Acid bromide, enol

The Hell-Volhard-Zelinskii reaction is a bit more complex than it looks and actually involves substitution of an acid bromide enol rather than a carboxylic acid enol. The process begins with reaction of the carboxylic acid with PBr3 to form an acid bromide plus HBr (Section 21.4). The HBr then catalyzes enolization of the acid bromide, and the resultant enol reacts with Br2 in an cr-substitution reaction to give an cv-bromo acid bromide. Addition of water hydrolyzes the acid bromide in a nucleophilic acyl substitution reaction and yields the a-bromo carboxylic acid product. 

Acid bromide, enol of, 849 from carboxylic acids, 800... 

In the presence of an electrophile, tautomerization of a substrate with a C=0 double bond to its enol only takes place when catalyzed by either a Bronsted- or a Lewis acid. The proton-catalyzed mechanism is shown for the ketone — enol conversion B — iso-B (Figure 12.4), the carboxylic acid —> enol conversion A — E (Figure 12.6), the carboxylic acid bromide — enol conversion E —> G (Figure 12.7) and the carboxylic acid ester — enol conversion diethyl-malonate —> E (Figure 12.9). Each of these enol formations is a two-step process consisting of the protonation to a carboxonium ion and the latter s deprotonation. The mechanism of a Lewis acid-catalyzed enolization is illustrated in Figure 12.5, exemplified by the ketone —> enol conversion A —> iso-A. Again, a protonation to a carboxonium ion and the latter s deprotonation are involved the Lewis acid-complexed ketone acts as a proton source (see below). 

The Hell-Volhard-Zelinskii reaction involves formation of an intermediate acid bromide enol, with loss of stereochemical configuration at the chirality center. Bromination of (/ )-2-phenylpropanoic acid can occur from either face of the enol double bond, producing racemic 2-bromo-2-phenylpropanoic acid. If the molecule had a chirality center that didn t take part in enolization (Problem 22.33), the product would be optically active. 

As was pointed out in Part A, Section 7.3, under many conditions halogenation is faster than enolization. When this is true, the position of substitution in unsymmetrical ketones is governed by the relative rates of formation of the isomeric enols. In general, mixtures are formed with unsymmetrical ketones. The presence of a halogen substituent decreases the rate of acid-catalyzed enolization and therefore retards the introduction of a second halogen at the same site. Monohalogenation can therefore usually be carried out satisfactorily. A preparatively useful procedure for monohalogenation of ketones involves reaction with cupric chloride or cupric bromide.81 82 83 84 85 86... 

Formation of the acyl bromide speeds up the reaction because acid-catalyzed enolization of the acyl bromide occurs much more readily than enolization of the parent acid. Bromine probably reacts with the enol of the acyl bromide in the same way as it reacts with the enols of ketones (Section 17-2 A). 

If the enolization has enough time to proceed, the transformation in Figure 12.4 completely leads to a brominated /J-ketoester. Basically, the same method can be employed to also a-brominate ketones (Figure 12.5), alkylated malonic acids (Figure 12.6), acid bromides (Figure 12.7,12.8) and acid chlorides (not shown). The mechanistic details are detailed in the cited figures. Look at how similar they are. 

The bromine is introduced onto the a-carbon by treating the carboxylic acid with Br2 and a catalytic amount of PBr, in a process known as the Hell-Volhard-Zelinsky reaction. This reaction proceeds through an enol intermediate. Because carboxylic acids form enols only with difficulty, a catalytic amount of PBr3 is added to form a small amount of the acyl bromide, which enolizes more readily than the acid. Addition of bromine to the enol produces an a-bromoacyl bromide (see Section 20.2). This reacts with a molecule of the carboxylic acid in a process that exchanges the Br and OH groups to form the... 

Show all of the steps in the mechanism for the acid-catalyzed enolization of the acyl bromide in the Hell-Volhard-Zelinsky reaction ... 

