The accelerating influence of water as a solvent on the rate of the Claisen rearrangement has been demonstrated on several substrates, thus illustrating the enormous potential it holds for those engaged in the synthesis of natural and unnatural products. Claisen rearrangement products which hitherto were inaccessible due to decomposition at high temperatures or elimination can now be realized through the agency of water.Sir: The accelerating influence of water as a solvent on the rate of the Claisen rearrangement' has been demonstrated in one instance by determining the first-order rate constants for the rearrangement of allyl vinyl ether 1 (R = Na, Me) in solvents ranging in polarity from cyclohexane to water.* We detail below the results of a study which clearly demonstrate the effectiveness of employing water as a solvent for the Claisen rearrangement and, more importantly, illustrates the enormous potential it holds for those engaged in the synthesis of natural and unnatural products. Claisen rearrangement products which hitherto were inaccessible due to decomposition a t high temperatures or elimination can now be realized through the agency of water. CHO 0 -A RO,C(CHz)6 -L ( C H 2 ) & 0 2 R 1 2In our preliminary study, substrate 1 (R = Na) was shown to undergo [3,3]-sigmatropic rearrangement in water (0.01 M in 1 and 0.01 M in pyridine) at 60 "C, giving rise to aldehyde 2 (R = H) after 3.5 h in 85% isolated yield.Rearrangement of the corresponding ester 1 (R = Me) in water is equally facile and efficient at 60 "C, giving rise to 2 (R = Me) in comparable yield despite a heterogeneous reaction medium. In sharp contrast ester 1 (R = Me) in benzene requires 108 h at 60 "C in order to realize a 64% yield (85% based on recovered starting material) of aldehyde 2 (R = Me). Similar results were observed with substrate 3 (Table I). Once again in the case of 3 the Claisen rearrangement is dramatically accelerated in water. Even more profound was the data obtained with substrate 5 (Table I). Note that after 5 h at 100 "C (bath temperature) an 80% isolated yield of aldehyde 6 was realized. In contrast, the results in toluene are disappointing. In the cases where the solubility of a substrate in water is negligible, one can employ cosolvents (see Table I) such as methanol, pyridine, and dimethyl sulfoxide, provided the amount of cosolvent is kept to a minimum. The effect of employing cosolvents is to decrease the rate of the Claisen rearrangement but not to the extent that reaction is no longer practical.Several years ago, M~M u r r y ,~ in connection with a synthesis of aphidicolin, had considerable difficulties ~~~ ~ (1)For g&erG reviews &I theclaisen rearrangement, see: (a) Ziegler, F. E. Chem. Rev., 1988,88,1423. (b) Rhoads, S. J.; Raulins, N. R. Org. react. (N.Y.) 1975,22, 1. (c) Also, see: Gajewski, J. J.; Jurayj, J.; Kimbrough, D. R.; Gande, M. E.; Ganem, B.; Carpenter, B. K. J. Am. Chem. SOC. 1987, 109, 1170. Coates, R. M.; Rogers, B. D.; Hobbs, S. J.; Peck, D. R.; Curran, D. P. J. Am. Chem. SOC. 1987, 109, 1160...

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The heat of reaction is an important parameter in the safe, successful scale-up of chemical processes. Reaction heat data is used to calculate the potential adiabatic temperature rise of the desired reaction, providing a worst-case scenario for rapid reaction of the entire batch with no heat loss to the surroundings. The data is used in parallel with information regarding the thermal stability of reaction mixtures/components and an intimate knowledge of the process to analyze the risk associated with running it on-scale. If the level of risk is judged to be unacceptable, the analysis can be used to make rational process changes in order to reduce the risk to an acceptable level. The Pfizer global process safety network provides a heat of reaction for all processes run in our kilo laboratories, pilot plant, and manufacturing facilities. In general, there are two methods used to determine reaction heats: (1) experimental measurement using some form of calorimetry, or (2) estimation techniques. Since experimental measurement is not always practical, accurate, or necessary, we set out to show that estimation techniques could be used reliably and efficiently to provide heat of reaction data for a wide range of chemistry. To gain confidence in our ability to accurately predict reaction heats, we carried out a comparative study of measured versus estimated values. The results of this study will be discussed in detail, including rationalization of any significant disparity through further analysis to more fully understand the limitations/advantages of both techniques. To help ensure consistent application of measurement/ estimation across the Pfizer global process safety network, we developed a decision tree to determine whether estimation or measurement should be considered for a particular reaction. In order to maximize the efficiency gain and to ensure accuracy in our estimations, we have created a heat estimation database that allows for (1) rapid archival/retrieval of model compounds, (2) calculation of reaction heat and adiabatic temperature rise, and (3) reporting/documentation of the results.