Thermodynamic enolates

Cyclopentenones 1 disconnect to 1,4-dicarbonyl compounds 2. Any of the methods in chapter 25 may be used to make these but the regioselectivity of the cyclisation is an important consideration. If R = Me 3, cyclisation can lead only to 1 R = Me but, if R = Et 4, could cyclise to 5 or 6 depending on which ketone forms the enolate. Thermodynamically 6 is favoured as it has a more highly substituted alkene, but it is close. 

We have established that enols are, in general, less stable than the keto form of the molecule. We might hope to see stable enols if we changed that situation by adding some feature to the molecule that stabilized the enol thermodynamically. Or we might try to create an enol that would revert only slowly to the keto form—in other words, it would be kinetically stable. We shall look at this type first. 

Enolates are selectively formed by treating ketones with a strong base such as lithium diisopropylamide (LDA) [LiN(i-C3H7)2] and tetrahydrofuran (THE) at —78°C, NaH or alkoxide ion. LDA and THE at —78°C give less stable, i.e. less substituted, enolate (kinetic enolate) 3.5 from unsymmetrical ketone 3.4, whereas methoxide (CEisO ) forms the more stable, i.e. more substituted, enolate (thermodynamic enolate) 3.6 from unsymmetrical ketone 3.4. 

The formation constants of an actinium isopropyltropolonate complex were determined. Thermochemically relevant studies of thorium enolates generally involve bis(pentamethyl-cyclopentadienyl)thorium derivatives. Cp 2Th(Cl)(C(0)CFl2Bu-f) with an anionic acyl group that readily rearranges to the isomeric enolate Cp 2Th(Cl)OCH=CHBu-t. The Z-isomer is formed upon heating and the -isomer upon catalysis with Cp 2ThH2. Is the E or Z enolate thermodynamically more stable For the simple alkyl enolates MeCH=CHOR, the equilibration reaction of the Z- and E-isomers is nearly thermo-neutral . Consider the two species Cp 2Th(H)OCH(Bu-t)2 and Cp 2Th(H)0-2,6-C6H3 (Bu-f)2. The reversible addition of CO yields the rp- formyl derivative in reactions that are 19 4 and 25 6 kJmoR exothermic. These formyl species dimerize to form the classical enediolate, Cp 2Th(OR)OCH=CHO(OR)ThCp 2. This product is formed as the Z-isomer, plausibly thermodynamically preferred over the -isomer, much as (Z)-MeOCH=CHOMe is preferred over its E-counterpart by 6.0 0.2 kJmoR. ... 

Thermodynamic Enolate- Reversible deprotonation to give the most stable enolate more highly substituted C=C of the enol form... 

The ketone is added to a large excess of a strong base at low temperature, usually LDA in THF at -78 °C. The more acidic and less sterically hindered proton is removed in a kineti-cally controlled reaction. The equilibrium with a thermodynamically more stable enolate (generally the one which is more stabilized by substituents) is only reached very slowly (H.O. House, 1977), and the kinetic enolates may be trapped and isolated as silyl enol ethers (J.K. Rasmussen, 1977 H.O. House, 1969). If, on the other hand, a weak acid is added to the solution, e.g. an excess of the non-ionized ketone or a non-nucleophilic alcohol such as cert-butanol, then the tautomeric enolate is preferentially formed (stabilized mostly by hyperconjugation effects). The rate of approach to equilibrium is particularly slow with lithium as the counterion and much faster with potassium or sodium. 

The addition of large enolate synthons to cyclohexenone derivatives via Michael addition leads to equatorial substitution. If the cyclohexenone conformation is fixed, e.g. as in decalones or steroids, the addition is highly stereoselective. This is also the case with the S-addition to conjugated dienones (Y. Abe, 1956). Large substituents at C-4 of cyclic a -synthons direct incoming carbanions to the /rans-position at C-3 (A.R. Battersby, 1960). The thermodynamically most stable products are formed in these cases, because the addition of 1,3-dioxo compounds to activated double bonds is essentially reversible. 

In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

The following acid-catalyzed cyclizations leading to steroid hormone precursors exemplify some important facts an acetylenic bond is less nucleophilic than an olelinic bond acetylenic bonds tend to form cyclopentane rather than cyclohexane derivatives, if there is a choice in proton-catalyzed olefin cyclizations the thermodynamically most stable Irons connection of cyclohexane rings is obtained selectively electroneutral nucleophilic agents such as ethylene carbonate can be used to terminate the cationic cyclization process forming stable enol derivatives which can be hydrolyzed to carbonyl compounds without this nucleophile and with trifluoroacetic acid the corresponding enol ester may be obtained (M.B. Gravestock, 1978, A,B P.E. Peterson, 1969). 

