Tautomers aldehydes

Of all the methods described for the synthesis of thiazole compounds, the most efficient involves the condensation of equimolar parts of thiourea (103) and a-haloketones or aldehydes to yield the corresponding 2-aminothiazoles (104a) or their 2-imino-A-4-thiazoline tautomers (104b) with no by-products (Method A, Scheme 46). 

The aldehyde or ketone is called the keto form and the keto enol equilibration referred to as keto-enol isomerism or keto-enol tautomerism Tautomers are constitu tional isomers that equilibrate by migration of an atom or group and their equilibration IS called tautomerism The mechanism of keto-enol isomerism involves the sequence of proton transfers shown m Figure 9 6... 

Aldehydes and ketones ( keto forms) normally exist in equilibrium with their enol tautomers. 

Methods of the first type have been used for both qualitative and quantitative investigation. An important limitation is that the rates of interconversion of the tautomeric forms must be small as compared with those of the test reaction (s). The method is further complicated since the test reactions are sometimes complex and it is difficult to be certain that only one tautomer is reacting. An even more fundamental objection is that much chemical evidence is based on incorrect reaction mechanisms. Thus, the formation of condensation products (30) with aldehydes has repeatedly been quoted as evidence for structures of type 31 and against type 32,. whereas if 31 does react with an aldehyde it must either first tautomerize to 32 or ionize to 33. 

The chemistry of alkynes is dominated by electrophilic addition reactions, similar to those of alkenes. Alkynes react with HBr and HC1 to yield vinylic halides and with Br2 and Cl2 to yield 1,2-dihalides (vicinal dihalides). Alkynes can be hydrated by reaction with aqueous sulfuric acid in the presence of mercury(ll) catalyst. The reaction leads to an intermediate enol that immediately isomerizes to yield a ketone tautomer. Since the addition reaction occurs with Markovnikov regiochemistry, a methyl ketone is produced from a terminal alkyne. Alternatively, hydroboration/oxidation of a terminal alkyne yields an aldehyde. 

Carbonyl compounds are in a rapid equilibrium with called keto-enol tautomerism. Although enol tautomers to only a small extent at equilibrium and can t usually be they nevertheless contain a highly nucleophilic double electrophiles. For example, aldehydes and ketones are at the a position by reaction with Cl2, Br2, or I2 in Alpha bromination of carboxylic acids can be similarly... 

Ring-chain tautomerism occurs in sugars (aldehyde vs. the pyranose or ftira-nose structures). In benzamide carboxaldehyde (125), whose ring-chain tautomer is... 

Although the conversion of an aldehyde or a ketone to its enol tautomer is not generally a preparative procedure, the reactions do have their preparative aspects. If a full mole of base per mole of ketone is used, the enolate ion (10) is formed and can be isolated (see, e.g., 10-105). When enol ethers or esters are hydrolyzed, the enols initially formed immediately tautomerize to the aldehydes or ketones. In addition, the overall processes (forward plus reverse reactions) are often used for equilibration purposes. When an optically active compound in which the chirality is due to an asymmetric carbon a to a carbonyl group (as in 11) is treated with acid or base, racemization results. If there is another asymmetric center in the molecule. 

Another related reaction is the Barton reaction, by which a methyl group in the 0 position to an OH group can be oxidized to a CHO group. The alcohol is first converted to the nitrite ester. Photolysis of the nitrite results in conversion of the nitrite group to the OH group and nitrosation of the methyl group. Hydrolysis of the oxime tautomer gives the aldehyde, for example,... 

The high selectivity of the catalyst in forming ( )-alkenes can be used in interesting ways (eq. 1). For example, in acetone-iie solution, within 15 min at room temperature allyl alcohol is converted to nearly pure enol (E)-26. Under these mild conditions, the product slowly isomerizes to the more stable aldehyde tautomer. We know of one other report of rapid enol formation from allyl alcohol, using a Rh... 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

Condensation of [3- or "y-amino alcohols with aldehydes or ketones RR CO gives the product 27. In solution the position of the equilibrium varies with R and R, and with the solvent (73). When the carbonyl reactant is a substituted benzaldehyde, the solid is found (IR, KBr) to comprise molecules of the open-chain structure 27a, whereas aliphatic aldehydes and ketones give crystals of dihydro- 1,3-benzoxazines, 27b. An interesting case is that of the condensation product of o-hydroxybenzylamine with cyclopentanone, for which McDonagh and Smith (73) suggest that ring and chain tautomers coexist in the solid. 

Enol esters are distinct from other esters not because of a particular stability or lability toward hydrolases, but due to their hydrolysis releasing a ghost alcohol (an enol), which may immediately tautomerize to the corresponding aldehyde or ketone. A well-studied example is that of vinyl acetate (CH3-C0-0-CH=CH2), a xenobiotic of great industrial importance that, upon hydrolysis, liberates acetic acid (CH3-CO-OH) and acetaldehyde (CH3-CHO), the stable tautomer of vinyl alcohol [25], The results of two studies are compiled in Table 7.1, and demonstrate that vinyl acetate is a very good substrate of carboxylesterase (EC 3.1.1.1) but not of acetylcholinesterase (EC 3.1.1.7) or cholinesterase (EC 3.1.1.8). The presence of carboxylesterase in rat plasma but not in human plasma explains the difference between these two preparations, although the different experimental conditions in the two studies make further interpretation difficult. 

