Ketone beta-carbon

When Schiff s bases (242), derived from ketones and tm-butylamine, were reacted with dimethyl methoxymethylenemalonate in diphenyl ether at 80-130°C for 1-15 hr, then at 190-250°C for 1-3 hr, 2-hydroxy-3-pyridinecarboxylates (243) were obtained by a one-pot procedure. In the first step of the reaction, the beta-carbon of the enamine moiety was involved instead of the amino group (89JHC773). 

The experimental evidence [22,89,90,110-115] suggests that ketones react with OH radicals via a hydrogen abstraction mechanism, leading to a water molecule and a new radical. Nevertheless, there is a peculiarity in the ketones -I- OH reactions hydrogen atoms attached to carbon atoms in beta positions to the carbonyl group are the most likely to be abstracted [110-113,115]. However, if the beta carbon is a primary carbon, its contribution to the total reaction is much less important. The contribution is about 66% [116] to 67% [117] for secondary beta carbons, while it is only about 11% [116] to 17% [117] for primary ones. To explain the large contribution of the beta abstractions, Wallington and Kurylo [90] have proposed a complex... 

The carbonyl group of the ketones weakly deshields the geminal olefinic proton but strongly de-shields the cis and trans hydrogens bonded to the beta carbon atom. Its effect is similar to that of the unsaturated carbon atom of the nitrile (-C=N) functional group. 

The fatty acyl CoA molecules that enter mitochondria are then degraded in a catabolic process called (i-oxidation. During p-oxidation, the second (or beta) carbon down the chain from the carbonyl of the fatty acyl CoA molecule is oxidized to a ketone ... 

A typical retrosynthesis of a P-hydroxy ketone or P-hydroxy aldehyde involves making a disconnection between the two functional groups, more specifically, between the alpha carbon and the carbon bearing the OH group (the beta carbon). The carbon that now has an OH on it used to be a carbonyl carbon (C=0), which was an electrophilic carbon. Therefore, the other carbon group must have been introduced as a nucleophile this is a logical disconnection since a carbon alpha to a carbonyl can be a nucleophile as an enolate. 

Dehydration of an aldol product is no more than a functional group interconversion, so the retrosynthesis of a a,P-unsaturated ketone or aldehyde involves making the same disconnection as used for a P-hydroxy ketone or aldehyde between the alpha and beta carbons. It may help to start the retrosynthesis by adding water back in (undoing the dehydration step) to give the more recognizable P-hydroxy carbonyl compound before making the disconnection. 

Ultimately, a complete retrosynthesis of a P-amino ketone leads to the three components needed in a Mannich reaction a ketone, an aldehyde, and an amine. The retrosynthesis of a P-amino ketone begins with making a disconnection between the alpha carbon and the carbon bearing the amino group (the beta carbon). This aldol-like disconnection leads to a nucleophilic alpha carbon (enol) and an electrophilic imine carbon (C=N). Further disconnection of the imine affords the two necessary building blocks for its formation an aldehyde and an amine. 

The Robinson annulation involves two reactions occurring in tandem a Michael reaction followed by an aldol condensation (loss of water is normally expected in this reaction so the aldol product is typically dehydrated to give an a,P-unsaturated cyclohexenone product). The reaction of an enolate as a nucleophile attacking the beta carbon of methyl vinyl ketone as the electrophile (a Michael reaction) forms the first carbon-carbon bond in the Robinson annulation and results in a 1,5-dicarbonyl product. The methyl group from MVK serves as the nucleophile for the second part of the reaction when it finds a carbonyl electrophile six atoms away to undergo an intramolecular aldol reaction. After dehydration, an a,P-unsaturated cyclohexenone product is formed. Ultimately, two new carbon-carbon bonds are formed within the cyclohexenone moiety. 

Identification of the four-carbon methyl vinyl ketone unit within the cyclohex-enone TM leads to the appropriate disconnections. The first retrosynthetic step is a retro-aldol, so a disconnection is made between the alpha and beta carbons. The alpha carbon will be introduced as an enolate nucleophile the other carbon was a carbonyl electrophile. 

