Enolate ions acylation

We ve now studied three of the four general kinds of carbonyl-group reactions and have seen two general kinds of behavior. In nucleophilic addition and nucleophilic acyl substitution reactions, a carbonyl compound behaves as an electrophile. In -substitution reactions, however, a carbonyl compound behaves as a nucleophile when it is converted into its enol or enolate ion. In the carbonyl condensation reaction that we ll study in this chapter, the carbonyl compound behaves both as an electrophile and as a nucleophile. 

Tire mechanism of the Claisen condensation is similar to that of the aldol condensation and involves the nucleophilic addition of an ester enolate ion to the carbonyl group of a second ester molecule. The only difference between the aldol condensation of an aldeiwde or ketone and the Claisen condensation of an ester involves the fate of the initially formed tetrahedral intermediate. The tetrahedral intermediate in the aldol reaction is protonated to give an alcohol product—exactly the behavior previously seen for aldehydes and ketones (Section 19.4). The tetrahedral intermediate in the Claisen reaction, however, expels an alkoxide leaving group to yield an acyl substitution product—exactly the behavior previously seen for esters (Section 21.6). The mechanism of the Claisen condensation reaction is shown in Figure 23.5. 

The mechanism of the Dieckmann cyclization, shown in Figure 23.6, is the same as that of the Claisen condensation. One of the two ester groups is converted into an enolate ion, which then carries out a nucleophilic acyl substitution on the second ester group at the other end of the molecule. A cyclic /3-keto ester product results. 

Step 1 of Figure 27.7 Claisen Condensation The first step in mevalonate biosynthesis is a Claisen condensation (Section 23.7) to yield acetoacetyl CoA, a reaction catalyzed by acetoacetyl-CoA acetyltransferase. An acetyl group is first bound to the enzyme by a nucleophilic acyl substitution reaction with a cysteine —SH group. Formation of an enolate ion from a second molecule of acetyl CoA, followed by Claisen condensation, then yields the product. 

Step 2 of Figure 29.3 Conjugate Addition of Water The a,(3-unsaturated acyl CoA produced in step 1 reacts with water by a conjugate addition pathway (Section 19.13) to yield a jG-hydroxyacyl CoA in a process catalyzed by enoyl CoA hydratase. Water as nucleophile adds to the 3 carbon of the double bond, yielding an enolate ion intermediate that is protonated on the a position. 

The retro-Claisen reaction occurs by initial nucleophilic addition of a cysteine -SH group on the enzyme to the keto group of the /3-ketoacyl CoA to yield an alkoxide ion intermediate. Cleavage of the C2-C3 bond then follows, with expulsion of an acetyl CoA enolate ion. Protonation of the enolate ion gives acetyl CoA, and the enzyme-bound acyl group undergoes nucleophilic acyl substitution by reaction with a molecule of coenzyme A. The chain-shortened acyl CoA that results then enters another round of tire /3-oxidation pathway for further degradation. 

Resolution (enantiomers), 307-309 Resonance, 43-47 acetate ion and, 43 acetone anion and. 45 acyl cations and, 558 allylic carbocations and, 488-489 allylic radical and, 341 arylamines and, 924 benzene and, 44. 521 benzylic carbocation and, 377 benzylic radical and, 578 carbonate ion and. 47 carboxylate ions and, 756-757 enolate ions and, 850 naphthalene and, 532 pentadienyl radical and. 48 phenoxide ions and, 605-606 Resonance effect, 562 Resonance forms, 43... 

A number of other methods exist for the a halogenation of carboxylic acids or their derivatives. Acyl halides can be a brominated or chlorinated by use of NBS or NCS and HBr or HCl. The latter is an ionic, not a free-radical halogenation (see 14-2). Direct iodination of carboxylic acids has been achieved with I2—Cu acetate in HOAc. " ° Acyl chlorides can be a iodinated with I2 and a trace of HI. Carboxylic esters can be a halogenated by conversion to their enolate ions with lithium A-isopropylcyclohexylamide in THF and treatment of this solution at -78°C with... 

The enolate ions of acetoacetic ester and other active methylene compounds react with 0-propiolactone to give the ethoxycarbonyl derivative, but the yields are generally not high. Application of this reaction to 2-ethoxycarbonyldodecanone (equation 53) has been recently patented, with the product reported to be a useful perfume intermediate (77JAP(K)77133952). The reaction is used quite widely with diketene, which gives C-acylation rather than alkylation of the enolate ion, followed by cyclization (72CPB1574). 

