The Dinuclear Zn(II) Complex Catalyzed Cyclization of a Series of 2- Hydroxypropyl Aryl Phosphate RNA Models: Progressive Change in Mechanism from Rate-Limiting P-O Bond Cleavage to Substrate Binding

A methoxide-bridged dinuclear Zn(II) complex of 1,3-[N,N'- bis(1,5,9-triazacyclododecane)]propane (1-Zn(II) sub(2):( super(-)OCH sub(3))) was prepared, and its catalysis of the cyclization of a series of 2- hydroxypropyl aryl phosphates (4a-g) was investigated in methanol at [eqn]pH 9.8, T = 25 degree C by stopped-flow spectrophotometry. An X-ray diffraction structure of the hydroxide analogue of 1-Zn(II) sub(2):( super(-)OCH sub(3)), namely 1-Zn(II) sub(2):( super(-)OH), reveals that each of the Zn(II) ions is coordinated by the three N's of the triazacyclododecane units and a bridging hydroxide. The cyclizations of substrates 4a-g reveal a progressive change in the observed kinetics from Michaelis-Menten saturation kinetics for the poorer substrates (4-OCH sub(3) (4g); 4-H (4f); 3-OCH sub(3) (4e); 4-Cl (4d); 3-NO sub(2), (4c)) to second-order kinetics (linear in 1-Zn(II) sub(2):( super(-)OCH sub(3))) for the better substrates (4-NO sub(2),3-CH sub(3) (4b); 4-NO sub(2), (4a)). The data are analyzed in terms of a multistep process whereby a first formed complex rearranges to a reactive complex with a doubly activated phosphate coordinated to both metal ions. The kinetic behavior of the series is analyzed in terms of change in rate-limiting step for the catalyzed reaction whereby the rate-limiting step for the poorer substrates (4g-c) is the chemical step of cyclization of the substrate, while for the better substrates (4b,a) the rate-limiting step is binding. The catalysis of the cyclization of these substrates is extremely efficient. The k sub(cat)/K sub(M) values for the catalyzed reactions range from 2.75 x 10 super(5) to 2.3 x 10 super(4) M super(-1) s super(-1), providing an acceleration of 1 x 10 super(8) to 4 x 10 super(9) relative to the methoxide reaction (k sub(2) super(OCH3), which ranges from 2.6 x 10 super(-) super(3) to 5.9 x 10 super(- ) super(6) M super(-1) s super(-1) for 4a-g). At a [eqn]pH of 9.8 where the catalyst is maximally active, the acceleration for the substrates ranges from (1 - 4) x 10 super(12) relative to the background reaction at the same [eqn]pH. Detailed energetics calculations show that the transition state for the catalyzed reaction comprising 1-Zn(II) sub(2), methoxide, and 4 is stabilized by about - 21 to -23 kcal/mol relative to the transition state for the methoxide reaction. The pronounced catalytic activity is attributed to a synergism between a positively charged catalyst that has high affinity for the substrate