Secondary alcohols dehydration

The characteristic reaction of an alcohol on being heated with KHS04 is acid-catalyzed dehydration. Secondary alcohols dehydrate faster than primary alcohols, and so a reasonable first step is... 

Secondary alcohols dehydrate faster than primary alcohols, and so a reasonable first step is... 

Tertiary alcohols are more readily dehydrated than secondary alcohols, whilst primary alcohols are dehydrated with comparative difficulty. Thus the reaction proceeds easily with 33 per cent, sulphuric acid (1 acid 2 water, by volume) for amyl alcohol, but 50 per cent, (by volume) is required for aec.-amyl alcohol. Higher concentrations of acid tend to lead to increasing polymerisation of the olefine and are therefore usually avoided. 

The alicyclic secondary alcohol, cycZohexanol, may be dehydrated by concentrated sulphuric acid or by 85 per cent, phosphoric acid to cyciohexene. It has a higher boiling point (82-83°) than amylene and therefore possesses some advantage over the latter in.the study of the reactions of unsaturated hydrocarbons. 

The widely used Moifatt-Pfltzner oxidation works with in situ formed adducts of dimethyl sulfoxide with dehydrating agents, e.g. DCC, AcjO, SO], P4O10, CCXTl] (K.E, Pfitzner, 1965 A.H. Fenselau, 1966 K.T. Joseph, 1967 J.G. Moffatt, 1971 D. Martin, 1971) or oxalyl dichloride (Swem oxidation M. Nakatsuka, 1990). A classical procedure is the Oppenauer oxidation with ketones and aluminum alkoxide catalysts (C. Djerassi, 1951 H. Lehmann, 1975). All of these reagents also oxidize secondary alcohols to ketones but do not attack C = C double bonds or activated C —H bonds. 

Like tertiary alcohols secondary alcohols normally undergo dehydration by way of carbocation intermediates... 

In general, the reactions of the perfluoro acids are similar to those of the hydrocarbon acids. Salts are formed with the ease expected of strong acids. The metal salts are all water soluble and much more soluble in organic solvents than the salts of the corresponding hydrocarbon acids. Esterification takes place readily with primary and secondary alcohols. Acid anhydrides can be prepared by distillation of the acids from phosphoms pentoxide. The amides are readily prepared by the ammonolysis of the acid haUdes, anhydrides, or esters and can be dehydrated to the corresponding nitriles (31). 

The reaction gives poor yields of ethers with secondary and tertiary alcohols dehydration to form the corresponding olefin is a more favorable reaction. The reaction fails for the production of diaryl ethers from phenols. 

If homolytic reaction conditions (heat and nonpolar solvents) can be avoided and if the reaction is conducted in the presence of a weak base, lead tetraacetate is an efficient oxidant for the conversion of primary and secondary alcohols to aldehydes and ketones. The yield of product is in many cases better than that obtained by oxidation with chromium trioxide. The reaction in pyridine is moderately slow the intial red pyridine complex turns to a yellow solution as the reaction progresses, the color change thus serving as an indicator. The method is surprisingly mild and free of side reactions. Thus 17a-ethinyl-17jS-hydroxy steroids are not attacked and 5a-hydroxy-3-ket-ones are not dehydrated. 

All secondary alcohols are not dehydrated by this system instead, formates are sometimes produced, presumably by reaction with DMF ... 

Without exception the 17-secondary alcohols give three products, the dehydration products with migration of the 13j5-methyl group, the 17a-fluoro derivatives and the 17/5-chlorofluoroacetates. ... 

The reaction is an F.1 process and occurs through the three-step mechanism shown in Figure 17.6). As usual for El reactions (Section 11.10), only tertiary alcohols are readily dehydrated with acid. Secondary alcohols can be made to react, but the conditions are severe (75% H2S04,100 °C) and sensitive molecules don t survive. Primary alcohols are even less reactive than secondary ones, and very harsh conditions are necessary to cause dehydration (95% H2S04,150 °C). Thus, the reactivity order for acid-catalyzed dehydrations is... 

