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The Skaggs Institute
for Chemical Biology


Click Chemistry “On Water”: Organic Reactions in Aqueous Suspensions


K.B. Sharpless, V.V. Fokin, B. Boren, M. Cassidy, B. Colasson, T. Chan, A. Feldman, R. Fraser, T.V. Hansen, B. Hatano, T. Hirose, A. Krasinski, Y. Liu, J. Loren, R. Manetsch, A. McPherson, S. Narayan, S. Pitram, L.K. Rasmussen, J. Raushel, S. Röper, W. Sharpless, S. Silverman, A. Sugawara, X. Wang, J. Wassenaar, M. Whiting, P. Wu

The goal of our research program is the development of selective and reliable chemical transformations that are easy to perform on any scale. During the past year, we looked at several such reactions and further expanded our earlier studies of performing these and related transformations in water.

Water, the lingua franca of life on Earth, is rarely used or even considered as a solvent for organic reactions. The 2 foremost reasons chemists shy away from water is the lack of solubility of most organic compounds in this medium and concerns that the high acid-base reactivity will interfere with the desired reaction. However, water as a solvent is hard to ignore. Beyond being the most abundant natural solvent, water has extraordinary physical properties, and although the reasons mentioned for avoiding it seem well founded, many examples indicate that reactions commonly performed in organic solvents work equally well, if not better, in water.

The study of organic reactions in aqueous solvents has an intriguing history. Most notably, certain pericyclic reactions such as Diels-Alder cycloadditions and Claisen rearrangements of hydrophobic compounds are accelerated in dilute aqueous solutions. Yet, either organic cosolvents and/or substrate modifications are almost always used in preparative-scale reactions performed in water because it is assumed that solubility is required for efficient reaction. Not only do these strategies detract from the simplicity and advantages sought from the use of water in the first place, but the venerable assumption corpora non agunt nisi soluta (substances do not interact unless dissolved) can be distinctly counterproductive.

In recent years, we have focused on the development of a modular approach to synthesis, called click chemistry, that relies on a few nearly perfect reaction types. In the course of this work, we noticed that many such reactions often proceed optimally in pure water, particularly when the organic reactants are insoluble in the water phase. Several examples presented in the following illustrate a remarkable phenomenon: a substantial acceleration in rate when insoluble reactants are stirred in aqueous suspension, denoted here as “on water” conditions. Even when the rate acceleration is negligible, the use of water as the only supporting medium has other advantages, including ease of product isolation and, above all, safety, thanks to its high heat capacity and unique redox stability.

In connection with our studies on the reactivity of strained olefins, we explored the preparation of 1,2-diazetidines from quadricyclane (1 in Fig. 1) by the 2σ+ 2σ+ 2π cycloaddition with azodicarboxylates.

Fig. 1. Reaction of quadricyclane (1) with DMAD (2). Yields are of isolated pure products.

The typical reaction conditions involve heating quadricyclane with dimethyl azodicarboxylate (DMAD; 2 in Fig. 1) in toluene or benzene at 80°C for 24 hours or longer. In contrast, when a mixture of DMAD and quadricyclane is vigorously stirred on water, the reaction is complete within a few minutes at ambient temperature. The corresponding neat (solvent-free) reaction of these 2 liquids takes nearly 2 days to reach completion, indicating that the rate acceleration is not the sole consequence of an increase in the effective concentration of reagents.

As the cycloaddition of DMAD with quadricyclane shows, the on-water method consists simply of stirring the reactants with water to generate an aqueous suspension. Nonpolar liquids that separate from water into a clear organic phase are ideal candidates for these reactions. Solid reactants can also be used, provided one reaction partner is a liquid and adequate mixing is ensured. Vigorous stirring promotes the reaction, most likely by increasing the area of surface contact between the organic and aqueous phases. The observed rate acceleration does not depend on the amount of water used, as long as sufficient water is present for clear phase separation to occur. The product is isolated simply by phase separation or filtration.

Nonpericyclic reactions such as the opening of epoxides and aziridines with heteroatom nucleophiles also derive unique benefits from the on-water environment. Hydrogen bonding is crucial for the activation of such electrophiles, so these opening processes are autocatalytic and difficult to control under neat conditions. Here too, we find that water alone is the solvent of choice. The reactions are completed in shorter times than in other protic solvents, and the pure product often precipitates, to be isolated by simple filtration.

