Synthesis of alcohols

Alcohols are important synthetic intermediates because they can be transformed into many other functional groups. Fortunately, they can also be synthesized from several classes of compounds, some of which contain oxygen and some of which do not. We will find that each method for the synthesis of alcohols has certain limitations that determine the scope of the reaction. Thus, it is important to learn what can and cannot be done with each set of reagents. 

To synthesize an alcohol (or any other compound), conditions must be chosen that produce only the correct compound with a minimum of by-products in the smallest number of steps. As the number of steps in a synthetic sequence increases, the chance of obtaining a high yield of the end product decreases. 

The selection of a given reaction to synthesize an alcohol is often based on a knowledge of the mechanisms of the various potential reactions. For that reason, we have to understand how differences in molecular structure can affect the final yield of product. We can t simply select a reagent because it works for some other compound. We must always ask whether the reaction will occur in good yield for the selected compound. 

The light induced reactions of bromine with organoboranes proceed through a-bro-mination 38) followed by facile migration of an alkylgroup in the presence of nucleophiles, such as water 39,40) (Eq. 1). Thus, this sequence provides means of coupling 

The results of coupling of two different alkyl groups via bromination-oxidation are assembled in Table 1. 

Disiamylborane is a highly selective hydroborating agent with excellent steric control. Thus, it reacts selectively with less substituted olefins in the presence of more substituted 43) as  

This generalization is true for both simple as well as conjugated dienes (Eqs. 4 and 5)441, 

This feature has been clearly extended to the hydroboration of myrcene (4) which has three reactive double bonds. The use of one equivalent of disiamylborane converts selectively one of the three double bonds to the alcohol (5) while two equivalents afford a diol (6) (Eq. 6) 45-46). 

We ve already looked at several alcohol synthesis reactions hydration of an alkene, oxymeixruration/demeicu ration, hydroboration, and nucleophilic substitution. 

Another method of synthesizing an alcohol is with an organometallic compound. 

Grignard reagents will react in a similar fashion with C=N, CSN, S=0, N=0. 

The Grignard is a strong enough base to deprotonate the following species 0—H, 

—C C-H. Grignard reagents are made in ether, and are incompatible with water and acids stronger than water. 

There are a number of methods for synthesizing alcohols. Some of the methods are suitable only for the preparation of small quantities of alcohol, while other methods are industrially important for the synthesis of thousands of gallons of alcohol. 

The hydration of alkenes is one important method of synthesizing alcohols. Industrially, sulfuric acid is used as a catalyst, while small-scale preparations often utilize toxic mercury compounds. (Definitely not the kind of stuff you want to drink.) 

Mechanism of the Markovnikov addition of water to an alkene to yield an alcohol. 

Oxymercuration-demercuration is a useful laboratory method for the synthesis of small quantities of alcohol. Like the catalytic hydration reaction, this process is an example of Markovnikov addition. It s a useful procedure because it tends to result in high yields and rearrangements rarely occur. 

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Synthesis of alcohols using organolithi um reagents (Section 14 7) Organolithi um reagents react with aldehydes and ketones in a manner similar to that of Grignard reagents to produce alcohols... 

A reaction useful only with sub strates that do not undergo E2 elimi nation readily It is rarely used for the synthesis of alcohols since alkyl halides are normally prepared from alcohols... 

Although the chemical reactions of epoxides will not be covered m detail until the fol lowing chapter we shall introduce their use m the synthesis of alcohols here... 

The reaction of esters with Gngnard reagents and with lithium aluminum hydride both useful m the synthesis of alcohols were described earlier They are reviewed m Table 20 4 on page 848... 

Hydroboration - regloseiective and stereoselective (syn) addition of BH3 (RBH2, R2BH) to olefins. Synthesis of alcohol including optically active alcohols from olefins. Also useful In synthesis of ketones by stitching ot olefins and CO... 

Meerwein-Pondorff reduction is the synthesis of alcohols by heating carbonyl compounds with aluminium isopropoxide in isopropanol and distilling off acetone by-product... 

All that has been said in this section applies with equal force to the use of organo-lithium reagents in the synthesis of alcohols. Grignard reagents are one source of nucleophilic carbon organolithium reagents are another. Both have substantial carbanionic char acter in their- car bon-metal bonds and undergo the same kind of reaction with aldehydes and ketones. 

The reaction of esters with Gr-ignard reagents and with lithium aluminum hydride, both useful in the synthesis of alcohols, were described earlier. They are reviewed in Table... 

Aluminum Organic Synthesis of Alcohols (Ziegler-Alfol Process)... 

The catalyst is phosphoric acid. The laboratory synthesis of alcohols is by nucleophilic substitution of haloalkanes. 

Sachs, M.M. Freeling, M. (1978). Selective synthesis of alcohol dehydrogenase during anaerobictreatment of maize. Mo/ecw/ar andCcMera/Ccncrics, 161,111-15. 

Scheme 4.9. Synthesis of Alcohols, Aldehydes, Ketones, and Amines from... 

Scheme 9.6 Synthesis of alcohol 6 from resolved acid 11.

However, since the goal of this work was the synthesis of alcohols from olefins via hydrohydroxymethylation (75, 76), little attention was given to developing a shift-catalyst per se. Pettit has recently reexamined some of this work and shown that, by careful control of the pH of the reaction mixture, systems based on either Fe(CO)5 or Cr(CO)6 can be developed for the production of either formic acid or methanol from carbon monoxide and water (77, 78). Each of these latter systems involves the formation of metal hydride complexes consequently, molecular hydrogen is also produced according to the shift reaction [Eq. (16)]. 

The synthesis of alcohols, ethers, and ketones by metal-catalyzed addition of water or alcohols to alkenes and alkynes is a well-established reaction in organic chemistry. Many regio- and stereoselective modifications of these reactions are known. In contrast, the analogous addition of ammonia or primary and secondary amines to nonactivated alkenes and alkynes has not had a comparable development, in spite of extensive efforts. In this section, we summarize the recent results of amination to unsaturated compounds. 

In summary, the research effort aimed towards active, chemoselective hydrogenations of certain C=0 and C=N bonds have delivered several catalysts that approach the level of activity required for use in the synthesis of alcohols and amines. However, other classes of substrate require considerable additional investigations to be conducted before homogeneous catalysts may be considered for this purpose. 

Reaction of telluronium salts/n-BuLi with carbonyl compounds synthesis of alcohols with telluronium salt (a2) (typical procedure) A solution of n-BuLi (1.1 mmol) in hexane is added to a solution of the telluronium salt (0.459 g, 1.2 mmol) in THF (6 mL) at -78°C under N2. The mixture is warmed at -60°C and stirred for 10 min. After cooling again at -78°C, p-chlorobenzaldehyde (0.140 g, 1.0 mmol) in THF (2 mL) is added. The mixture is then allowed to warm at room temperature. After the reaction is complete (monitored by TLC), the usual work-up and flash chromatography yield pure p-chlorophenyl(phenyl)carbinol. 

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