Secondary alcohols hydrogen halide reactions

The hydrogenolyaia of cyclopropane rings (C—C bond cleavage) has been described on p, 105. In syntheses of complex molecules reductive cleavage of alcohols, epoxides, and enol ethers of 5-keto esters are the most important examples, and some selectivity rules will be given. Primary alcohols are converted into tosylates much faster than secondary alcohols. The tosylate group is substituted by hydrogen upon treatment with LiAlH (W. Zorbach, 1961). Epoxides are also easily opened by LiAlH. The hydride ion attacks the less hindered carbon atom of the epoxide (H.B. Henhest, 1956). The reduction of sterically hindered enol ethers of 9-keto esters with lithium in ammonia leads to the a,/S-unsaturated ester and subsequently to the saturated ester in reasonable yields (R.M. Coates, 1970). Tributyltin hydride reduces halides to hydrocarbons stereoselectively in a free-radical chain reaction (L.W. Menapace, 1964) and reacts only slowly with C 0 and C—C double bonds (W.T. Brady, 1970 H.G. Kuivila, 1968). 

Secondary and pnmary alcohols do not react with HCl at rates fast enough to make the preparation of the conespondmg alkyl chlorides a method of practical value There fore the more reactive hydrogen halide HBr is used even then elevated temperatures are required to increase the rate of reaction... 

As carbocations go CH3" is particularly unstable and its existence as an inter mediate m chemical reactions has never been demonstrated Primary carbocations although more stable than CH3" are still too unstable to be involved as intermediates m chemical reactions The threshold of stability is reached with secondary carbocations Many reactions including the reaction of secondary alcohols with hydrogen halides are believed to involve secondary carbocations The evidence m support of tertiary carbo cation intermediates is stronger yet... 

The SnI mechanism is generally accepted to be correct for the reaction of tertiary and secondary alcohols with hydrogen halides It is almost certainly not correct for methyl alcohol and primary alcohols because methyl and primary carbocations are believed to be much too unstable and the activation energies for their formation much too high for them to be reasonably involved The next section describes how methyl and primary alcohols are converted to their corresponding halides by a mechanism related to but different from S l... 

It IS important to note that although methyl and primary alcohols react with hydro gen halides by a mechanism that involves fewer steps than the corresponding reactions of secondary and tertiary alcohols fewer steps do not translate to faster reaction rates Remember the order of reactivity of alcohols with hydrogen halides is tertiary > sec ondary > primary > methyl Reaction rate is governed by the activation energy of the slowest step regardless of how many steps there are... 

Alcohols react with hydrogen halides to yield al kyl halides The reaction is useful as a synthesis of al kyl halides The reactivity of hydrogen halides de creases in the order HI > HBr > HCI > HF Alcohol re activity decreases in the order tertiary > secondary > primary > methyl... 

Section 4 9 The potential energy diagrams for separate elementary steps can be merged into a diagram for the overall process The diagram for the reac tion of a secondary or tertiary alcohol with a hydrogen halide is charac terized by two intermediates and three transition states The reaction is classified as a ummolecular nucleophilic substitution, abbreviated as SnI... 

The reactions of alcohols with hydrogen halides to give alkyl halides (Chapter 4) are nucleophilic substitution reactions of alkyloxonium ions m which water is the leaving group Primary alcohols react by an 8 2 like displacement of water from the alkyloxonium ion by halide Sec ondary and tertiary alcohols give alkyloxonium ions which form carbo cations m an S l like process Rearrangements are possible with secondary alcohols and substitution takes place with predominant but not complete inversion of configuration... 

When applied to the synthesis of ethers the reaction is effective only with primary alcohols Elimination to form alkenes predominates with secondary and tertiary alcohols Diethyl ether is prepared on an industrial scale by heating ethanol with sulfuric acid at 140°C At higher temperatures elimination predominates and ethylene is the major product A mechanism for the formation of diethyl ether is outlined m Figure 15 3 The individual steps of this mechanism are analogous to those seen earlier Nucleophilic attack on a protonated alcohol was encountered m the reaction of primary alcohols with hydrogen halides (Section 4 12) and the nucleophilic properties of alcohols were dis cussed m the context of solvolysis reactions (Section 8 7) Both the first and the last steps are proton transfer reactions between oxygens... 