To circumvent the need for strong acid and allow the dehydration of secondary alcohols, reagents have been developed that are effective under mild, basic conditions. One such reagent, phosphorus oxychloride (POCI3) in the basic amine solvent pyridine, is often able to effect the dehydration of secondary and tertiary alcohols at 0 °C. 

Diethyl ether and other simple symmetrical ethers are prepared industrially by the sulfuric acid-catalyzed dehydration of alcohols. The reaction occurs by SN2 displacement of water from a protonated ethanol molecule by the oxygen atom of a second ethanol. Unfortunately, the method is limited to use with primary alcohols because secondary and tertiary alcohols dehydrate by an El mechanism to yield alkenes (Section 17.6). 

Step 2 of Figure 29.12 Isomerization Citrate, a prochiral tertiary alcohol, is next converted into its isomer, (2, 35)-isocitrate, a chiral secondary alcohol. The isomerization occurs in two steps, both of which are catalyzed by the same aconitase enzyme. The initial step is an ElcB dehydration of a /3-hydroxy acid to give cfs-aconitate, the same sort of reaction that occurs in step 9 of glycolysis (Figure 29.7). The second step is a conjugate nucleophilic addition of water to the C=C bond (Section 19.13). The dehydration of citrate takes place specifically on the pro-R arm—the one derived from oxaloacetate—rather than on the pro-S arm derived from acetyl CoA. 

The general features of this elegant and efficient synthesis are illustrated, in retrosynthetic format, in Scheme 4. Asteltoxin s structure presents several options for retrosynthetic simplification. Disassembly of asteltoxin in the manner illustrated in Scheme 4 furnishes intermediates 2-4. In the synthetic direction, attack on the aldehyde carbonyl in 2 by anion 3 (or its synthetic equivalent) would be expected to afford a secondary alcohol. After acid-catalyzed skeletal reorganization, the aldehydic function that terminates the doubly unsaturated side chain could then serve as the electrophile for an intermolecular aldol condensation with a-pyrone 4. Subsequent dehydration of the aldol adduct would then afford asteltoxin (1). 

Quinoxalinecarbaldehyde (64) gave 2-(p-cyanostyryl)qumoxaline (65) [Ph CH2CN, trace of HN(CH2)5 or Na0H-H20, EtOH, 20°C, briefly 60%] other well-activated methylene synthons likewise gave products such as 2-(2,2-diacetylvinyl)- (66, Q = R = Ac) (66%), 2-(2-acetyl-2-benzoylvinyl)-(66, Q = Ac, R = Bz) (94%), or 2-(2,2-dimethoxycarbonylvinyl)quinoxaline (66, Q = R = C02Me) (58%) but some such synthons produced only the intermediate secondary alcohols, such as 2-(l-hydroxy-2-nitroethyl)quinoxa-line (67) (36%), without final dehydration under these conditions. ... 

Many such hydroxyquinoxalines have been made by primary synthesis (see Chapter 1) and some by hydrolysis of extranuclear halogenoquinoxalines (see Section 3.4.2) in addition, during extranuclear alkylidenation of methylquinox-alines (see Section 2.2.1.4) the intermediate secondary alcohols may sometimes be isolated, especially with heavily substituted aldehydes, when dehydration can be difficult or even impossible. ° ... 

When proton acids catalyze alcohol dehydration, the mechanism is El. ° The principal process involves conversion of ROH to ROHj and cleavage of the latter to R and H2O, though with some acids a secondary process probably involves conversion of the alcohol to an inorganic ester and ionization of this (illustrated for H2SO4) ... 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

Some primary and secondary alcohols also undergo rearrangements of their carbon skeleton during dehydration. 

The Lewis base sites of the aluminas also participate in the dehydration of primary and secondary alcohols by the removal of a proton from either the j8- or y-carbon atom in relation to the a carbon containing the hydroxyl group. 

Rate Constants and Activation Energies of Dehydration of Secondary Alcohols over... 

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