Entropically favored reaction

Ca readily forms complexes with several organic and inorganic compounds such as citrate, lactate, hydrogen carbonate, polyphosphates, etc. When the complexes are formed, a considerable amount of water is released from the coordination sphere of the ion this entropically favored reaction stabilizes the complexes. 

It has been proposed that the reaction is promoted by the formation of the active species 73, in which, the cationic center of the tin(II) triflate activates an aldehyde, and, at the same time, the electronegative fluoride is able to interact with a silicon atom of the silyl enol ether to make the enol ether more reactive. This dual process results in the formation of the entropically favored intermediate (Scheme 3-25).46... 

Side reactions that occur with intramolecular cycloaddition, such as linear oligomerization or dimerization of the nitrile oxide, are not very common when shorter chain lengths n < 1) are used due to the entropically favored intramolecular process. A rather unusual result in this regard involves the formation of a fused cyclooctane instead of the less-strained six-membered ring (also fused) in the cycloaddition of the nitrile oxide derived from p-naphthoquinone (Scheme 6.43). This result is consistent with the effect of electron-withdrawal in the enedione part, leading to increased reactivity (247), and also reflects the known sluggishness of cyclohexenes towards nitrile oxides (cf. Section 6.2.1.2). 

This is consistent with DFT calculations on [CH3MgCl2], which reveal that the six-centered transition state for the enolisation reaction 66 is entropically favored over the four-centered transition state for the Grignard reaction 67 (Scheme 14). 

In contrast to intermolecular versions, intramolecular allylmagnesiation of alkenes (metallo-ene reaction) is entropically favored, and thus more efficient and selective. Felkin and coworkers have demonstrated that 2,7-octadienylmagnesinm bromide 73 prepared from 72 undergoes intramolecular allylmagnesiation in refluxing ether to give 74 stereo selectively (Scheme 49). ... 

Although thermal [2 + 2] cycloadditions are forbidden as concerted reactions by the orbital symmetry conservation rules the same structural features which promote intermolecular cy-cioadditions will also promote intramolecular reactions. In addition, the proximity between two alkene moieties dictated by the tether length and rigidity would make these processes entropically favorable. A few reports have documented thermal intramolecular cycloadditions to cyclopropenes and activated alkenes. The thermal Cope rearrangement of allylcyclopropenes apparently proceeds by a two-step mechanism in which intramolecular [2 + 2] adducts have been observed.72-73... 

With the knowledge that 14 can activate aldehydes in 1, the role of 1 in the reaction was explored further. Specifically, the relative rates of C—H bond activation and guest ejection, and the possibility of ion association with 1, were investigated. The hydrophobic nature of 14 could allow for ion association on the exterior of 1, which would be both cn t h al pi cal I y favorable due to the cation-it interaction, and entropically favorable due to the partial desolvation of 14. To explore these questions, 14 was irreversibly trapped in solution by a large phosphine, which coordinates to the iridium complex and thereby inhibits encapsulation. Two different trapping phosphines were used. The first, triphenylphosphine tris-sulfonate sodium salt (TPPTS), is a trianionic water-soluble phosphine and should not be able to approach the highly anionic 1, thereby only trapping the iridium complex that has diffused away from 1. The second phosphine, l,3,5-triaza-7-phosphaadamantane (PTA), is a water-soluble neutral phosphine that should be able to intercept an ion-associated iridium complex. 

Addition reactions of carbon radicals to C—O and C—N multiple bonds are much less-favored than additions to C—C bonds because of the higher ir-bond strengths of the carbon-heteroatom multiple bonds. This reduction in exothermicity (additions to carbonyls can even be endothermic) often reduces the rate below the useful level for bimolecular additions. Thus, acetonitrile and acetone are useful solvents because they are not subject to rapid radical additions. However, entropically favored cyclizations to C—N and C—O bonds are very useful, as are fragmentations (see Chapter 4.2, this volume). 

The N-(bicycloalkenyl)nitrone (37) afforded the tetracyclic isoxazolidine (38) in 67% yield none of the regioisomeric isoxazolidine was observed (Scheme 9).17 The authors attributed this to non-bonded C—H interactions as shown, but the observed isoxazolidine was also entropically favored, forming via a six-membered, as opposed to a seven-membered, carbocyclic transition state. The N-(bicycloalkenyl)ni-trone formed from (39) and furfural cyclized in 45% yield predominantly to the tetracyclic product (40b), but some (41b) was also produced (95 5 ratio).18 Reaction of (39) and formaldehyde gave a mixture of (40a) and (41a) (62 38 ratio). The authors attribute the somewhat higher regioselectivity for (40b) in part to non-bonded interaction of the 2-furyl substituted methylene with the C-8 endocyclic C—H bond. 

Before blunt-end ligation of an insert, the vector needs to be dephosphorylated because resealing of the two ends of the linear vector to form a circular plasmid representing an intramolecular reaction is entropically favored, and thus faster (Chapter 2, Section 2.2.3), than the intermolecular insertion of the blunt-end frag-... 