Since the TM contains a cyclohexenone moiety, two disconnections can be made around the four-carbon methyl vinyl ketone unit within the six-membered cyclohexenone ring. The first disconnection is through the double bond of the cyclohexenone (aldol disconnection). The second disconnection is from an alpha carbon (Nu ) to the beta carbon of the MVK unit (E ) (Michael disconnection). 

Although the major fraction of the partial positive charge (blue) of an a,)8-unsaturated aldehyde or ketone is on the carbonyl carbon, there is nevertheless a significant partial positive charge on the beta carbon. 

A lithium diorganocopper reagent adds to the beta carbon of an a,j8-unsaturated aldehyde or ketone. Therefore, locate each carbon beta to the carbonyl group in this target molecule and disconnect at those points. 

The alcohols are intermediates in the formation of ketones. Isomerization of the products is not observed. Hydroxylation at the 2-position is favored over that at the 3-position, and the latter is preferred over hydroxylation at the 4-position. Solubility and concentration in the reaction medium, intrazeolite diffusion of the reactants, steric hindrance at the reactive carbon center, and C-H bond strength influence the reactivity and H202 selectivity (Table XXIV). The advantage of the large-pore Ti-beta over TS-1 in the oxidation of bulky alkane molecules is shown by the results in Table XXV. 

Reduction of carbonyl compoundsThe reagent reduces aldehydes or ketones to alcohols in refluxing cyclohexane in 2-5 hours yields are 60-80%. The reduction probably involves hydride transfer from the carbon beta to the magnesium center. 

Based on the above discussion it was thought that the trifluoro-methyl ketones would be more polarized and thus create a great electrophilicity on the carbonyl carbon which facilitates -OH attack by the serine residue. Yet there is no carbon-oxygen bond to be cleaved In the ketone moiety, and therefore the enzyme-trifluoromethyl ketone transition state complex does not undergo catalytic conversion. The above rationale seems reasonable as trifluoromethyl ketones were found to be extraordinary selective and potent inhibitors of cholinesterases (56) of JHE from T. ni (57) and of meperidine carboxylesterases from mouse and human livers (58). Since JH homologs are alpha-beta unsaturated esters, a sulfide bond was placed beta to the carbonyl in hopes that it would mimic the 2,3-olefln of JHs and yield more powerful inhibitors (54). This empirical approach was extremely successful since it resulted in compounds that were extremely potent inhibitors of JHEs from different species (51,54,59). 

A15.1.1.5 Ketone and Aldehyde. Aldehydes and ketones are characterized by the presence of an acyl group (RCO ) bonded either to hydrogen or to another carbon, respectively. In both cases, carbonyl carbon is electrophilic. A carbon that is beta to carbonyl can be nucleophilic (when deprotonated). Aldehydes tend to be more electrophilic than ketones, in general. 

Another well known example of successful application of Beta zeolite is the substitution of AICI3 for Friedel-Crafts acylation. This reaction is an important industrial process, used for the preparation of various pharmaceuticals, agrochemicals and other chemical products, since it allows us to form a new carbon-carbon bond onto an aromatic ring. Friedel-Crafts acylations generally require more than one equivalent of for example, AICI3 or BF3. This is due to the strong complexation of the Lewis acid by the ketone product. 

For example, at the roughest level of approximation, all carbonyl carbons can be treated as identical they all have similar thermochemistry and all can undergo certain types of reactions (e.g. they all can be formed by beta-scission reactions of the corresponding alkoxy radicals). However, if one looks at the situation more carefully, the carbonyl groups in ketones, ketenes, aldehydes,... 

Two acetyl CoAs can combine to form acetoacetyl CoA by the reverse of b-ketothiolase. The acetoacetyl CoA then combines with another acetyl CoA to make hydroxymethyl glutaryl CoA (HMG CoA) by the enzyme hydroxymethyl glutaryl CoA synthase. The HMG CoA in the mitochondrion can be cleaved by HMG CoA lyase in the mitochondrion to form acetoacetate and acetyl CoA. In this conversion, the formation of acetoacetyl CoA from two acetyl CoAs releases a free CoA and formation of HMG CoA from acetyl CoA and acetoacetyl CoA also releases a free coenzyme A. Thus, the release of free coenzyme A allows beta oxidation to continue with the production of acetoacetate. During diabetes and starvation, almost 90% of carbon from a fatty acid such as oleate can be accounted for in the form of ketone bodies during experiments with perfused livers. At this time, it would be worth noting that this process occurs in the mitochondrion later it will be seen that HMG CoA in the cytosol is a major precursor for cholesterol synthesis. 