Catalytic hydrogenation of the 14—15 double bond from the face opposite to the C18 substituent yields (196). Compound (196) contains the natural steroid stereochemistry around the D-ring. A metal-ammonia reduction of (196) forms the most stable product (197) thermodynamically. When R is equal to methyl, this process comprises an efficient total synthesis of estradiol methyl ester. Birch reduction of the A-ring of (197) followed by acid hydrolysis of the resultant enol ether allows access into the 19-norsteroids (198) (204). 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the case of formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and will be discussed more fully in Chapter 1 of Part B. Most ketones, highly symmetric ones being the exception, can give rise to more than one enolate. Many studies have shown tiiat the ratio among the possible enolates that are formed depends on the reaction conditions. This can be illustrated for the case of 3-methyl-2-butanone. If the base chosen is a strong, sterically hindered one and the solvent is aptotic, the major enolate formed is 3. If a protic solvent is used or if a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Enolate 3 is the kinetic enolate whereas 2 is the thermodynamically favored enolate. 

There have been numerous studies of the rates of deprotonation of carbonyl compounds. These data are of interest not only because they define the relationship between thermodynamic and kinetic acidity for these compounds, but also because they are necessary for understanding mechanisms of reactions in which enolates are involved as intermediates. Rates of enolate formation can be measured conveniently by following isotopic exchange using either deuterium or tritium ... 

The aldol addition can be carried out under either ofitwo broad sets of conditions, with the product being determined by kinetic factors undenone set of conditions and by thermodynamic factors under the other. To achieve kinetic control, the enolate that is to... 

For the other broad category of reaction conditions, the reaction proceeds under conditions of thermodynamic control. This can result from several factors. Aldol condensations can be effected for many compounds using less than a stoichiometric amount of base. Under these conditions, the aldol reaction is reversible, and the product ratio will be determined by the relative stability of the various possible products. Conditions of thermodynamic control also permit equilibration among all the enolates of the nucleophile. The conditions that permit equilibration include higher reaction temperatures, protic solvents, and the use of less tightly coordinating cations. 

When the aldol reaction is carried Wt under thermodynamic conditions, the product selectivity is often not as high as under kinetic conditions. All the regioisomeric and stereoisomeric enolates may participate as nucleophiles. The adducts can return to reactants, and so the difference in stability of the stereoisomeric anti and syn products will determine the product composition. 

Protonation of the a-carbanion (50), which is formed both in the reduction of enones and ketol acetates, probably first affords the neutral enol and is followed by its ketonization. Zimmerman has discussed the stereochemistry of the ketonization of enols and has shown that in eertain cases steric factors may lead to kinetically controlled formation of the thermodynamically less stable ketone isomer. Steroidal unsaturated ketones and ketol acetates that could form epimeric products at the a-carbon atom appear to yield the thermodynamically stable isomers. In most of the cases reported, however, equilibration might have occurred during isolation of the products so that definitive conclusions are not possible. 

If the equilibrium were established rapidly, reduction of the free ketone as it formed would result in a substantial loss of product. Lithium enolates are more covalent in character than are those of sodium and potassium and consequently are the least basic of the group. This lower thermodynamic basicity appears to be paralleled by a lower kinetic basicity several workers have shown that lithium enolates are weaker bases in the kinetic sense than are those of sodium and potassium." As noted earlier, conjugated enones... 

As first demonstrated by Stork,the metal enolate formed by metal-ammoni reduction of a conjugated enone or a ketol acetate can be alkylated in liquic ammonia. The reductive alkylation reaction is synthetically useful since ii permits alkylation of a ketone at the a-position other than the one at whicf thermodynamically controlled enolate salt formation occurs. Direct methyl-ation of 5a-androstan-17-ol-3-one occurs at C-2 whereas reductive methyl-... 

A commonly used alternative to the direct bromination of ketones is the halogenation of enol acetates. This can be carried out under basic conditions if necessary. Sodium acetate, pyridine or an epoxide is usually added to buffer the reaction mixture. The direction of enolization is again dependent upon considerations of thermodynamic and kinetic control therefore, the proportion of enol acetates formed can vary markedly with the reaction conditions. Furthermore, halogenation via enol acetates does not necessarily give the same products as direct halogenation of ketones 3. 23... 

The enolization of 5a-3-ketones appears to be cleanly directed to C-2, whereas that of 5j5-3-ketones is less selective. Remote substituents can have a significant effect on the kinetic and thermodynamic enol acetylation of 5j3-steroids. ... 

In general bromination of 20-ketones is directed to the introduction of functionality at C-21. However, on occasion 17-bromo compounds are required for dehydrobromination to A -20-ketones, although these are generally obtained in other ways. Kinetic enolization of a 20-ketone gives the A °-enol, whereas the thermodynamic product is the A kjsomer. An interesting enolate trapping reaction has been used recently to prepare 16-methyl-A -20-ketones ... 

Bromination of 5j5-3-ketones yields the equatorial 4 -bromo compounds (22) as the thermodynamic or kinetic products,although the presence of a considerable amount of 2-bromo isomer has been reported in bromination with phenyltrimethylammonium bromide-perbromide. This is in keeping with other evidence that enolization of 5j5-3-ketones is not specifically directed to C-4. Cleaner results would probably be obtained via thermodynamic enol acelylation. ... 

A useful alternate procedure which allows the generation and alkylation of the less stable enolate anion has been reported by Stork.This method takes advantage of the fact that the thermodynamically less stable enolate anion formed in the lithium ammonia reduction of a conjugated enone... 

The heats of reaction for O-alkylation and C-alkylation of enolate anions clearly show that the latter reactions lead to the thermodynamically more stable products 12). 

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