In order to optimize the antitumoral properties of radicicol, particularly in vivo, the same group synthesized the analogous cycloproparadicicol, where the epoxide function is replaced by a cyclopropane [64]. Submitted to the conditions of the previous RCM reaction (CH2C12, 42°C, 19h), cydopropyl triene 94 leads to the expected macrolide 95 in only 16% yield, along with 30% of the corresponding 28-membered dimeric macrocycle (Scheme 2.37). After numerous assays, the best conditions tested (toluene, 110 °C, 10 min) brought the yield up to 55%. In this case, the balance between thermodynamic and kinetic factors seems decisive for the course of the reaction. The fact that the monomeric product is predominant at elevated temperature indicates that this form is entropically favored. 

In contrast, intramolecular versions of the metallo-ene process may be regio- and stereo-selective as well as entropically favored and are thus more efficient, similar to intramolecular ene reactions (Volume 5, Chapter 1.1) and [4 + 2] cycloadditions (Volume 5, Chapter 4.4). This holds for two different modes of cyclization in which the enophile is linked by a suitable bridge, either to the terminal carbon atom C-3 (type I) or to the central carbon aton C-2 (type II) of the metallo-ene unit (Scheme 18). The prc nsity of the cyclized alkylmetal intermediates (F) and (H) for further functionalizations and cycli-zations, involving the metallated and two alkenic sites, offers a considerable potential in organic synthesis. 

Whereas stoichiometric additions of allylpalladium species to norbomene and 1,3-dienes are known (c/. Section 1.2.2.4), simple alkenes (e.g. styrene, cyclohexene, 1,4-cyclohexadiene and 1,5-cycloocta-diene) did not undergo this reaction. However, it can be assumed that the intramolecular ene process (L) — (M) (Scheme 36) is entropically favored and that a subsequent irreversible -elimination (M) —> (N) withdraws the ene product (M) from the equilibrium (L) (M). Further options are insertionfreduc-tive elimination processes (M) (O). The thereby regenerated Pd° species should continue the catalytic... 

In context with synthetic work on quassinoids, Grieco and coworkers found an even more striking rate enhancement of aqueous Diels-AIder reactions when the diene partner contains a suitably placed ionic substituent (Scheme 57, Table 8). The concentration-dependent increase of rate, yield and endo selectivity observed, particularly, with the sodium salt of dienoic acid (245b) in water (entry 3) was assigned to an entropically favorable interaction of the reactants within an aggregate. 

The X-ray crystal structure of plastocyanin has recently been established (10), which indicated that the core of the molecule is hydrophobic and notably aromatic because six of the seven phenylalanine residues are clustered there. Polar side chains are distributed on the exterior of plastocyanin molecule. Many hypotheses have been proposed to explain the electron-transfer pathway to and from the metal center of plastocyanin, such as a tunnelling mechanism along hydrophobic channels (11). High reactivity and entropic favorability have been reported for the electron-transfer reaction of plastocyanin with Fe(II) complex (12). The Cu complex bound to the amphiphilic block copolymer is interesting as a metal compound of plastocyanin, because both polymer and apoprotein environments are considered to produce a hydrophobic environment and a large effect on the electron-transfer reaction through its entropic contribution. 

We used triazolium salt 7 as the catalyst for the intramolecular Stetter reaction of 2-formylphenoxycrotonates 11 affording the corresponding 4-chromanones 12 [49], since these were known to be highly active substrates in the non-enan-tioselective thiazolium-catalyzed Stetter reaction [50] (Scheme 7). Apparently, the entropically favorable proximity of the reacting functionalities leads to a strong enhancement of the reactivity. 

The reaction mechanism shown in Figure 6 suggests the involvement of several proton transfer reactions and one would expect the participation of amino acid residue as acid/base catalysts. In a systematic mutagenesis study, the replacement of amino acid residues lining the active site cavity had only minor impact on catalytic rates. This suggests that the contribution of enzyme catalysis is mainly entropic, via the generation of a favorable reaction topology. 

In other host molecules, binding sites are located in such a way that the substrates or reagent and substrate are bound in proper proximity within a host molecule. The proximity is entropically favorable for a reaction and thus rate accelerations have been observed. In addition, the proper placement of the reactants leads to altered selectivities. For instance Sanders described a macrocyclic trimeric porphyrin in which two substrates are preorganized in such a way that the stereochemistry of a Diels-AIder reaction is governed by the inclusion (see Figure 7.7). 

We have seen that when the products are at a lower enthalpy than the reactants (AH° < 0), a chemical reaction is energetically favored. We have also seen that when the products are more disordered than the reactants (AS > 0), a chemical reaction is entropically favored. 

This in turn means that any attempt to find a catalyst for a given reaction must start either with an estimate of the thermodynamics of the process or other evidence, such as a report of prior success, to show that the reaction is thermodynamically feasible. Even if a reaction is endoenergetic, all may not be lost if the desired endoenergetic catalytic reaction can be coupled to an exoenergetic one to make the overall process favorable. The reaction of equation (1) is endoenergetic at room temperature and pressure, but inclusion of an oxidant, as in equation (2), makes the overall process exoenergetic and therefore favorable. Another approach is to recognize that equation (1) is entropically favored by the production of H2 and thus elevation of temperature may be sufficient to make it favorable. 

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