The effects of micellization on reactivity have been investigated for a wide variety of ionic organic reactions other than those discussed previously in Sections IV and V, e.g. the Cannizzaro reaction, racemiza-tion, acid catalyzed enolization, base catalyzed hydrolysis of a,]8-un-saturated ketones, and coupling of quinonediimines with phenols. In the case of the Cannizzaro reaction of benzaldehyde (equation 43), the cationic surfactants eicosanyltrimethylammonium bromide and octa-decyltrimethylammonium bromide increased and the anionic surfactant... 

The overall result of the HeU-Volhard-Zeiinskii reaction is the c formation of an acid into an u-bromo acid. Note, thou, that the key step involves a substitution of an add bromide enol rather than a rarboxdic acid enol. The reaction is analogous in all respects to what occurs durjg ketone bromination. 

The first step in the Hell-Volhard-Zelinskii reaction takes place bet PBra and a carboxylic acid to yield an intermediate acid bromide plus] (Section 21.4). The HBr thus formed catalyzes enolization of the acid I mide, and the resultant enol reacts rapidly with Brg in an a-substittttif reaction. Addition of water results in hydrolysis of the a-bromo acid 1 mide (a nucleophilic acyl substitution reaction) and gives the n-bromo< boxylic acid product. 

In the presence of a Lewis acid, silyl enol ethers can be alkylated with reactive secondary halides, such as substituted benzyl halides, and with chloromethylphenyl sulfide (ClCH2SPh), an activated primary halide. Thus, reaction of the benzyl chloride 10 in the presence of zinc bromide with the trimethylsilyl enol ether derived from mesityl oxide allowed a short and efficient route to the sesquiterpene ( )-ar-turmerone (1.22). Reaction of ClCH2SPh with the trimethylsilyl enol ethers of lactones in the presence of zinc bromide, followed by 5-oxidation and pyrolytic ehmination of the resulting sulfoxide (see Section 2.2), provides a good route to the a-methylene lactone unit common in many cytotoxic sesquiterpenes (1.23). Desulfurization with Raney nickel, instead of oxidation and elimination, affords the a-methyl (or a-alkyl starting with RCH(Cl)SPh) derivatives. ... 

Volhard (1834-1910), and Nicolai D. Zelinsky (1861-1953). The first step is formation of the acid bromide through reaction with PBr3. The acid bromide is in equilibrium with its enol form (Fig. 19.41). Bromination of the enol form with Br2 gives an isolable a-bromo acid bromide. 

The carboxylic acid itself is not brominated in the Hell— Volhard—Zelinsky reaction. Rather, a small amount of the carboxylic acid is converted into an acid bromide, which has a substantially higher concentration of the enol tautomer than the carboxylic acid. 

Whereas carboxylic esters had been considered to be inert under the conditions of boron enolate formation by enolization [2c], Corey s group elaborated protocols that allowed for the generation of boron enolates from esters. Thus, trans-boron enolates 100 result from simple carboxylic esters by deprotonation, while 5-phenyl thiopropionate formed cis-enolate 101 - in accordance with Masamune s observation. In both cases, the C2-symmetric diazaborolidine 99 served as the Lewis acid for enolization (Scheme 2.28) [112]. The stereochemical divergence of ester and thioester has been rationalized by postulating an E2-type elimination mechanism starting from the complex 102 that loses bromide in a... 

In the research groups of Seebach [67, 153] and Tidwell [154], alkyl and aryl lithium compounds were found to add readily to ketenes 153 that are accessible by various methods, as, for example, treatment of acid chlorides with triethy-lamine or acid bromides with zinc. As a result, ketone enolates 154 are formed. Due to the high reactivity of the ketenes, the protocol permits to access even sterically hindered trisubstituted enolates, the configuration of which depends on the steric demand of the substituents and R. Thus, alkyllithium reagents add from the sterically less hindered side, so that enolates 154 form with high diastereoselectivity. Of course, the ketone enolates thus generated are pure regioisomers. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

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