Treatment of benzaldehydes with ethyl diazoacetate and a catalytic quantity of the iron Lewis acid [ -CpFe(CO)2(THF)]+BF4 yields the expected homologated ketone (80). However, the major product in most cases is the aryl-shifted structure (81a), predominantly as its enol tautomer, 3-hydroxy-2-arylacrylic acid (81b). This novel reaction occurs via a 1,2-aryl shift. Although the mechanism has not been fully characterized, there is evidence for loss of THF to give a vacancy for the aldehyde to bind to the iron, followed by diazoacetate attachment. The product balance is then determined by the ratio of 1,2-aryl to -hydride shift, with the former favoured by electron-donating substituents on the aryl ring. An alternative mechanism involving epoxide intermediates was ruled out by a control experiment. 

Bis [(trifluoromethyl)thio] acetaldehyde (83a) has been prepared from an enam-ine precursor (84), although refluxing in aqueous ethanolic HCl is required to effect this reaction.The aldehyde is less stable than its enol tautomer (83b), and many reactions typical of aldehydes fail. For example, addition of aqueous silver nitrate immediately yields the silver salt of (83b), rather than giving precipitation of (elemental) silver. The (trifluoromethyl)thio substituent has pseudohalogenic character and, together with the hydroxy group, stabilizes the alkene tautomer in the manner of a push-pull alkene. The enol-aldehyde equilibrium mixture in acetonitrile shows an apparent of 2.6 when titrated with aqueous hydroxide. 

There is a distinct relationship between keto-enol tautomerism and the iminium-enamine interconversion it can be seen from the above scheme that enamines are actually nitrogen analogues of enols. Their chemical properties reflect this relationship. It also leads us to another reason why enamine formation is a property of secondary amines, whereas primary amines give imines with aldehydes and ketones (see Section 7.7.1). Enamines from primary amines would undergo rapid conversion into the more stable imine tautomers (compare enol and keto tautomers) this isomerization cannot occur with enamines from secondary amines, and such enamines are, therefore, stable. 

The reaction is exactly analogous to the chemical aldol reaction (also shown), but it utilizes an enamine as the nucleophile, and it can thus be achieved under typical enzymic conditions, i.e. around neutrality and at room temperature. There is one subtle difference though, in that the enzyme produces an enamine from a primary amine. We have indicated that enamine formation is a property of secondary amines, whereas primary amines react with aldehydes and ketones to form imines (see Section 7.7.1). Thus, a further property of the enzyme is to help stabilize the enamine tautomer relative to the imine. 

The Mannich reaction is best discussed via an example. A mixture of dimethylamine, formaldehyde and acetone under mild acidic conditions gives N,N-dimethyl-4-aminobutan-2-one. This is a two-stage process, beginning with the formation of an iminium cation from the amine and the more reactive of the two carbonyl compounds, in this case the aldehyde. This iminium cation then acts as the electrophile for addition of the nucleophile acetone. Now it would be nice if we could use the enolate anion as the nucleophile, as in the other reactions we have looked at, but under the mild acidic conditions we cannot have an anion, and the nucleophile must be portrayed as the enol tautomer of acetone. The addition is then unspectacular, and, after loss of a proton from the carbonyl, we are left with the product. 

The meso-ionic 1,3-oxazol-S-ones show an incredible array of cycloaddition reactions. Reference has already been made to the cycloaddition reactions of the derivative 50, which are interpreted as involving cycloaddition to the valence tautomer 51. In addition, an extremely comprehensive study of the 1,3-dipolar cycloaddition reactions of meso-ionic l,3-oxazol-5-ones (66) has been undertaken by Huisgen and his co-workers. The 1,3-dipolarophiles that have been examined include alkenes, alkynes, aldehydes, a-keto esters, a-diketones, thiobenzophenone, thiono esters, carbon oxysulfide, carbon disulfide, nitriles, nitro-, nitroso-, and azo-compounds, and cyclopropane and cyclobutene derivatives. In these reactions the l,3-oxazol-5-ones (66)... 

In the currently accepted mechanistic pathway outlined in Scheme 7, the key step in the Biginelli sequence involves the acid-catalyzed formation of an Wacyliminium ion intermediate of type 719 from the aldehyde and urea precursors <1997JOC7201, 2000ACR879, 20040R1>. Interception of the iminium ion 719 by the CH-acidic carbonyl component 715, presumably through its enol tautomer, produces an open-chain ureide 720, which subsequently cyclizes to hexahydropyrimidine 721. Acid-catalyzed elimination of water from 721 ultimately leads to the... 

The UV-visible absorption spectrum of the monoprotonated form of PLP was divided mathematically into individual bands for the aldehyde with dipolar ionic ring (+), the aldehyde tautomer with an uncharged ring (0) and the hydrate of the dipolar ion. The following fractions were estimated (Harris et al, 1976, Biochem. Biophys. Acta. 521,181-194. 

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