Acetoacetic acid bromination

It was shown that an enol intermediate was initially formed in the decarboxylation of l -ketoacids and presumably in the decarboxylation of malonic acids. It was found that the rate of decarboxylation of a,a-dimethylacetoacetic acid equalled the rate of disappearance of added bromine or iodine. Yet the reaction was zero order in the halogen . Qualitative rate studies in bicyclic systems support the need for orbital overlap in the transition state between the developing p-orbital on the carbon atom bearing the carboxyl group and the p-orbital on the i -carbonyl carbon atom . It was also demonstrated that the keto, not the enol form, of p ketoacids is responsible for decarboxylation of the free acids from the observa-tion that the rate of decarboxylation of a,a-dimethylacetoacetic acid k cid = 12.1 xlO sec ) is greater than that of acetoacetic acid (fcacw = 2.68x10 sec ) in water at 18 °C. Enolization is not possible for the former acid, but is permissible for the latter. Presumably this conclusion can be extended to malonic acids. 

The spontaneous enolization of acetoacetic acid (measured as bromination) is 60 times faster than that of ethyl acetoacetate and 10 to 10 times faster than that of levulinic acid but the acetoacetate anion is unreactive. Also the glycollate- and acetate-catalysed enolization of acetoacetic acid is 30 to 40 times faster than the analogously catalysed enolization of ethyl acetoacetate [103]. A mechanism as symbolized by 64, where B is a water molecule or an acetate or a glycollate ion seems reasonable [101]. Similar rate enhancements were found in the enolization (studied as bromination) of 65 and 66 [104]. 

To 16.3 g Na in 210 ml ethanol add 93 g ethyl-acetoacetate (ethyl-3-oxo-butanoate), heat to boil and add dropwise 92 g (II) over 20 minutes. Stir and reflux five hours and cool to precipitate. Filter, wash with ethanol and dissolve precipitate in 800 ml water. Cool to 0° C and slowly add 80 ml ice cold concentrated HC1 to precipitate. Filter, wash with water and ligroin to get about 108 g 6-carbethoxy-4,5-dihydro-olivetol (ID) (reciystallize from petroleum ether). To 104 g (III) in 260 ml glacial acetic acid at room temperature with good stirring, add dropwise over one hour 69 ml Bromine. Heat-four to five hours at 60° C, cool and add 300 ml water and let stand twelve hours. Oil separates which will precipitate on agitation and... 

A 1M p-methoxy-aniline (p-anisidine), 0.5 M ethyl-gamma-Br-acetoacetate (brominate as described above for 1-methyl-DET synthesis) cool and add 250 ml ether. Filter, evaporate in vacuum and reflux residue fifteen hours with 60 g ZnCI2 in 250 ml ethanol. Evaporate in vacuum, wash precipitate with water and dissolve residue in benzene. Wash with 4N HCI and water and dry, evaporate in vacuum. Reflux prcipitate two hours in ethanol-KOH to get about 70% yield of 5-methoxy-indoleacetic acid (I). 

Another reaction in which the cleavage of a carbon-hydrogen bond is important is the bromination of ketones. In the bromination of ethyl acetoacetate and 2-carboethoxycyclopentanone, it was shown that multivalent cations are catalysts. In the latter reaction, cupric, nickelous, lanthanum, zinc, plumbous, manganous, cadmium, magnesium, and calcium ions were effective (45). One can interpret the effect of the metal ion in terms of its catalysis of the proton transfer from the ester to a base, whether the reaction is carried out in dilute hydrochloric acid solution (acid-catalyzed bromination) or in acetate buffer (base-catalyzed bromination). 

As a synthetic route, this organoborane synthesis parallels the aoetoaoetic ester and malonic ester syntheses. An acetone unit is furnished by acetoacetic ester or, here, by bromoacetone an acetic add unit is furnished by malonic ester or, here, by bromoacetic ester. In these syntheses, bromine plays the same part that the —COOEt group did by increasing the acidity of certain a-hydrogens, it determines where in the molecule reaction will take place it is easily lost from the molecule when its job is done. Unlike the loss of —COOEt, the departure of —Br is an integral part of the alkylation process. 

