Organic synthesis, thermodynamically

The different ratios of 52/53 produced by cycloadditions performed at atmospheric and high pressure, and the forma tion of the unusual trans adducts 53, have been explained by the facts that (i) Diels-Alder reactions under atmospheric pressure are thermodynamically controlled, and (ii) the anti-endo adducts 52 are converted into the short-lived syn-endo adducts 54 which tautomerize (via a dienol or its aluminum complexes) to 53. The formation of trans compounds 53 by induced post-cycloaddition isomerization makes the method more flexible and therefore more useful in organic synthesis. 

Hetero Diels-Alder reactions are very useful for constructing heterocyclic compounds, and many important chiral molecules have thus been synthesized. Although the retro Diels-Alder reaction does not itself involve the asymmetric formation of chiral centers, this reaction can still be used as an important tool in organic synthesis, especially in the synthesis of some thermodynamically less stable compounds. The temporarily formed Diels-Alder adduct can be considered as a protected active olefin moiety. Cyclopentadiene dimer was initially used, but it proved difficult to carry out the pyrrolytic process. Pentamethyl cyclopentadiene was then used, and it was found that a retro Diels-Alder reaction could easily be carried out under mild conditions. 

Using the unsymmetrically substituted acetylene Me3SiC=CPh, the kinetically favored substituted complex 8a is formed initially, cycloreversion of which gives the symmetrically substituted and thermodynamically more stable product 8b. Due to steric reasons, the other conceivable symmetric product 8c is not formed [9]. Such metallacycles are typically very stable compounds and are frequently used in organic synthesis, as shown by the detailed investigations of Negishi and Takahashi [lm], Bis(trimethylsilyl)acetylene complexes are a new and synthetically useful alternative. 

If the cycloaddition and cycloreversion steps occurred under the same conditions, an equilibrium would establish and a mixture of reactant and product olefins be obtained, which is a severe limitation to its synthetic use. In many cases, however, the two steps can very well be separated, with the cycloreversion under totally different conditions often showing pronounced regioselectivity, e.g. for thermodynamic reasons (product vs. reactant stability), and this type of olefin metathesis has been successfully applied to organic synthesis. In fact, this aspect of the synthetic application of four-membered ring compounds has recently aroused considerable attention, as it leads the way to their transformation into other useful intermediates. For example aza[18]annulene (371) could be synthesized utilizing a sequence of [2 + 2] cycloaddition and cycloreversion. (369), one of the dimers obtained from cyclooctatetraene upon heating to 100 °C, was transformed by carbethoxycarbene addition to two tetracyclic carboxylates, which subsequently lead to the isomeric azides (368) and (370). Upon direct photolysis of these, (371) was obtained in 25 and 28% yield, respectively 127). Aza[14]annulene could be synthesized in a similar fashion I28). 

Collections of fundamental and thermodynamic data can be found in an earlier review [158] and in standard resources [13, 14]. However, due to the reactivity of iodine there are many less common or more reactive forms of iodine that have been less well characterized. For example, a blue 12 cation, a brown I3+, or a green I5+ cation are formed in concentrated sulfuric acid and 1+ is stabilized in donor environments such as pyridine [159]. So-called hypervalent iodine reagents have been developed as a versatile oxidation tool in organic synthesis and often iodine derivatives are employed as electron transfer catalysts. Some fundamental thermodynamic data and typical applications of iodine are summarized in Scheme 5. 

The Durham precursor route to polyacetylene is an excellent example of the application of organic synthesis to produce a precursor polymer whose structure is designed for facile conversion to polyacetylene. Durham polyacetylene was first disclosed by Edwards and Feast, working at the University of Durham, in 1980 227). The polymer (Fig. 6 (I)) is effectively the Diels-Alder adduct of an aromatic residue across alternate double bonds of polyacetylene. The Diels-Alder reaction is not feasible, partly for thermodynamic reasons and partly because it would require the polymer to be in the all m-conformation to give the required geometry for the addition to take placed 228). However, the polymer can be synthesised by metathesis polymerization of the appropriate monomer. 

