Thermodynamic control solvents

An interesting case are the a,/i-unsaturated ketones, which form carbanions, in which the negative charge is delocalized in a 5-centre-6-electron system. Alkylation, however, only occurs at the central, most nucleophilic position. This regioselectivity has been utilized by Woodward (R.B. Woodward, 1957 B.F. Mundy, 1972) in the synthesis of 4-dialkylated steroids. This reaction has been carried out at high temperature in a protic solvent. Therefore it yields the product, which is formed from the most stable anion (thermodynamic control). In conjugated enones a proton adjacent to the carbonyl group, however, is removed much faster than a y-proton. If the same alkylation, therefore, is carried out in an aprotic solvent, which does not catalyze tautomerizations, and if the temperature is kept low, the steroid is mono- or dimethylated at C-2 in comparable yield (L. Nedelec, 1974). 

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. 

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. 

Entries 7, 8, and 10 describe so-called Idnetically controlled syntheses starting from activated substrates such as ethyl esters or lactose. In two reaction systems it was possible to demonstrate that ionic liquids can also be useful in a thermodynamically controlled synthesis starting with the single components (Entry 11) [39]. In both cases, as with the results presented in entry 6, the ionic liquids were used with addition of less than 1 % water, necessary to maintain the enzyme activity. The yields observed were similar or better than those obtained with conventional organic solvents. 

Lubineau and coworkers [18] have shown that glyoxal 8 (Ri = R2 = H), glyoxylic acid 8 (Ri = H, R2 = OH), pyruvic acid 8 (Ri = Me, R2 = OH) and pyruvaldehyde 8 (Ri = H, R2 = Me) give Diels-Alder reactions in water with poor reactive dienes, although these dienophiles are, for the most part, in the hydrated form. Scheme 6.6 illustrates the reactions with (E)-1,3-dimethyl-butadiene. The reaction yields are generally good and the ratio of adducts 9 and 10 reflects the thermodynamic control of the reaction. In organic solvent, the reaction is kinetically controlled and the diastereoselectivity is reversed. 

The majority of biocatalytic reactions are thermodynamically controlled. Product yield is thus dependent on the equilibrium position of a reaction. Optimization of the product yield requires knowledge of the equilibrium position in different organic solvents. Several works described and compared models for the prediction of the equilibrium position in two-phase media [6, 28, 29, 33]. 

The general mechanistic features of the aldol addition and condensation reactions of aldehydes and ketones were discussed in Section 7.7 of Part A, where these general mechanisms can be reviewed. That mechanistic discussion pertains to reactions occurring in hydroxylic solvents and under thermodynamic control. These conditions are useful for the preparation of aldehyde dimers (aldols) and certain a,(3-unsaturated aldehydes and ketones. For example, the mixed condensation of aromatic aldehydes with aliphatic aldehydes and ketones is often done under these conditions. The conjugation in the (3-aryl enones provides a driving force for the elimination step. 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

Given their extraordinary reactivity, one might assume that o-QMs offer plentiful applications as electrophiles in synthetic chemistry. However, unlike their more stable /tora-quinone methide (p-QM) cousin, the potential of o-QMs remains largely untapped. The reason resides with the propensity of these species to participate in undesired addition of the closest available nucleophile, which can be solvent or the o-QM itself. Methods for o-QM generation have therefore required a combination of low concentrations and high temperatures to mitigate and reverse undesired pathways and enable the redistribution into thermodynamically preferred and desired products. Hence, the principal uses for o-QMs have been as electrophilic heterodienes either in intramolecular cycloaddition reactions with nucleophilic alkenes under thermodynamic control or in intermolecular reactions under thermodynamic control where a large excess of a reactive nucleophile thwarts unwanted side reactions by its sheer vast presence. 

