J. Am. Chem. Soc. zyxwvu 1986, zyxwvu 108,479-483 479 Decreasing Reactivity with Increasing Nucleophile Basicity. The Effect of Solvation on Pnuc for Phosphoryl Transfer to Amines zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA William P. Jencks,* Martin T. Haber, Daniel Herschlag, and Karen L. Nazaretian Contribution No. 1574 zyxwvut from the Graduate Department zyxwvu of Biochemistry, Brandeis University, Waltham, Massachusetts 02254. Received July zyxwv 1. 1985 Abstract: Rate zyxwvutsr constants for the reactions of substituted quinuclidines with pnitrophenyl phosphate, 2,4-dinitrophenyl phosphate, 2,4-dinitrophenyl phosphate complexed with calcium, and phosphorylated pyridine decrease with increasing pKa of the amine. Plots of log k against pK, give slopes of zyxwvutsr @ , , = -0.05, -0.10, -0.1 1, and 4.10, respectively, for these.compounds; &, = -0.01 for phosphorylated 4-morpholinopyridine. These negative slopes are attributed to a requirement for desolvation of the amine before nucleophilic attack, which is more difficult with more basic amines; a value of Pd = -0.2 for the desolvation step is suggested. Nucleophilic reagents are likely to be hydrogen bonded to hydroxylic solvents, so that structure-reactivity correlations may reflect the behavior of the desolvation step as well as nucleophilic attack. The dependence of the reaction rate on the basicity of an attacking nucleophile is given by the slope, &, of a plot of log k against the pKa of the protonated nucleophile, BH”. The observed value of Dnuc includes the dependence of desolvation as well as nucleophilic attack on the basicity of the nucleophile, so that the amount of nucleophilic attack in the transition state may be underestima.ted if desolvation is neglected. The desolvation step will have a small or negligible influence on the observed value of & , when there is a large amount of bond formation in a late transition state that resembles BH”, which is the reference com- pound for the Br~nsted correlation and corresponds to the de- velopment of a full positive charge on the amine.2,3 However, for early transition states, in which the nucleophilic attack step has only a small dependence on basicity, the increase in the strength of hydrogen bonding to the solvent with increasing basicity can cause a significant decrease in the observed dependence of the rate on the basicity of the nucleophile if an initial desolvation step is required. Conversely, in the reverse reaction or in any reaction in which there is a large amount of bond breaking in the transition state, incomplete solvation of the leaving group may cause an increase in -@ , and an overestimation of the amount of bond breaking. We report here several reactions of monosubstituted phosphates with substituted quinuclidines that decrease in rate with increasing basicity of the quinuclidine; i.e., &,, is negative. The reaction requires desolvation of the attacking amine, with the equilibrium constant Kd in eq 1, before nucleophilic attack of the free amine, with the rate constant k. A negative value of onw will be observed zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDC r when the dependence on amine basicity for the desolvation step is more important than @ for nucleophilic attack, Le., when the negative value of @d for Kd causes a rate decrease that is larger than the rate increase from @ , , for reaction of the desolvated amine (k in eq 1). It is believed that there is little bond formation to the nucleophile in the open, “exploded”, transition states for reactions of phosphate ester dianions and phosphorylated pyri- (1) Supported in part by grants from the National Institutes of Health (5 RO1-GM 20888-28) and the National Science Foundation (EM 81-17816). (2) Hupe, D. J.; Jencks, W. P. J. Am. Chem. Soc. 1977, 99, 451-464. (3) Jencks, W. P.; Brant, S. R.: Gandler, J. R.; Fendrich, G.; Nahmura, C. J. Am. Chem. Soc. 1982, 104, 7045-7051. dines;ea in fact, the rate constants for reactions of substituted pyridines with the dianion of 2,4-dinitrophenyl phosphate show no dependence on amine basicity. Nevertheless, these second-order reactions are much faster than hydrolysis, so that there must be a significant amount of bond formation to the nucleophile in the transition state in spite of the fact that the observed value of & , is zero.5 Similar behavior has been observed for reactions of two quinuclidines with phosphorylated 4-morpholinopyridine and the statistically corrected rate constants for the reactions of tri- ethylenediamine (pKa = 9.2) with 2,4-dinitrophenyl phosphate and phosphorylated 3-methoxypyridine are larger than those for quinuclidine (pK, = 11 S).538 Several diamine monocations are known to be more reactive toward monosubstituted phosphate derivatives than the more basic free diamines, but this difference has been ascribed to an electrostatic effecL4s5 In addition to its inherent interest and its effects on struc- ture-reactivity parameters, desolvation is of interest because it is one of the mechanisms by which enzymes can utilize noocovalent binding interactions with specific substrates to increase reaction rates.9 Experimental Section Substituted quinuclidines, pyridine, and disodium p-nitrophenyl phosphate were purified by distillation or recrystallization. 4- Morpholinopyridine and phosphorylated 4-morpholinopyridine were prepared as described previously8 and 2,4-dinitrophenyl phosphate was kindly donated by Prof. David Chipman. Glass-distilled water was used throughout. Pseudo-first-order rate constants were determined spectrophotomet- rically. The ionic strength was maintained at 1.0 with potassium chloride, unless noted otherwise. The reactions were usually carried out with use of the amine nucleophile, 95% free base, as the buffer. Some experiments in the presence of calcium ion were carried out at lower fractions of free base, in order to avoid precipitation of calcium hydroxide, and the fast reactions of phosphorylated pyridines were carried out in the presence of 0.05 M potassium carbonate or potassium hydroxide, in order to neutralize excess acid from the synthesis mixture. Initial rates of reactions ofp-nitrophenyl phosphate dianion at 39 OC were followed at 410 or 400 nm, as described previ~usly.~ First-order rate constants for reactions of 2,4-dinitrophenyl phosphate at 39.1 f 0.2 OC were determined at 360 nm. Rate constants for reactions of phos- phorylated 4-morpholinopyridine at 25 OC were determined at 300 nm (295 nm for 3-quinuclidinone) and reactions of phosphorylated pyridine at 25 “C were followed at 270 nm. The phosphorylated pyridine was (4) Kirby, A. J.; Jencks, W. P. J. Am. Chem. SOC. 1965,87, 3209-3216. (5) Kirby, A. J.; Varvoglis, A. G. J. Chem. SOC. I? 1968, 135-141. (6) Skoog, M. T.; Jencks, W. P. J. Am. Chem. Soc. 1983,105,3356-3357. (7) Bourne, N.; William, A. J. Am. Chem. SOC. 1983, 105, 3357-3358. (8) Skoog, M. T.; Jencks, W. P. J. Am. Chem. Soc. 1984,106,7597-7606. (9) See, for example: Jencks, W. P. Adv. Enzymol. 1975, 43, 219-410. Bourne, N.; William, A. J. Am. Chem. SOC. 1984, 106, 7591-7596. 0002-7863/86/ 1508-0479$01.50/0 0 1986 American Chemical Society