Rate enhancement in aqueous media

For a long time, solvent polarity was believed to have no effect on the course of a Diels-Alder reaction. Berson, however, showed a clear relationship between the endo/exo product ratio and solvent polarity in the 

There are many examples of Diels-Alder reactions that exploit this rate enhancement effect. Grieco s interest in quassinoids led him to react 114 and 115 in benzene at ambient temperature, and this gave a 1 1.18 mixture of 116 and 117 in 52%, but required a reaction time of 288 h. O when the same reaction was done in water, an 82% yield was obtained (1.3 1 116/117) after 168 h. Diels-Alder cyclization with the free acid rather than the ester, in water, gave an 85% yield (1.5 1 116/117) in 17 h. Similar reaction in 1 1 aqueous methanol gave a quantitative yield after 97 h (1 1.25 116/117). When the sodium salt of the acid was used, a quantitative 

Grieco and co-workers also showed that iminium salts such as 123, formed by reaction of an amine and formaldehyde (sec. 4.4) reacted with cyclopentadiene in aqueous media to give a near-quantitative yield of the Diels-Alder adduct. An internal Diels-Alder reaction was also possible (sec. 11.8). Treatment of an aqueous solution of 124 with formaldehyde at 50°C gave a 98% yield of indolizidine 125. 

The use of highly polar media such as water clearly assists the Diels-Alder reaction, and similar rate enhancement has been observed in other reactions. Grieco et al. showed that 5.0 M lithium perchlorate in diethyl ether is an effective medium for these reactions, There is a problem, however, because weak acids in highly polar media such as this become strong acids, and protonation of dienes in intramolecular reactions can lead to diene isomerization that is competitive with cycloaddition. 25 Grieco and Kaufman found that for such 

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Not only Diels-Alder cycloadditions but also 1,3-dipolar cycloaddition reactions can be subject to hydrophobic rate enhancements. For example, the reaction of C,N-diphenylnitrone with di-n-butyl fumarate at 65 °C to yield an isoxazolidine is about 126 times faster in water than in ethanol, while in nonaqueous solvents there is a small 10-fold rate decrease on going from n-hexane to ethanol as solvent - in agreement with an isopolar transition-state reaction [cf. Eq. (5-44) in Section 5.3.3] [858]. Because water and ethanol have comparable polarities, the rate increase in water cannot be due to a change in solvent polarity. During the activation process, the unfavourable water contacts with the two apolar reactants are reduced, resulting in the observed rate enhancement in aqueous media. Upon addition of LiCl, NaCl, and KCl (5 m) to the aqueous reaction mixture the reaction rate increases further, whereas addition of urea (2 m) leads to a rate decrease, as expected for the structure-making and structure-breaking effects of these additives on water [858]. 

In many instances, Diels-Alder reactions give poor yields and/or require excessively harsh reaction conditions and long reaction times. There are several fairly straightforward techniques that increase the rate and, in some cases, the selectivity of Diels-Alder reactions. The three most important methods are catalysis by Lewis acids, rate enhancement in aqueous media and the use of high pressure (usually greater than 5 kbar). These three methods will be the focus of this section. 

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