Carbonyl tautomers

Thomsont Click Organic Interactive to learn to interconvert enol and carbonyl tautomers. 

In 2-hydroxyfuran (Scheme 12), tautomerism always involves loss of aromatic stabilization, but the energy loss is far less here. Moreover, favorable interaction in the carbonyl tautomers offsets part of this loss, and the higher bond energy of the carbonyl group means that the carbonyl form is favored for... 

However, 2-aminopyridine and 4-aminopyridine exist almost entirely as the amino tautomers - indeed, we have just seen 2-aminopyridine as a product of the Chichibabin reaction. Which tautomer is preferred for hydroxy and amino heterocycles is not always easily explained but, as a generalization, we find that the oxygen derivatives exist as carbonyl tautomers and amino heterocycles favour the amino tautomers. At this stage, we should just register the potential for tautomerism in aminopyridines we shall see important examples with other heterocycles (see Section 11.6.2). 

The diazinone tautomers are identified by using terminology such as 3(2//)-pyridazinone for the carbonyl tautomer of 3-hydroxypyrazine. The 3(2//) prefix signifies the position of the oxygen (3-pyridazinone) and specifies the NH is at position 2. Note that, in addition to the diazine-diazinone tau-tomerism, when the nitrogens have a 1,3-relationship there is further tautomerism possible, e.g. 4(1//)-pyrimidone 4(3//)-pyrimidone. 

Before turning to the dihydro and tetrahydro derivatives of the fundamental ring systems, we deal with two special classes. The pyrrolenines and the thiophene sulfones both contain two double bonds in the heterocyclic ring, but in each case the conjugation does not include all the ring atoms. Finally we consider hydroxy derivatives, most of which exist predominantly as the non-aromatic carbonyl tautomers. 

In the majority of cases, the equilibrium lies predominantly in favor of the carbonyl tautomer, and for this reason these compounds are considered in the present section. (Most amino and mercapto analogues, while also tautomeric, exist predominantly as such, and they are therefore considered as substituted aromatic compounds.)... 

Hydroxy compounds are considered in Section 3.3.2.5, with their non-aromatic carbonyl tautomers. 

In compounds with several potential hydroxyl groups, such as the oxauracil (17) (79JHC161) and the barbituric acid analogue (53) (61JOC3461), the carbonyl tautomers are usually preferred. 

In general, when hydroxyl groups might seem possible, as in barbituric acid analog 33, the carbonyl tautomers are preferred (84MI1), possibly because of the more favorable antiparallel orientation of the CO and NH dipoles. 

The normal addition process is identical to the other reactions that have been encountered so far in this chapter The nucleophile bonds to the carbonyl carbon and the electrophile bonds to the oxygen of the carbonyl group. In a conjugate addition the nucleophile bonds to the /3-carbon. The electrophile, a proton, can bond to either the a-carbon or the oxygen of the resonance stabilized anion. It actually reacts faster at the oxygen, producing an enol in an overall 1,4-addition. However, as discussed in Section 11.6, ends are less stable than the carbonyl tautomers, so the product that is isolated contains the carbonyl group. 

This compound is a tautomer of an amide. Tautomerization occurs in the same manner as was the case for the conversion of an enol to its carbonyl tautomer. 

O In base a proton is first removed from the carbon of the carbonyl tautomer. 

If, instead, the proton is added to the carbon, the carbonyl tautomer forms in the reverse of the first step. 

If a simple enol is generated by some reaction, such as the addition of water to an alkyne described in Section 11.6, the enol cannot be isolated because it rapidly converts to the more stable carbonyl tautomer. The lifetime of CH2=CHOH, the simplest enol, is about 1 minute in aqueous solution at pH 7, about 1 second in acidic solution, and about 10-6 second in basic solution. 

An alcohol with the hydroxyl group bonded to a carbon atom of a carbon-carbon double bond. Most enols are unstable, spontaneously isomerizing to their carbonyl tautomers, called the keto form of the compound. See tautomers, (p. 411)... 

A distinction cannot be drawn between the pseudobase and its ring-opened amino-carbonyl tautomer (Section V,A) as the predominant species... 

Enols are generally more acidic (pA a ca 11-12) than their corresponding carbonyl tautomer (pATa ca 17-25). Exceptions to this arise when the carbonyl derivative is either destabilized relative to the enol component, or when the enol is exceptionally stable, as in the case of phenol [pATa (H20) = 9.95] vs. cyclohexa-2,4-dienone [pATa (H20) = —3 1]. Enol acidity can be controlled by O-H bond strength. In certain cases, the relative proportion of enol content can be determined by the relative strengths of the C=0 and C—H bonds in the carbonyl tautomer versus the C=C and O—H bonds in the enol. ... 