Of special interest for petrochemical and organic synthesis is the implementation of thermodynamically hindered reactions, among which incomplete benzene hydrogenation or incomplete cyclohexene and cyclohexadiene dehydrogenation should be mentioned. Cost-effective methods of cyclohexene production would stimulate the creation of new processes of phenol, cyclohexanol, cyclohexene oxide, pyrocatechol synthesis, cyclohexadiene application in synthetic rubber production, and a possibility for designing caprolactam synthesis from cyclohexene and cyclohexadiene via combined epoxidation. At present, the most... 

Two complementary procedures have been developed for alkylation of secondary amines [11] - both of which involve the use an excess of amine to drive the reaction to completion. The remaining amine was removed from the required tertiary amine using a polymer supported isocyanate 5 as a nucleophilic scavenger (under thermodynamic control) (Table 1 entry 2). The use of this amine scavenger has subsequently been applied in the purification of urea-based libraries prepared by solid-phase organic synthesis [12],... 

Lanthanide hydride derivatives are commonly synthesized by hydrogenol-ysis of lanthanide alkyl complexes [212], In order to further exploit the thermodynamic stability of the Al-N bond dizsobutylaluminum hydride (DIBAH), a common cocatalyst in diene polymerization mixtures and well-established reducing agent in organic synthesis, was used in the hydrogenol-... 

For any candidate molecule, one must consider the relative location of the highest occupied molecular orbital (HOMO) of D and the lowest unoccupied molecular orbital (LUMO) of the A molecule. The "parent" neutral molecule and the "daughter" radical anion radical A- or cation radical D+ must be thermodynamically and kinetically stable, as well as energetically accessible. Since most organic synthesis is done in solutions, the species should not oxidize or reduce the solvent. In addition, the second ionization state (D2+ or A-) must also be stable, since an additional electron or a hole must also fleetingly reside on D+ or A-. There are, at present, four methods useful for stabilizing these systems ... 

Carbon-centered radicals play an important role in organic synthesis, biological chemistry, and polymer chemistry. The radical chemistry observed in these areas can, to a good part, be rationalized by the thermodynamic stability of the open shell species involved. Challenges associated with the experimental determination of homolytic bond dissociation energies (BDEs) have lead to the widespread use of theoretically calculated values. These can be presented either directly as the enthalpy for the C-H bond dissociation reaction described in Equation 5.1, the gas-phase thermodynamic values at the standard state of 298.15K and 1 bar pressure being the most commonly reported values. 

Michael addition of metal enolates to a,/3-unsaturated carbonyls has been intensively studied in recent years and provides an established method in organic synthesis for the preparation of a wide range of 1,5-dicarbonyl compounds (128) under neutral and mild conditions . Metal enolates derived from ketones or esters typically act as Michael donors, and a,-unsaturated carbonyls including enoates, enones and unsaturated amides are used as Michael acceptors. However, reaction between a ketone enolate (125) and an a,/3-unsaturated ester (126) to form an ester enolate (127, equation 37) is not the thermodynamically preferred one, because ester enolates are generally more labile than ketone enolates. Thus, this transformation does not proceed well under thermal or catalytic conditions more than equimolar amounts of additives (mainly Lewis acids, such as TiCU) are generally required to enable satisfactory conversion, as shown in Table 8. Various groups have developed synthons as unsaturated ester equivalents (ortho esters , thioesters ) and /3-lithiated enamines as ketone enolate equivalents to afford a conjugate addition with acceptable yields. 

From a thermodynamic point of view, an organic synthesis can be likened to a complex and hazardous climb up a mountain, with many detours up and down but eventually leading to a certain point positioned at a higher level. The schematic profile of a hypothetical route from starting compound A to final product P is presented in Fig. 1. This profile graphically illustrates three important peculiarities which are generally featured in a typical synthetic... 

C-H and C-C bond activations by ruthenium complexes have formed the focus of this chapter, and consequently other important reactions to cleave chemical bonds such as dihydrogen, C-S and M-R have not been described. Today, ruthenium is regarded as a powerful tool for cleaving a variety of both activated and unactivated chemical bonds under homogeneous conditions. Important factors that provide these activities include 1) coordinative unsaturation of the ruthenium center 2) a close proximity of the bond to the ruthenium metal and 3) kinetic preference and thermodynamic stability of the products. It is likely that the combined use of ruthenium complexes and modern strategies in organic synthesis and catalysis will provide many opportunities for the creation of new reaction processes in the futtue. 

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