Hydrophobic effect transitions

Breslow immediately grasped the significance of his observation. He interpreted this discovery in terms of a hydrophobic effect Since in the Diels-Alder reaction. .. the transition state. .. brings together two nonpolar groups, one might expect that in water this reaction could be accelerated by hydrophobic interactions ". ... 

The Diels-Alder reaction is one of the most important methods used to form cyclic structures and is one of the earliest examples of carbon-carbon bond formation reactions in aqueous media.21 Diels-Alder reactions in aqueous media were in fact first carried out in the 1930s, when the reaction was discovered,22 but no particular attention was paid to this fact until 1980, when Breslow23 made the dramatic observation that the reaction of cyclopentadiene with butenone in water (Eq. 12.1) was more than 700 times faster than the same reaction in isooctane, whereas the reaction rate in methanol is comparable to that in a hydrocarbon solvent. Such an unusual acceleration of the Diels-Alder reaction by water was attributed to the hydrophobic effect, 24 in which the hydrophobic interactions brought together the two nonpolar groups in the transition state. 

Similar results were obtained for analogous complexes of the de-( er -butyl)ated macrocycle (L24)2-. The ter7-butyl substituents do not affect the regiochemistry of this particular Diels-Alder reaction, but they clearly increase its rate. The observed trend is indicative of a small stabilization of the transition-state by hydrophobic effects (AAG 3 kJ/mol k coinpiex/k l) lckgr(nin(i = expiAAG /RT)). This would be consistent with our earlier observation that complexes bearing less polar carboxylate anions have the higher stability constants (see Section III.E). 

The simplest interpretation is that AH for protein folding has a large ACp term, as described in Chapter 17 for overall denaturation. If the transition state for folding is relatively compact and shields the hydrophobic side chains, then there will be the characteristic ACp term associated with the hydrophobic effect (cf. equation 17.1) ... 

The experiments which yielded the diffusion coefficients for acetaminophen in PNIPAAm gel in Fig. 16 also yielded the corresponding partition coefficients. While the diffusion coefficients fit theory, the partition coefficients as plotted in Fig. 18 do not at all. In fact, a trend opposite to theory is observed as the partition coefficients are seen to increase as the gel swelling decreases. In fact, above the transition temperature of the gel, at 35 °C, the partition coefficient is seven times the maximum possible size exclusion coefficient, 1. This implies the dominance of hydrophobic effects over steric effects, since acetaminophen is a relatively small, nonionic but hydrophobic solute, and while the gel mesh size shrinks with increasing temperature, its level of hydrophobicity increases with temperature. 

Special properties of water as solvent, with the hydrophobic effect promoting rapid and selective reactions have been reviewed. The use of addition of prohydrophobic and antihydrophobic materials to the water solution to understand the geometry of transition states for a number of classical reactions has been discussed.279 Guanine bases in DNA are the most sensitive to oxidation. The oxidation of guanine bases by various one- and two-electron processes has been reviewed. Some key intermediates and the description of the oxidation products that can be generated from these intermediates depending on the reaction conditions are described.280... 

Hydrophobic effects have been shown to dominate the geometries of the transition states for the simple Diels-Alder reactions of cyclopentadiene and methyl acrylates ... 

As a first step toward this purpose, we have studied the chelation effect of tetrapeptides of sequences Cys-X-Y-Cys, by preparation of metal complexes of mainly the first transition series. The hydrophobic effect of the peptides was also studied by utilizing the side chain bulkiness of the amino acid residues interposed between the two cysteine residues. A special effect of aromatic side chains of tyrosine, phenylalanine, and tryptophan has also been examined in order to assess their ability to ease electron transfer to and from the nearby iron core. 

Diels-Alder reactions have been performed in most alternative reaction media. For certain substrates this reaction is significantly accelerated in fluorous solvents (Figure 1.9) This has been ascribed to a fluorophobic effect, analogous to the better-known hydrophobic effect where there is an inverse relationship between reaction rate and the solubility of reagents. However, it should be noted that in general cycloaddition reactions (including Diels-Alder reactions) are faster in water and this can be attributed to additional hydrogen bond stabilization of the transition state. 

Optical turbidity measurements showed a LCST for aqueous solutions of P14 up to 17°C. On the other hand, solutions of copolymer with cyclohexyl P15 have a transition at 31°C, which is 4°C lower than that of pure NIPAAM polymer P16 (Table 3). The lower LCST for P15 compared to P16 is attributed to the hydrophobic effect [60], which is the decrease of the LCST with increasing numbers of hydrophobic side-chain groups. 

Three years after the first notion of the large effects of water on the rate of the Diels-Alder reactions", the same authors demonstrated that the endo/exo selectivity is also increased in water. Studying the influence of salting-in and salting-out agents , the authors pinpointed hydrophobic effects as the most important contributors to the enhanced endo/exo selectivities- because hydrophobic effects are assumed to stabilize the more compact endo-transition structure more than the era-transition structure. This difference in compactness of both structures is evident from the well-known smaller activation volume of the endo-cycloaddition (vide supra). Additionally, the high polarity of water significantly enhances the endo/exo selectivity . 

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