Although aldol condensation is another type of ionic reaction, it deserves special consideration. It can lead to two classes of sugars. Condensation of an aldehyde in an a-position of a free carbonyl group under mildly akaline conditions still seems possible. This very simple reaction can also be quite efficient. Thus diacetal 7.59, quantitatively prepared by treatment of mannose with acetone in an acidic medium, is at equilibrium with the carbonyl tautomer. Condensation with formaldehyde, used in aqueous solution in the presence of potassium carbonate, gives the hydroxymethylated sugar 7.60 in 86% yield (Ho 1979). 

Circular dichroism measurements have been considered in order to observe the carbonyl tautomers which are particularly quickly fading. Carbonyl compounds absorb near 280 nm due to the utt transition of the C=O double bond. The beginning of this band is visible in aqueous solutions of sugars, but because of its weak intensity, it is largely masked by the shoulder of a more intense one. For this reason, extinction cannot be directly determined. But what is characteristic is the presence of a circular dichroism in this region, that is to say an extinction difference of fit - = Aff between left- and right-circulatory polarized light. This is... 

Pyridines with an oxygen at either the 2- or 4-position exist predominantly as carbonyl tautomers, which are therefore known as pyridones (see also 2.5). In the analogous oxygen heterocycles, no alternative tautomer is possible the systems are known as pyrones . The extent to which such molecules are aromatic has been a subject for considerable speculation and experimentation, and estimates have varied considerably. The degree of aromaticity depends on the conriibution that dipolar stractures, 25 and 27, with a complete pyridinium (pyrylium) ring make to the overall structure. Pyrones are less aromatic than pyridones, as can be seen from their tendency to undergo addition reactions (11.2.2.4), and as would be expected... 

In 3-oxy-isoquinoline there is an interesting and instructive situation here the two tautomers are of comparable stability. 3-Isoquinolinol is dominant in dry ether solution, 3-isoquinolone is dominant in aqueous solution. A colourless ether solution of 3-isoquinolinol turns yellow on addition of a little methanol because of the production of some of the carbonyl tautomer. The similar stabilities are the consequence of the balancing of two opposing tendencies the presence of an amide unit in 3-isoquinolone forces the benzene ring into a less favoured quinoid stracture conversely, the complete benzene ring in isoquinolinol necessarily means loss of the amide unit and its contribution to stability. One may contrast this with 1-isoquinolone which has an amide, as well as a complete benzene unit. °... 

The carbonyl tautomers deprotonate at N-H, generating ambident anions that can react at either oxygen or nitrogen, depending on the exact conditions for example 0-alkylation can be achieved with silver carbonate. They are converted, as with the pyridones, into halo-quinolines and halo-isoquinolines by reaction with phosphorus halides. 

The most studied diazine derivatives are the oxy- and amino-pyrimidines, since uracil, thymine and cytosine are found as bases in DNA and RNA. Carbonyl tautomers are the preferred forms. It is the enamide-Uke character of the double bonds in diazine diones that allows electrophilic substitution - uracil, for example, can be brominated at C-5. One amino-substituent permits electrophilic ring substitution and two amino, or one amino and one oxy, substituents, permit substitution with even weakly electrophilic reactants. 

With the exception of 5-hydroxypyrimidine, which is analogous to 3-hydroxypyridine, aU the mono-oxygenated diazines exist predominantly as carbonyl tautomers and are thus categorised as diazinones. 

Oxindole exists as the carbonyl-tautomer, the hydroxy 1-tautomer ( 2-hydroxyindole ) being undetectable. There is nothing remarkable about the reactions of oxindole for the most part it is a typical 5-membered lactam, except that deprotonation at the p-carbon (pA a 18) occurs more readily than with simple amides, because the resulting anion is stabilised by an aromatic indole resonance contributor. Such anions will react with electrophiles like alkyl halides and aldehydes at the p-carbon, the last with dehydration and the production of aldol condensation products. Oxindoles can be oxidised to isatins (20.13.3) via easy 3,3-dibromination, then hydrolysis. Bromination of oxindole with A -bromosuccinimide gives... 

Pittman and co-workers investigated the structure and properties of 2,4-diamino-6-hydroxy-l,3,5-triazine, 2,4,6-triamino-l,3,5-triazine, and 2,4-diamino-1,3,5-triazine by ab initio calculations at the SCF level with several different basis sets. The hydroxy tautomer of 4,6-diamino-2-hydroxy-l,3,5-triazine (7) was predicted to be 4.82 kcal mol more stable than its 1//-carbonyl tautomer (8), and... 

Direct preparation of poly(vinyl alcohol) would require an enol as the monomer. However, recall that most enols cannot be isolated because they spontaneously isomerize to the carbonyl tautomer (see Section 11.6). 

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