture of E and Zisomers

SYNTHESIS, REDOX REACTIONS & ELIMINATION

OCOCH3 C6H5CO2OH C6H6/5C H O H

ALCOHOLS, ETHERS & AMINES II

H2/Pd-C EtOH N OH NH2

SYNTHESIS, REDOX REACTIONS & ELIMINATION

ALCOHOLS, ETHERS & AMINES II

SYNTHESIS, REDOX REACTIONS & ELIMINATION

ALCOHOLS, ETHERS & AMINES II

1) C6H4(CO)2N 2) N2H4/ (Gabriel synthesis)

1) NaN3/DMF/ 2) H2/Pd-C/MeOH (azide reduction)

1) NH2OH 2) H2/Pd-C (Oxime Reduction)

Reaction synopsis Preparation of Alcohols by Reduction:

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

SYNTHESIS, REDOX REACTIONS & ELIMINATION

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

Reagents: 1) Hg(OCOCF3)2/THF/ROH; 2) NaBH4/NaOH/H2O Regiochemistry: Markovnikov

The Darzens glycidic ester condensation

X = OR, NR2 Reagents: KOBut/R2CO

Sharpless Asymmetric Epoxidation of Allylic Alcohols:

Proceeds with high levels of stereoselectivity to give enantiomer shown.

Preparation of Amines by Reduction:

ALCOHOLS, ETHERS & AMINES II

SYNTHESIS, REDOX REACTIONS & ELIMINATION

ALCOHOLS, ETHERS & AMINES II

Ag2O/H2O (forms AgOH; AgI is formed)

SYNTHESIS, REDOX REACTIONS & ELIMINATION

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

OH 1) KH/C6H5Me 2) CS2 3) MeI

ALCOHOLS, ETHERS & AMINES II

SYNTHESIS, REDOX REACTIONS & ELIMINATION

Reaction synopsis Dehydration of Alcohols:

Hofmann Exhaustive Methylation:

15.3 OXIDATION OF ALCOHOLS

ALCOHOLS, ETHERS & AMINES II

SYNTHESIS, REDOX REACTIONS & ELIMINATION

(b) MnO2/CH3(CH2)3CH3/25C. (d) KMnO4/H2O. (f) (COCl)2/(CH3CH2)3N/CH2Cl2/-78C.

ALCOHOLS, ETHERS & AMINES II

O IO(OH)3 O CHO CHO

SYNTHESIS, REDOX REACTIONS & ELIMINATION

Reaction synopsis Oxidation of Alcohols: (a) To aldehydes and ketones

(b) To carboxylic acids