This methodology provides for spiroannelation at a carbon beta to the ketone, and is a complementary protocol for the cyclization of a,o>-dihaloalkanes to the kinetic enolates of 1,3-cycloalkanedione enol ethers (at the alpha position).7... 

The Knorr Pyrrole Synthesis. In this process, the starting materials are an alpha-amino ketone, or less commonly an alpha-amino aldehyde, and a beta-ketoester. In the latter, the protons on the alpha carbon are activated both by the keto and the ester carbonyls and are especially easily removed. The Knorr process starts with the condensation of the amino group with the keto group in the usual way to tie the two molecules together as in 4.29 of the example shown in Scheme 4.31. This species then undergoes intramolecular aldol-type condensation to form a reduced pyrrole derivative 4.30. 

One of the functions of hepatic P-oxidation is to provide ketone bodies, acetoac-etate and p-hydroxybutyrate, to the peripheral circulation. These can then be utilized by peripheral tissues such as brain and heart. Beta-oxidation itself produces acetyl-CoA which then has three possible fates entry to the Krebs cycle via citrate S5mthase keto-genesis or transesterification to acetyl-carnitine by the action of carnitine acetyltrans-ferase (CAT). Intramitochondrial acetyl-carnitine then equilibrates with plasma via the carnitine acyl-camitine translocase and presumably via the plasma membrane carnitine transporter. Human studies have shown that acetyl-carnitine may provide up to 5% of the circulating carbon product from fatty acids and can be taker and utilized by muscle and possibly brain." In addition, acyl-camitines are of important with regard to the diagnosis of inborn errors of P- oxidation. For these reasons, we wished to examine the production of acetyl-carnitine and other acyl-camitine esters by neonatal rat hepatocytes. 

The key is to recognize that a COOH group beta to a ketone can be lost by decarboxylation. Once you find where that COOH group might have been located, you should see which carbons of the target molecule can be derived from the carbon skeleton of ethyl acetoacetate and which carbons can be derived from an a,/3-unsaturated carbonyl compound. 

Various other inorganic sorbents are used occasionally in TLC for rather specific separation problems. These sorbents are generally unavailable as precoated plates and must be prepared from aqueous or alcoholic slurries. For further details, see Rossler (1969). Magnesium oxide layers were developed with petroleum ether (30-50°C)-benzene (3 1) for the separation and quantification of alpha- and beta-carotene in lettuce and snails (Drescher et al., 1993). Zinc carbonate with a starch binder has been used to separate aldehydes, ketones, and other carbonyl groups (Rossler, 1969). Magnesium silicate (talc or Florisil) prepared as an alcoholic slurry has been used, to separate pesticides (Getz and Wheeler, 1968), fatty acids, and lanatosides (Rossler, 1969). Charcoal has been combined with silica gel for ketone separations (Rossler, 1969). Two forms of charcoal are available, polar and nonpolar, and each type has very different capabilities. Charcoal has had very limited use in TLC, partly because of the difficulty of zone detection on the layer. For a discussion of the adsorptive properties of charcoal, see Snyder (1975). 

Beta-keto esters can be prepared by treating the enolate of a ketone with diethyl carbonate. Draw a plausible mechanism for this reaction. 

This will always be the case whenever an enolate attacks a carbonyl group, regardless of the structure of the starting ketone and the structure of the enolate. The alpha carbon of the enolate is directly attacking the carbonyl group of the ketone. That wiU always place the OH group in the beta position. Always. This product is called a jS-hydroxy ketone, and the reaction is called an aldol addition. 

The mechanism for the Baeyer-Villiger oxidation of aromatic aldehydes catalyzed by Sn-beta zeolite is similar to that established for cyclic ketones. For this reaction, Corma et al. [40] suggested that the activation of the carbonyl bond is the result of the coordination to the Lewis acidic center followed by a nucleo-phihc attack of the hydrogen peroxide onto the more electrophilic carbonyl carbon atom. In the similar reaction, Bronsted sites are active for oxidation of aromatic aldehydes with H2O2 provided that the molecule does not contain ole-finic groups. 

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