Selectivity, thermodynamic control

Heats of reaction Heats of reaction can be obtained as differences between the beats of formation of the products and those of the starting materials of a reaction. In EROS, heats of reaction arc calculated on the basis of an additivity scheme as presented in Section 7.1. With such an evaluation, reactions under thermodynamic control can be selected preferentially (Figure 10.3-10). 

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). 

Dimethylborane+propene C2 and 2-propyldimethyl borane depict the regioisomeric transition state and addition product. Calculate the energies of these species relative to those of the alternative transition state and product. Given these energy differences, and the experimental observation that this addition is almost completely selective for the anti-Markovnikov product, does it appear that this reaction is under kinetic or thermodynamic control Explain. 

Assuming selective formation of the most stable carbocation, which product(s) would be obtained from HCl addition to isoprene Would this outcome be different from the one predicted on the basis of thermodynamic control ... 

The surprising selectivity in the formation of 4 and 5 is apparently due to thermodynamic control (rapid equilibration via the 1,3-boratropic shift). Structures 4 and 5 are also the most reactive of those that are present at equilibrium, and consequently reactions with aldehydes are very selective. The homoallylic alcohol products are useful intermediates in stereoselective syntheses of trisubstituted butadienes via acid- or base-catalyzed Peterson eliminations. 

The basc-eatalyzcd addition of nilroalkancs to carbonyl compounds is a reversible reaction and proceeds under thermodynamic control. Thus low (R, R )/(R, S ) selectivities arc observed in the classical Henry reaction which leads to the silylated x-nitro alcohols 2. 

The diastereoselective intramolecular Michael addition of /(-substituted cyclohexcnoncs results in an attractive route to ra-octahydro-6//-indcn-6-ones. The stereogenic center in the -/-position of the enone dictates the face selectivity, whereas the trans selectivity at Cl, C7a is the result of an 6-exo-trig cyclization. c7.v-Octahydro-5//-inden-5-ones are formed as the sole product regardless of which base is used, e.g., potassium carbonate in ethanol or sodium hydride in THF, under thermodynamically controlled conditions139 14°. An application is found in the synthesis of gibberellic acid141. 

Under thermodynamically controlled conditions, using triethylamine as base for the addition of enones to 5 and sodium methoxide in methanol as base for the addition of a,/ -unsaturated esters, the diastereomeric ratios of 6 range from 95 5 to 97 3. The excellent diasteroselectivities are retained in the Michael addition of 5 to -substituted enones and esters, however, modest synjami selectivities are found212,213. 

Until the early 1970s, the absence of suitable techniques for probing the detailed microstructure of polymers or for examining the selectivity and rates of radical reactions prevented the traditional view front being seriously questioned. In more recent times, it has been established that radical reactions, more often than not, are under kinetic rather than thermodynamic control and the preponderance of... 

Shorter chain dienes have an increased propensity to form stable five-, six-, and seven-membered rings. This thermodynamically controlled phenomenon is known as the Thorpe-Ingold effect.15 Since ADMET polymerization is performed over extended time periods under equilibrium conditions, it is ultimately thermodynamics rather than kinetics that determine the choice between a selected diene monomer undergoing either polycondensation or cyclization. 

Owing to the fully reversible equilibrium nature of the aldol addition process, enzymes with low diastereoselectivity will typically lead to a thermodynamically controlled mixture of erythro/threo-isomers that are difficult to separate. The thermodynamic origin of poor threo/erythro selectivity has most recently been turned to an asset by the design of a diastereoselective dynamic kinetic resolution process by coupling of L-ThrA and a diastereoselective L-tyrosine decarboxylase (Figure 10.47)... 

There are very few examples of asymmetric synthesis using optically pure ions as chiral-inducing agents for the control of the configuration at the metal center. Chiral anions for such an apphcation have recently been reviewed by Lacour [19]. For example, the chiral enantiomerically pure Trisphat anion was successfully used for the stereoselective synthesis of tris-diimine-Fe(ll) complex, made configurationally stable because of the presence of a tetradentate bis(l,10-phenanthroline) ligand (Fig. 9) [29]. Excellent diastereoselectivity (>20 1) was demonstrated as a consequence of the preferred homochiral association of the anion and the iron(ll) complex and evidence for a thermodynamic control of the selectivity was obtained. The two diastereoisomers can be efficiently separated by ion-pair chromatography on silica gel plates with excellent yields. 

