Carbonyl Addition Reactions in Chloroformates

Background:  Two decades ago, phenyl chloroformate (PhOCOCl) was extensively studied in 49 solvent mixtures and an addition-elimination (A-E) mechanism was proposed. Since then, it has served as a reference compound in linear free energy relationship studies (LFERs). First, the solvolysis of 4, 5-dimethoxy-2-nitrobenzyl chloroformate or 6-Nitroveratryl chloroformate (NVOC-Cl) was studied in twenty solvents of varying polarity. The goal was to determine the mechanism of reaction of NVOC-Cl in binary aqueous-organic mixtures of differing nucleophilicity (N_T) and ionizing power (Y_Cl) values. Then, Phenyloxy carbonyl tosylate (PhOCOOTs) was synthesized and its specific rates were determined in the same set of solvents as PhOCOCl. The goal here is to determine the presence or absence of any correlation trends between the rates of reaction (energy barriers) observed and the differences in anionic leaving group abilities (between the chloride and tosyl anions). Methods:  The kinetic runs in constant temperature water-baths were followed using the titrimetric or conductometric methods. For the study of NVOC-Cl, an approximate 1 M stock solution in acetonitrile was made. For PhOCOOTs, the compound was synthesized from equimolar additions of silver tosylate to PhOCOCl. A rapid precipitation of silver chloride occurred and the resulting solution was used directly as the source of the substrate. Results:In the study of NVOC-Cl and PhOCOOTs, the specific rates and associated standard deviations were obtained by averaging all of the values from, at least, duplicate runs. A direct comparison to the Grunwald-Winstein (G-W) analyses obtained for phenyl chloroformate (PhOCOCl) in identical solvents strongly suggests that the addition step within an addition-elimination mechanism is highly favored for NVOC-Cl. In the study of PhOCOOTs, the specific rates of PhOCOOTs in a set of solvents were found to be very similar to those observed for PhOCOCl, indicating that the change in leaving group bears no impact on the addition-elimination mechanism. Conclusions: For NVOC-Cl, a direct correlation with PhOCOCl showed R = 0.993 and an F-test value of 1316, strongly indicating that NVOC-Cl also follows an addition-elimination pathway. For PhOCOOTs, the goal was to determine whether the tosyl leaving group played an important role in the rate-determining step. Since the rates of reaction of PhOCOOTs were similar to PhOCOCl, the rate-determining transition state of PhOCOOTs is the same as PhOCOCl, and hence, it is appropriate to use PhOCOCl as a standard for A-E reactions. Acknowledgements: Support is from an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences (NIGMS) at the National Institutes of Health (8 P20 GM103446-14, Delaware INBRE program); a National Science Foundation (NSF) Experimental Program to Stimulate Competitive Research grant EPS-0814251 (Delaware EPSCoR program); an NSF S-STEM grant 1355554; and the State of Delaware.