Enols acidity

NSAIDs are of diverse chemical structures salicylates (aspirin, sulphasalazine), indole acetic acids (indomethacin, etodolac), heteroaryl acetic acids (diclofenac), arylpropionic acids (ibuprofen, naproxen), anthranilic acids (mefenamic acid) and enolic acids (piroxicam, meloxicam). 

Amination of ketene has been studied by ab initio methods.Reactions of ammonia, its dimer, and its (mono)hydrate with ketene have been calculated and compared with earlier smdies of ammonia (at lower levels of theory), of water, and of water dimer. In general, the results favour initial addition of ammonia to the C=0 bond (giving the enol amide), as against addition to the C=C bond (which gives the amide directly). Amide formation is compared with the corresponding hydration reaction where enol acid and acid are the alternative immediate products. Most of the reactions, i.e. both additions and tautomerizations, are suggested to involve cyclic six-membered transition states. 

Apart from the salicylates NSAIDs include several classes of weak acids like propionic acid derivatives such as ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid and suprofen. Phenylbutazone is the most important representative of the pyrazolon derivatives which have a bad reputation for their risk of potentially fatal bone-marrow toxicity. To the acetic acid derivatives belong in-domethacin, diclofenac and sulindac. Sulindac is a pro-drug with less toxicity than indomethacin. The enolic acids include piroxicam, droxicam and tenoxicam. Meloxicam is an analog of piroxicam and has a high selectivity for COX-2. 

In practice, the Konstanecki-Robinson synthesis of chromones commences with O-benzoylation not C-benzoylation, to afford ester 9.24. Base-catalysed rearrangement produces the required 1,3-diketone 9.21, via intramolecular benzoylation of the intermediate enolate. Acid-catalysed dehydration then affords flavone 9.19. 

The Merck group s efforts to find a more stable substitute for the DKA pharmacophore resulted in the design of 8-hydroxy-[l,6]naphthyridines such as compound 10,19 wherein the keto-enol-acid triad was replaced with a 1,6-naphthyridine ketone bearing a phenolic hydroxyl group. Further refinement of compound 10—replacement of the naphthyridine phenyl ketone with a 4-fluorobenzyl carboxamide and addition of a six-membered sulfonamide at the 5-position of the naphthyridine core—resulted in compound 11, the second IN inhibitor to reach the clinic.20 The discovery of liver toxicity in long-term safety studies of compound 11 in dogs led to the suspension of clinical development21 of this compound. 

A second IN inhibitor has reached Phase III clinical trials since the launch of raltegravir. Elvitegravir (13) is a dihydroquinolone carboxylic acid the monoketo acid motif of this series of inhibitors is proposed to mimic the keto-enol-acid triad of the DKA lead structures.24 Like raltegravir, elvitegravir is a specific inhibitor of HIV-1 strand transfer.25... 

Fig. 4 Determination of acetophenone enol acidity constant by flash spectroscopy. Enolate absorption (310 nm) as a function of pH (Haspra et al., 1979). (Reprinted by courtesy of Angewandte Chemie, Verlag Chemie, GmbH, Weinheim, Germany)...

From all this recent work, it appears that the problem of enol acidity constants is going to be solved, even though data are at present scarce. In particular, the method suggested by Haspra et al. (1979) is certainly very powerful. 

Some typical ketone to enolate acidity constants (water 25°C)... 

Nonselective COX inhibitors derive from salicylic acid. The majority are carbonic acids, such as ibuprofen, naproxene, diclofenac, indometacin, and many more or enolic acids, such as azapropazone and meloxicam. All these drugs inhibit both COX enzymes. 

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. ... 

Enols (pATa ca = 11-12) are usually more acidic than alcohols [e.g. EtOH pATa (H2O) = 15.9 ] but are less acidic than phenols [e.g. PhOH pATa(H20) = 9.95 ]. The acidity of enols (and the basicity of the corresponding enolate) is surprisingly uniform when considering the relative acidity of the carbonyl derivative. The majority of enols derived from saturated aldehydes and ketones have pATa ca 11-12. For simple aldehydes and ketones, such as acetaldehyde (45) and acetone (45 ), their enol acidity (pATa ) in water is similar even when their keto acidity (pATa ) is moderately different. It is interesting to note that relative enol stability (pATs) plays little or no role in the relative acidity of enols for example, as is the case of 45 and 45. ... 

Enol acidity can be increased (or enolate basicity lowered) by increasing the conjugation of the resulting enolate. Interestingly, the enol of pentane-2,4-dione (48 ) was found to... 

Enol acidity can be increased by simply ensuring that conjugation is present in the enolic form but not the carbonyl form. 2-Indanone (49) has greater enolic acidity than both 2-tetralone (50) and 2-benzosuberone (51) due to more efficient tt-overlap with the adjacent aryl ring . By comparison, conjugation present in both the ketonic and enolic forms, such as in 1-tetralone (52) and 4-chromanone 52 ), increases enol acidity relative to saturated compounds such as acetone (45 ). 

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