Reaction of epoxide 4 with amine 5 is illustrative (Fig. 2).

Fig. 2. Application of the on-water method to the nucleophilic opening of an epoxide.

When heated at 50°C, the on-water reaction was completed overnight, whereas the reactions in ethanol solution and without solvent required approximately 3 days to reach completion. In toluene, less than 10% conversion occurred after 5 days at the same temperature.

To the best of our knowledge, these examples represent some of the largest rate accelerations due to water observed under preparative conditions, that is, at molar concentrations. A central theme in aqueous organic chemistry has been the need to promote solubility in these reactions. Clearly, solubility is not essential.

Although the reactivity phenomenon described here has immediate practical implications, its origins are unclear. Therefore, we plan to keep exploring the on-water phenomenon both for practical applications and for mechanistic understanding.

Publications

Dìaz, D.D., Punna, S., Holzer, P., McPherson, A.K., Sharpless, K.B., Fokin, V.V., Finn, M.G. Click chemistry in materials synthesis, I: adhesive polymers from copper-catalyzed azide-alkyne cycloaddition. J. Polym. Sci. A Polym. Chem. 42:4392, 2004.

Feldman, A.K.. Colasson, B., Fokin, V.V . One-pot synthesis of 1,4-disubstituted 1,2,3-triazoles from in situ generated azides. Org. Lett. 6:3897, 2004.

Feldman, A.K., Colasson, B., Sharpless, K.B., Fokin, V.V. The allylic azide rearrangement: achieving selectivity. J. Am. Chem. Soc. 127:13444, 2005.

Himo, F., Lovell, T., Hilgraf, R., Rostovtsev, V.V., Noodleman, L., Sharpless, K.B., Fokin, V.V . Copper(I)-catalyzed synthesis of azoles: DFT study predicts unprecedented reactivity and intermediates. J. Am. Chem. Soc. 127:210, 2005.

Johnson, S.M., Petrassi, H.M., Palaninathan, S.K., Mohamedmohaideen, N.N., Purkey, H.E., Nichols, C., Chiang, K.P., Walkup, T., Sacchettini, J.C., Sharpless, K.B., Kelly, J.W. Bisaryloxime ethers as potent inhibitors of transthyretin amyloid fibril formation. J. Med. Chem. 48:1576, 2005.

Krasinski, A., Radic, Z., Manetsch, R., Raushel, J., Taylor, P., Sharpless, K.B., Kolb, H.C. In situ selection of lead compounds by click chemistry: target-guided optimization of aceylcholinesterase inhibitors. J. Am. Chem. Soc. 127:6686, 2005.

Lewis, W.G., Magallon, F.. Fokin, V.V., Finn, M.G. Discovery and characterization of catalysts for azide-alkyne cycloaddition by fluorescence quenching. J. Am. Chem. Soc. 126:9152, 2004.

Loren, J.C., Krasinski, A., Fokin, V.V., Sharpless, K.B. NH-1,2,3-triazoles from azidomethyl pivalate and carbamates: base-labile N-protecting groups. Synlett 18:2847, 2005.

Loren, J.C., Sharpless, K.B. The Banert cascade: a synthetic sequence to polyfunctional NH-1,2,3-triazoles. Synthesis 9:1514, 2005.

Mocharla, V.P., Colasson, B., Lee, L.V., Röper, S., Sharpless, K.B., Wong, C.-H., Kolb, H.C. In situ click chemistry: enzyme-generated inhibitors of carbonic anhydrase II. Angew. Chem. Int. Ed. 44:116, 2004.

Narayan, S., Muldoon, J., Finn, M.G., Fokin, V.V., Kolb, H.C., Sharpless, K.B. “On water”: unique reactivity of organic compounds in aqueous suspensions. Angew. Chem. Int. Ed. 44:3275, 2005.

Zhang, L., Chen, X., Xue, P., Sun, H.H.Y., Williams, I.D., Sharpless, K.B., Fokin, V.V., Jia, G. Ruthenium-catalyzed cycloaddition of alkynes and organic azides. J. Am. Chem. Soc. 127:15998, 2005.

 

K. Barry Sharpless, Ph.D.
W.M. Keck Professor of Chemistry

Sharpless Web Site