Substitution reactions, alcohols reaction mechanisms

Figure21.1 The general mechanisms of nucleophilic addition and nucleophilic acyl substitution reactions. Both reactions begin with addition of a nucleophile to a polar C=0 bond to give a tetrahedral, alkoxide ion intermediate. (a) The intermediate formed from an aldehyde or ketone is protonated to give an alcohol, but (b) the intermediate formed from a carboxylic acid derivative expels a leaving group to give a new carbonyl compound.

Acidic ether cleavages are typical nucleophilic substitution reactions, either SN1 or Sn2 depending on the structure of the substrate. Ethers with only primary and secondary alkyl groups react by an S 2 mechanism, in which or Br attacks the protonated ether at the less hindered site. This usually results in a selective cleavage into a single alcohol and a single alkyl halide. For example, ethyl isopropyl ether yields exclusively isopropyl alcohol and iodoethane on cleavage by HI because nucleophilic attack by iodide ion occurs at the less hindered primary site rather than at the more hindered secondary site. 

We said in Section 17.4 that carboxylic acids are reduced by L1AIH4 to give primary alcohols, but we deferred a discussion of the reaction mechanism at that time. In fact, the reduction is a nucleophilic acyl substitution reaction in which —H replaces -OH to give an aldehyde, which is further reduced to a primary alcohol by nucleophilic addition. The aldehyde intermediate is much more reactive than the starting acid, so it reacts immediately and is not isolated. 

Addition of a proton occurs to give the more-substituted carbocation, so addition is regioselective and in accord with Markovnikov s rule. A more detailed discussion of the reaction mechanism is given in Section 6.2 of Part A. Owing to the strongly acidic and rather vigorous conditions required to effect hydration of most alkenes, these conditions are applicable only to molecules that have no acid-sensitive functional groups. The reaction is occasionally applied to the synthesis of tertiary alcohols. 

The mechanism of these bimolecular nucleophilic substitution reactions is shown in Scheme 11.3 for the reaction between a primary amine and the intermediate dichlorotriazine. A corresponding scheme can be drawn for reaction of a secondary amine, an alcohol or any other nucleophile in any of the replacement steps. It follows from this mechanism that the rate of reaction depends on ... 

The first evidence that an elimination-addition mechanism could be important in nucleophilic substitution reactions of alkanesulfonyl derivatives was provided by the observation (Truce et al., 1964 Truce and Campbell, 1966 King and Durst, 1964, 1965) that when alkanesulfonyl chlorides RCH2S02C1 were treated in the presence of an alcohol R OD with a tertiary amine (usually Et3N) the product was a sulfonate ester RCHDS020R with exactly one atom of deuterium on the carbon alpha to the sulfonyl group. Had the ester been formed by a base-catalysed direct substitution reaction of R OD with the sulfonyl chloride there would have been no deuterium at the er-position. Had the deuterium been incorporated by a separate exchange reaction, either of the sulfonyl chloride before its reaction to form the ester, or of the ester subsequent to its formation, then the amount of deuterium incorporated would not have been uniformly one atom of D per molecule. The observed results are only consistent with the elimination-addition mechanism involving a sulfene intermediate shown in (201). Subsequent kinetic studies... 

The direct action of nitric acid and its mixtures on the parent alcohol is by far the most important method for the production of nitrate esters on both an industrial and laboratory scale." While such reactions are essentially esterifications they are commonly referred to as 6>-nitrations because the reaction mechanism, involving substitution of hydrogen for a nitro group, is not dissimilar to other nitrations and frequently involves the same nitrating species. 

Consider a proposed nucleophilic substitution reaction on the secondary alcohol shown using aqueous HBr. As a secondary alcohol, either Sn2 or SnI mechanisms are possible (see Section 6.2.3), but SnI is favoured because of the acidic environment and the large fert-butyl group hindering approach of the nucleophile. The expected SnI bromide product is formed, together with a smaller amount of the El-derived alkene in a competing reaction. 

We begin by bringing you up to speed on mechanisms and reminding you how to push electrons around with those curved arrows. We jog your memory with a discussion of substitution and elimination reactions and their mechanisms, in addition to free radical reactions. Next you review the structure, nomenclature, synthesis, and reactions of alcohols and ethers, and then you get to tackle conjugated unsaturated systems. Finally, we remind you of spectroscopic techniques, from the IR fingerprints to NMR shifts. The review in this part moves at a pretty fast pace, but we re sure you can keep up. 

The prominent role of alkyl halides in formation of carbon-carbon bonds by nucleophilic substitution was evident in Chapter 1. The most common precursors for alkyl halides are the corresponding alcohols, and a variety of procedures have been developed for this transformation. The choice of an appropriate reagent is usually dictated by the sensitivity of the alcohol and any other functional groups present in the molecule. Unsubstituted primary alcohols can be converted to bromides with hot concentrated hydrobromic acid.4 Alkyl chlorides can be prepared by reaction of primary alcohols with hydrochloric acid-zinc chloride.5 These reactions proceed by an SN2 mechanism, and elimination and rearrangements are not a problem for primary alcohols. Reactions with tertiary alcohols proceed by an SN1 mechanism so these reactions are preparatively useful only when the carbocation intermediate is unlikely to give rise to rearranged product.6 Because of the harsh conditions, these procedures are only applicable to very acid-stable molecules. 

It has been demonstrated that in Bi(OTf)3-catalyzed alkylation reactions the optical activity of enantiopure benzyl alcohols is lost and a racemic product is isolated. This can be explained by a SA-l-type reaction mechanism and the existence of a carbocationic intermediate. However, diastereoselective substitutions of benzyl alcohols with a chiral centre in close neighborhood to the electrophilic carbon should be feasible (Scheme 23). 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

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