The first synthesis modelled on biomimetic lines was directed to obtaining anacardic acids by way of polyketides [237] and later to a (17 l)-orsellinic acid [43]. A less complicated approach based on the Michael addition of ethyl acetoacetate and ethyl octadec-2-enoate, has led to a C15 orsellinic acid, Fig (4)-56, 2,4-dihydroxy-6n-pentadecylbenzoic, considered to be the biogenetic precursor of the cashew phenols [238], notably cardol, by decarboxylation. The use of bromine at the aromatisation stage in this synthesis precluded the extension of the method to components with unsaturated side-chains, although bromination with copper(ii)bromide and thermal debromination offers an alternative procedure. In a more recent approach, by the use of an oxazole intermediate and its addition to ethyl acetoacetate, (15 0) and (15 1) anacardic acid have been obtained [239] as shown in Scheme 5a, b. The 8(Z),1 l(Z)-diene and 8(Z),1 l(Z),14-triene have also been synthesised [240] by way of ethyl 6-(7-formylheptyl)-2-methoxybenzoate (C), prepared from acyclic sources, rather than, as in previous work, by semisynthesis from the ozonisation of urushiol. 

Acetic add, frons-cyclohexanediaminetetra-metal complexes, 554 Acetic add, ethylenediaminetetra-in analysis, 522 masking, 558 metal complexes, 554 Acetic acid, iminodi-metal complexes, 554 Acetic acid, nitrilotri-metal complexes titrimetry, 554 Acetoacetic add ethyl ester bromination, 419 Acetone, acetyl-deprotonation metal complexes, 419 metal complexes reactions, 422 Acetone, selenoyl-liquid-liquid extraction, 544 Acetone, thenoyltrifluoro-liquid-liquid extraction, 544 Acetone, trifluorothenoyl-in analysis, 523 Acetonitrile electrochemistry in, 493 exchange reactions, 286 metal complexes hydrolysis, 428 Acetylacetone complexes, 22 liquid-liquid extraction, 543 Acetylacetone, hexafiuorothio-metal complexes gas chromatography, 560 Acetylactone, trifluorothio-metal complexes gas chromatography, 560 Acetylation metal complexes, 421 Acetylenedicarboxylic add dimethyl ester cycloaddition reactions, 458 Acid alizarin black SN metallochromic indicator, 556 Actinoids... 

The halogenation of arylhydrazones of arylaldehyde has been extended to the arylhydrazones of ethyl acetoacetate (5-s.10,13,17,30,31,95 yot example, reaction of XIX with bromine in glacial acetic acid/acetic anhydride, in the presence of sodium acetate, affords the hydrazidoyl bromide XX in excellent yield ( ). 

Anthracene Anthranilic acid Anthraquinone Antimony pentachloride Benzaldehyde Benzidine dihydrochloride 2,2 -Benzidinedisulfonic acid Benzoguanamine Benzotrifluoride Benzoyl chloride N-Benzylamine N-Benzyl-N-ethyl-m-toluidine Bisphenol A Bromine 4-Bromochloro benzene Butyl acetoacetate n-Butylamine t-Butylamine Ceteareth-15 o-Chloroaniline p-Chloroaniline m-Chlorobenzoic acid o-Chlorobenzoic acid p-Chlorobenzoic acid m-Chlorobenzotrifluoride o-Chlorobenzotrifluoride p-Chlorobenzotrifluoride Chloroform 4-Chloro-2-nitroaniline 2-Chloronitrobenzene... 

For example, a dilute aqueous solution of ethyl acetoacetate contains 0.4% of enol (determined by bromine titration) and the measured dissociation constant is 2 x 10 This is therefore effectively the dissociation constant of the keto form, and the constant for the enol form is 5 x 10 . Since the keto form usually predominates in aqueous solution, the enol form is commonly the stronger acid, but this is not always the case. For example, dimedone (5,5,-dimethyIcyclohexane-l,3-dione) exists in aqueous solution as 95% enol and 5% keto, and its apparent dissociation constant is 5.9 X 10 hence in this case the dissociation constants of the keto and enol forms are respectively 1.2 x lO and 5.6 x 10 . ... 

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