The preparation of ketones and ester from (3-dicarbonyl enolates has largely been supplanted by procedures based on selective enolate formation. These procedures permit direct alkylation of ketone and ester enolates and avoid the hydrolysis and decarboxylation of keto ester intermediates. The development of conditions for stoichiometric formation of both kinetically and thermodynamically controlled enolates has permitted the extensive use of enolate alkylation reactions in multistep synthesis of complex molecules. One aspect of the alkylation reaction that is crucial in many cases is the stereoselectivity. The alkylation has a stereoelectronic preference for approach of the electrophile perpendicular to the plane of the enolate, because the tt electrons are involved in bond formation. A major factor in determining the stereoselectivity of ketone enolate alkylations is the difference in steric hindrance on the two faces of the enolate. The electrophile approaches from the less hindered of the two faces and the degree of stereoselectivity depends on the steric differentiation. Numerous examples of such effects have been observed.51 In ketone and ester enolates that are exocyclic to a conformationally biased cyclohexane ring there is a small preference for... 

Freccero, M. Gandolfi, R. Sarzi-Amade, M. Selectivity of purine alkylation by a quinone methide. Kinetic or thermodynamic control J. Org. Chem. 2003, 68, 6411-6423. 

As a general phenomenon, observed already by Fischer and coworkers, activity and FT synthesis selectivity develop in the initial time of a run in a process of Formierung (formation)16—in modem terms self-organization and catalyst restructuring. In order to achieve high performance of synthesis with cobalt as catalyst, the temperature had to be raised slowly up to the temperature of steady-state conversion. A distinct thermodynamically controlled state of the Co surface, populated with reactants and intermediates, can be assumed. This state depends on temperature and particularly on CO partial pressure, and its catalytic nature changes with changing conditions. 

The book focuses on three main themes catalyst preparation and activation, reaction mechanism, and process-related topics. A panel of expert contributors discusses synthesis of catalysts, carbon nanomaterials, nitric oxide calcinations, the influence of carbon, catalytic performance issues, chelating agents, and Cu and alkali promoters. They also explore Co/silica catalysts, thermodynamic control, the Two Alpha model, co-feeding experiments, internal diffusion limitations. Fe-LTFT selectivity, and the effect of co-fed water. Lastly, the book examines cross-flow filtration, kinetic studies, reduction of CO emissions, syncrude, and low-temperature water-gas shift. 

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... 

As mentioned earlier, a random and statistical cyclization with two different and regio-defined Ti-compounds would produce a synthetically unattractive mixture of ten different zirconacycles. In reality, however, there are a few factors that can be exploited to produce a single desired zirconacycle. A systematic investigation has revealed that there are several discrete types offive-membered zirconacycle formation, as shown in Scheme 1.53 [88,89] (Generalization 20). In the Type I reaction, the cross-selective cyclization is kinetically favored. Presumably, little ethylene is displaced during the reaction. Type I reactions cannot be readily observed with ZrCp2 complexes with 1-butene. In contrast, Type II cyclization must be thermodynamically controlled, as 1-butene is readily displaced by a number of better Ti-ligands. It is predicted, however, that the cross-combination of the two Ti-com-... 

Although addition of activated phosphoramidite to hemiacetals of manno-pyranoses under thermodynamic control has been reported to deliver exclusively a-phosphates in some cases,43 anomeric mixtures with preponderance of a-anomer have been reported in other examples.10,44 Since formation of phosphorotetrazolidite is a rate-limiting step of the process, initial activation of phosphoramidite followed by addition of nucleophilic hemiacetal should accelerate condensation and favour the formation of the thermodynamic a-product. Indeed, reaction of hemiacetal 101 with dibenzyl phosphorotetrazolidite assured exclusive a-selectivity of the resulting glycosyl phosphate 102.43 The accumulation in the reaction mixture of mildly acidic 1H-tetrazole, which is liberated upon reaction of tetrazolidite with hydroxylic component, could also favour predominant formation of the a-phosphate (Scheme 18, A). Conventional hydrogenolysis afforded the a-mannosyl phosphate 103. 

Thermodynamically controlled self-assembly of an equilibrated ensemble of POMs with [AlVWnO40]6 as the main component could act as a catalyst for the selective delignification of wood (lignocellulose) fibers (Figure 13.2) [55], Equilibration reactions typical of POMs kept the pH of the system near 7 during the catalysis that avoided acid or base degradation of cellulose. 

Our hypothesis of steric factors dominating the stability of the emerging radical centers in the transition states readily explains the enantioselective epoxide opening of meso-epoxide 35 to 36 that is shown in Fig. 3 [59,60]. In the case of a reversible epoxide opening, a stability difference of at least 3 kcalmol 1 between the two radicals 37 and 38 is necessary to explain the observed selectivity. According to the calculations this seems highly unlikely. A thermodynamically controlled epoxide opening can therefore be ruled out. 

The possibility of obtaining, under kinetic control, a selective transformation of only one of the double bonds present in a dienic system, as well as the formation of 1,4-adducts under thermodynamic control, may find interesting applications. These two adducts may indeed be transformed into attractive synthetic intermediates, as shown in equation 97118. 

---