Oxidations usually proceed in the dark at or below room temperature in a variety of solvents ranging from aqueous bicarbonate to anhydrous benzene-pyridine. Base is quite commonly used to consume the hydrogen halide produced in the reaction, as this prevents the formation of high concentrations of bromine (or chlorine) by a secondary process. The reaction time varies from a few minutes to 24 hours or more depending on the nature of the reagent and the substrate. Thus one finds that NBS or NBA when used in aqueous acetone or dioxane are very mild, selective reagents. The rate of these oxidations is noticeably enhanced when Fbutyl alcohol is used as a solvent. In general, saturated, primary alcohols are inert and methanol is often used as a solvent. 

The reaction between perfluoraarylmagnesium halides and esters of dicar-boxyltc acids gives, besides the expected keto esters, secondary alcohols as reduction products [29, 30, 31] (equation 10) Such a reduction is enhanced by higher temperature The hydrogen necessary for reduction comes from the solvent, diethyl ether, which is dehydrogenated to ethyl vinyl ether, which has been identified as a by-product in a similar reaction of perfluoroalkyllithium compound [52]... 

One important experimental fact is that the rate of reaction of alcohols with hydrogen halides increases in the order methyl < primary < secondary < tertiary. This reactivity order parallels the caibocation stability order and is readily accommodated by the mechanism we have outlined. 

The nucleophilic addition of alcohols [130, 204-207], phenols [130], carboxylates [208], ammonia [130, 209], primary and secondary amines [41, 130, 205, 210, 211] and thiols [211-213] was used very early to convert several acceptor-substituted allenes 155 to products of type 158 and 159 (Scheme 7.25, Nu = OR, OAr, 02CR, NH2, NHR, NRR and SR). While the addition of alcohols, phenols and thiols is generally carried out in the presence of an auxiliary base, the reaction of allenyl ketones to give vinyl ethers of type 159 (Nu = OMe) is successful also by irradiation in pure methanol [214], Using widely varying reaction conditions, the addition of hydrogen halides (Nu= Cl, Br, I) to the allenes 155 leads to reaction products of type 158 [130, 215-220], Therefore, this transformation was also classified as a nucleophilic addition. Finally, the nucleophiles hydride (such as lithium aluminum hydride-aluminum trichloride) [211] and azide [221] could also be added to allenic esters to yield products of type 159. 

Secondary and tertiary alcohols undergo S l reactions with hydrogen halides. The reaction of an HX with 3° alcohol proceeds readily at room temperature, whereas the reaction of an HX with a 2° alcohol requires heat. 

Secondary and tertiary propargyl alcohols are directly converted to halo-allenes on reaction with concentrated aqueous hydrogen halides in the presence of the corresponding cuprous halide [60,72-73]. (See Table VII.) Better yields are obtained with hydrogen bromide. Hydrogen chloride yields chloroallene, propargyl chloride, and the chloro- 1,3-diene isomers (Eq. 60). 

More recently, the Noyori group described an organic solvent- and halide-free oxidation of alcohols with aqueous H2 0 2378,379- The catalyst system typically consists of Na2W04 and methyltrioctylammonium hydrogen sulfate, with a substrate-to-catalyst ratio of 50-500. Secondary alcohols are converted to ketones, whereas primary alcohols, in particular substituted benzylic ones, are oxidized to aldehydes or carboxylic acid by selecting appropriate reaction conditions379,38°. This system also catalyzed the chemoselective oxidation of unsaturated alcohols, the transformation exemplified in equation 65, with a marked prevalence for the hydroxy function. 

Koenigs-Knorr reaction is carried out using simple, liquid aglycons (methanol or ethanol, for example), the alcohol also serves as the solvent for the halide, and is frequently present in large excess. In such cases, the halide is rapidly converted into glycoside, and the water formed in the secondary reaction between the liberated hydrogen halide and silver carbonate is seldom cause for concern. 

Another variation of the palladium-catalyzed carbonylation reaction occurs when hydrogen is added rather than an alcohol or a primary or secondary amine. This variation leads to aldehyde formation the hydrogen reduces the acylpalladium intermediate to aldehyde and metal hydride (76). A basic tertiary amine is also added as in the ester-forming reaction to neutralize the hydrogen halide formed in the dissociation of the hydride ... 

However, the reaction of primary and secondary alcohols with hydrogen halides can generally be a problem since unwanted rearrangement reactions generally occurs. 

The least reactive of the hydrogen halides, HCl, requires the presence of zinc chloride for reaction with primary and secondary alcohols on the other hand, the very reactive /er/-butyl alcohol is converted to the chloride by simply being shaken with concentrated hydrochloric acid at room temperature. For example ... 

---