Primary alkyl alcohol synthesis

A considerable amount of hydrobromic acid is consumed in the manufacture of inorganic bromides, as well as in the synthesis of alkyl bromides from alcohols. The acid can also be used to hydrobrominate olefins (qv). The addition can take place by an ionic mechanism, usually in a polar solvent, according to Markownikoff s rule to yield a secondary alkyl bromide. Under the influence of a free-radical catalyst, in aprotic, nonpolar solvents, dry hydrogen bromide reacts with an a-olefin to produce a primary alkyl bromide as the predominant product. Primary alkyl bromides are useful in synthesizing other compounds and are 40—60 times as reactive as the corresponding chlorides (6). 

The most generally useful method of preparing ethers is by the Williamson ether synthesis, in which analkoxido ion reacts with a primary alkyl halide or tosylate in an S 2 reaction. As we saw earlier in Section 17.2, thealkoxide ion is normally prepared by reaction of an alcohol with a strong base such as sodium hydride, NaH. 

This is not a new reaction. This is just an Sn2 reaction. We are simply using the alkoxide ion (ethoxide in this case) to function as the attacking nucleophile. But notice the net result of this reaction we have combined an alcohol and an alkyl halide to form an ether. This process has a special name. It is called the Williamson Ether Synthesis. This process relies on an Sn2 reaction as the main step, and therefore, we must be careful to obey the restrictions of Sn2 reactions. It is best to use a primary alkyl halide. Secondary alkyl halides cannot be used because elimination will predominate over substitution (as seen in Sections 10.9), and tertiary alkyl halides certainly cannot be used. 

The heart of the preparation of capsaicin is a malonic ester synthesis. The first step is bromination of the primary alcohol by phosphorous tribromide. The resulting primary alkyl bromide is used to alkylate the sodium salt of diethyl malonate. A substituted malonic acid derivative is obtained following basic hydrolysis of the ester groups. 

Ethers For the synthesis of ether, the Williamson ether synthesis is considered as the best method. It involves the SN2 reaction between a metal alkoxide and a primary alkyl halide or tosylate. The alkoxide needed for the reaction is obtained by treating an alcohol with a strong base like sodium hydride. An alternative procedure is to treat the alcohol directly with the alkyl halide in the presence of silver oxide, thus avoiding the need to prepare the alkoxide beforehand. 

Two different approaches are commonly used for the synthesis of alkynes. In the first, an appropriate electrophile undergoes nucleophilic attack by an acetylide ion. The electrophile may be an unhindered primary alkyl halide (undergoes Sn2), or it may be a carbonyl compound (undergoes addition to give an alcohol). Either reaction joins two fragments and gives a product with a lengthened carbon skeleton. This approach is used in many laboratory syntheses of alkynes. 

The alkoxide ion is a strong nucleophile as well as a powerful base. Unlike the alcohol itself, the alkoxide ion reacts with primary alkyl halides and tosylates to form ethers. This general reaction, called the Williamson ether synthesis, is an SN2 displacement. The alkyl halide (or tosylate) must be primary so that a back-side attack is not hindered. When the alkyl halide is not primary, elimination usually results. 

Synthesis of Phenyl Ethers A phenol (aromatic alcohol) can be used as the alkoxide fragment, but not the halide fragment, for the Williamson ether synthesis. Phenols are more acidic than aliphatic alcohols (Section 10-6), and sodium hydroxide is sufficiently basic to form the phenoxide ion. As with other alkoxides, the electrophile should have an unhindered primary alkyl group and a good leaving group. 

The least expensive method for synthesizing simple symmetrical ethers is the acid-catalyzed bimolecular condensation (joining of two molecules, often with loss of a small molecule like water), discussed in Section 11-10B. Unimolecular dehydration (to give an alkene) competes with bimolecular condensation. To form an ether, the alcohol must have an unhindered primary alkyl group, and the temperature must not be allowed to rise too high. If the alcohol is hindered or the temperature is too high, the delicate balance between substitution and elimination shifts in favor of elimination, and very little ether is formed. Bimolecular condensation is used in industry to make symmetrical ethers from primary alcohols. Because the condensation is so limited in its scope, it finds little use in the laboratory synthesis of ethers. 

The corresponding thioether fnnctionalised NHC without a second chiral wingtip gronp bnt an asymmetric carbon atom in the thioether sidearm was also synthesised by Ros et al. [261], However, we will tnrn our attention towards a similar example from the same research gronp [262] where the NHC is pyrido[a] annulated [263], The synthesis is again rather facile and follows standard procedures (see Figure 4.86). The chiral thioether precursor compound is accessible as the alcohol and needs to be treated with tetrabromomethane and PPhj to generate the required primary alkyl bromide. 

Ethers are prepared either by a Williamson synthesis or by alkoxymercuration/demercuration sequence. The Williamson ether sy thesis involves S -2 attack of an alkoxide ion on a primary alkyl halide. The alkoxymercuration reaction involves the formation of an intermediate organomercury compound, followed by NaBH4 reduction of the C-Hg bond. The net result is Markovnikov addition of an alcohol to an alkene. 

Ethers are compounds that have two organic groups bonded to the same oxygen atom, ROR. The organic groups can be alkyl, vinylic, or aryl, and the oxygen atom can be in a ring or in an open chain. Ethers are prepared by either the Williamson ether synthesis, which involves Sf t2 reaction of an alkoxide ion with a primary alkyl halide, or the alkoxymercuration reaction, which involves Markovnikov addition of an alcohol to an alkene. 

During the endgame of the total synthesis of the stemona alkaloid (-)-stenine, Y. Morimoto and co-workers utilized the Finkelstein reaction to prepare a primary alkyl iodide from a primary alkyl mesylate. The mesylate was prepared from the corresponding primary alcohol with MsCI/EtsN. The resulting primary alkyl iodide was used in the subsequent intramolecular N-alkylation to construct the final perhydroazepine C-ring of the natural product. 

The first total synthesis of the clerodane alkaloid solidago alcohol was achieved in the laboratory of H.-S. Liu, using a highly diastereoselective DIels-Alder cycloaddition as the key step. The installation of the 3-furyl side chain required the conversion of the bicyclic primary alkyl bromide to the corresponding aldehyde. This was accomplished by the modified Kornblum oxidation, which employed silver tetrafluoroborate to activate the substrate. 

Ether synthesis Ethers can be prepared in high yield by the reaction of primary or secondary alcohols with primary alkyl chlorides in a two-phase system composed of excess 50% aqueous sodium hydroxide and the alkyl chloride functioning as the organic solvent. Tetra-n-butylammonium hydrogen sulfate (3-5 mole %) is used as the phase-transfer catalyst. Primary alcohols are alkylated in 3-4 hr secondary alcohols require longer reaction times or larger amounts of catalyst. Yields are unsatisfactory with secondary alkyl chlorides. 

Migration of all three primary alkyl groups from boron to the one carbon unit under the influence of TFAA is possible and results in tertiary alcohols. The synthesis of tri- -hexylmethanol is formulated. 

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