Furans can be prepared by acid catalyzed cyclization of masked 1,4-diketones. /3-Chloroallyl ketones which are obtained by alkylation of enamines or enolate ions behave as masked 1,4-diketones and afford furans on treatment with acid (67JA4557). 2,4-Dialkyl-furans (40) have been prepared by cyclization of the 3-chloroallyl ketone (39), which may be obtained by acylation of allyl chlorides (73KGS1434). 

The retro-acylation reactions of B-ketoaldehydes (388, X=H), B-diketones (388, X=alkyl) and the retro-Claisen reaction of B-ketoesters (388, X=0R) occur through the formation of an intermediate 389 which gives an ester 390 and the enolate ion 391. Protonation of 391 then gives the corresponding aldehyde (392, X=H), ketone (392, X=alkyl) or ester (392, X=0R). 

All three isomerizations discussed above seem to occur by analogous mechanistic pathways similar to the mechanism formulated for the Dakin-West reaction [82]. Deacylation of the starting material H by catalyst G affords, in a fast and reversible step (Scheme 13.47, step I), an acylpyridinium/enolate ion-pair I. From this ion pair, enantioselective C-acylation proceeds in the rate-determining and irreversible second step, furnishing the C-acylated product J (Scheme 13.47, step II). 

When A-acyl-ochloroaniline (314) is treated with LDA in THF-hexane solution, it forms the enolate ions which undergo cyclization to afford oxindoles 315. When R, R = Me, Ph, -Bu, the yield of 315 are 63-82%. When R = PhCH2, R = H the yield is 32% (equation 188)336. 

If the electrophile is an ester, then the ester undergoes a nucleophilic acyl substitution with the enolate ion serving as the nucleophile. First, the enolate adds to the ester to form a tetrahedral intermediate. Elimination of the leaving group (alkoxide) gives the substitution product. 

Enamines are intermediate in reactivity more reactive than an enol, but less reactive than an enolate ion. Enamine reactions occur under milder conditions than enolate reactions, so they avoid many side reactions. Enamines displace halides from reactive alkyl halides, giving alkylated iminium salts. The iminium ions are unreactive toward further alkylation or acylation. The following example shows benzyl bromide reacting with the pyrrolidine enamine of cyclohexanone. 

The Claisen condensation is a nucleophilic acyl substitution on an ester, in which the attacking nucleophile is an enolate ion. 

Many alkylation and acylation reactions are most effective using anions of /3-dicarbonyl compounds that can be completely deprotonated and converted to their enolate ions by common bases such as alkoxide ions. The malonic ester synthesis and the acetoacetic ester synthesis use the enhanced acidity of the a protons in malonic ester and acetoacetic ester to accomplish alkylations and acylations that are difficult or impossible with simple esters. 

Claisen condensation reaction (Section 23.7) a nucleophilic acyl substitution reaction that occurs when an ester enolate ion attacks the carbonyl group of a second ester molecule. The product is a p-keto ester. 

In the gas phase, the reaction of ethyl cations, C2H , with the ambident 2,4-pentanedione (which is 92% enolized at 25 °C in the gas phase) leads predominantly (>95%) to alkylation at the hard oxygen site and not at the soft carbon atom, as predicted by the HSAB concept [662]. Accordingly, the gas-phase alkylation of the enolate ion of cyclohexanone gives only the O- and no C-alkylation product [848], and the gas-phase acylation of acetophenone enolate with trifluoroacetylchloride leads predominantly to the 0-acylation product (0/C ratio = 6.0) [849]. 

Enamines may be regarded as synthetic equivalents of enolate ions and are closely related to the enolates derived from ketones in their reactions with acyl halides, alkyl halides and a,3-unsaturated compounds. 

In a similar manner the reaction of sodium 2-bromobenzoate with the carbanion derived from pentane-2,4-dione initially yields the dioxo acid (490). In ethanol, a retro-Claisen deacylation leads to 2-acetonylbenzoic acid (491), but at higher temperatures 3-methyI-isocoumarin is formed (Scheme 177) (75JCS(P1)1267). Copper(I) bromide may be used as a catalyst, although this is only necessary for the initial step. The cyclization process is considered to involve reaction between the carboxylate group and an enolate ion arising from loss of one of the acyl groups. A similar reaction occurs with l-bromo-2-naphthoic and 3-bromo-2-naphthoic acids giving the naphtho[2,l-c]pyran-4-one (492) and naphtho[2,3-c]pyran-l-one (493), respectively. 

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