The comparison of I —> N and N —> I may also be explained by the buffered pH in the diffusion layer and leads to an interesting comparison between a process under kinetic control versus one under thermodynamic control. Because the bulk solution in process N —> I favors formation of the ionized species, a much larger quantity of drug could be dissolved in the N —> I solvent if the dissolution process were allowed to reach equilibrium. However, the dissolution rate will be controlled by the solubility in the diffusion layer accordingly, faster dissolution of the salt in the buffered diffusion layer (process I—>N) would be expected. In comparing N—>1 and N —> N, or I —> N and I —> I, the pH of the diffusion layer is identical in each set, and the differences in dissolution rate must be explained either by the size of the diffusion layer or by the concentration gradient of drug between the diffusion and the bulk solution. It is probably safe to assume that a diffusion layer at a different pH than that of the bulk solution is thinner than a diffusion layer at the same pH because of the acid-base interaction at the interface. In addition, when the bulk solution is at a different pH than that of the diffusion layer, the bulk solution will act as a sink and Cg can be eliminated from Eqs. (1), (3), and (4). Both a decrease in the h and Cg terms in Eqs. (1), (3), and (4) favor faster dissolution in processes N —> I and I —> N as opposed to N —> N and I —> I, respectively. 

Alcohols will serve as hydrogen donors for the reduction of ketones and imi-nium salts, but not imines. Isopropanol is frequently used, and during the process is oxidized into acetone. The reaction is reversible and the products are in equilibrium with the starting materials. To enhance formation of the product, isopropanol is used in large excess and conveniently becomes the solvent. Initially, the reaction is controlled kinetically and the selectivity is high. As the concentration of the product and acetone increase, the rate of the reverse reaction also increases, and the ratio of enantiomers comes under thermodynamic control, with the result that the optical purity of the product falls. The rhodium and iridium CATHy catalysts are more active than the ruthenium arenes not only in the forward transfer hydrogenation but also in the reverse dehydrogenation. As a consequence, the optical purity of the product can fall faster with the... 

A theoretical study at a HF/3-21G level of stationary structures in view of modeling the kinetic and thermodynamic controls by solvent effects was carried out by Andres and coworkers [294], The reaction mechanism for the addition of azide anion to methyl 2,3-dideaoxy-2,3-epimino-oeL-eiythrofuranoside, methyl 2,3-anhydro-a-L-ciythrofuranoside and methyl 2,3-anhydro-P-L-eiythrofuranoside were investigated. The reaction mechanism presents alternative pathways (with two saddle points of index 1) which act in a kinetically competitive way. The results indicate that the inclusion of solvent effects changes the order of stability of products and saddle points. From the structural point of view, the solvent affects the energy of the saddles but not their geometric parameters. Other stationary points geometries are also stable. 

Andres, J., Bohm, S., Moliner, V., Silla, E. and Tunon, I. Atheoretical study of stationary structures for the addition of azide anion to tetrafuranosides modeling the kinetic and thermodynamic controls by solvent effects, J. Phys. Chem., 98 (1994), 6955-6960... 

Silver tetrafluoroborate in ether or toluene has also been used for the synthesis of glycosyl fluorides. Peracetylated 2-chloro-2-deoxy-D-gluco- and -mannopyranosyl fluorides have been prepared by treatment of the corresponding chlorides with the aforementioned reagent.50,51 Products of kinetic control were obtained when diethyl ether was used as the solvent, whereas products of thermodynamic control were obtained when toluene was used instead. Peracetylated... 

The regiochemistry of the addition depends on temperature and solvent. At low temperatures, under kinetic control, the AM products are favored while at room temperature or above, under thermodynamic control, the M adducts are generally formed. 

It has been demonstrated that organotin-mediated multiple carbohydrate esterifications can be controlled by the acytaring reagent and the solvent polarity. When acetyl chloride is used, the reactions are under thermodynamic control, whereas when acetic anhydride is employed, kinetic control takes place. Very good selectivity can furthermore be obtained in more polar solvents. These results can be used in the efficient preparation of prototype carbohydrate structures. 

The use of /i-ketocstcrs and malonic ester enolates has largely been supplanted by the development of the newer procedures based on selective enolate formation that permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of ketoesters intermediates. Most enolate alkylations are carried out by deprotonating the ketone under conditions that are appropriate for kinetic or thermodynamic control. Enolates can also be prepared from silyl enol ethers and by reduction of enones (see Section 1.3). Alkylation also can be carried out using silyl enol ethers by reaction with fluoride ion.31 Tetraalkylammonium fluoride salts in anhydrous solvents are normally the... 

While the Sn2 reaction represents an extreme case, it is clear that the solvent is capable of selectively stabilizing (or destabilizing) one product over another in a thermodynamically-controlled reaction, or one transition state over another in a kinetically-controlled reaction. Differentiation might be effected by steric and/or electronic considerations. 

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