Nucleophiles rate-limiting proton transfer

The absence of scatter in a Bronsted plot for a general base-catalysed reaction can imply that the reaction mechanism involves a rate-limiting proton transfer step. This is because proton transfer to the base in the reaction is closely similar to the equilibrium proton transfer to the base in the reaction which defines the p Ka of the conjugate acid of that base. The observation of scatter, especially for sterically hindered bases (such as 2,6-dimethylpyridine), is evidence that nucleophilic catalysis is operating as opposed to general base catalysis. 

Behavior according to Fig. 2 shows a transition from rate limiting proton transfer at low amine concentration to rate limiting nucleophilic attack at high amine concentration. This comes about because the k2p[RR NH] term in eq 3 is dominant and thus k2p changes from k2p < k -j at low to k2p >> k j at high amine concentration. This behavior is exemplified by the reactions of 2 with morpholine and aniline (5), and by the reaction of 3 with morpholine (7). 

The use of liquid ammonia as a solvent for Ar reactions has been explored. With 4-fluoronitrobenzene and chloropyrimidines, solvolysis occurs although substitution by added nucleophiles such as phenoxide or triazolate ions can compete successfully. Kinetic studies of the reactions of 2-chloro- and 2-ethoxy-3,5-dinitropyridine with substituted anilines in DMSO in the presence of DABCO indicate a base-catalysed pathway, which is likely to involve rate-limiting proton transfer from the zwitterionic intermediate to base." ° In the reaction of 2,6-bis(trifluoromethanesulfonyl)-4-nitroanisole, (26), with substituted anilines in DMSO/methanol mixtures, nucleophilic attack is rate-limiting. Rate constants have higher values in DMSO than in methanol, and in DMSO-rich mixtures, there is evidence, from changes in slope of Brpnsted and Hammett plots, that formation of the zwitterionic intermediate involves an SET process." ... 

Abstract. Nucleophilic addition of amines to olefins which are activated by electron withdrawing substituents occurs readily in aqueous dimethylsulfoxide. The reaction comprises two steps (1) nucleophilic addition to form a zwitterionic complex (2) removal of the ammonio proton of the zwitterion by a base. In most cases the first step is rate limiting but in some cases proton transfer is rate limiting. The latter situation prevails either when the reverse of the nucleophilic attack step is very rapid, as in the reaction of morpholine with benzylidenemalononitrile, or when the rate of proton transfer is depressed by a steric effect, as in the reaction of morpho-line with 1,l-dinitro-2,2-diphenylethylene. The steric effects in this latter system are among the most dramatic ones reported to date. Our data also show that the kinetic barrier to nucleophilic attack is substantially higher for nitro than for cyano activated olefins. This effect seems to be related to the well known fact that proton transfers involving nitro activated carbon acids are much slower than those of cyano activated carbon acids. 

Diffusion-limited rate control at high basicity may set in. This is more eommonly seen in a true Br nsted plot. If the rate-determining step is a proton transfer, and if this is diffusion controlled, then variation in base strength will not affect the rate of reaction. Thus, 3 may be zero at high basicity, whereas at low basicity a dependence on pK may be seen. ° Yang and Jencks ° show an example in the nucleophilic attack of aniline on methyl formate catalyzed by oxygen bases. 

An unusual kinetic result has been reported51 when phenylhydroxylamine reacted anaerobically with bisulphite anion. The product distribution was as expected, i.e. both 2- and 4-aminophenol and the 2- and 4-aminobenzenesulphonates were formed. Kinetic measurements showed a first-order dependence upon [bisulphite], in contrast to the earlier work with Cl- and later with N3 -. The authors propose a mechanism involving direct attack by the nucleophile at the 2- and 4-positions as the rate-limiting step, followed by proton transfers and solvent attack to form the sulphonate products. 

Since morpholine and piperidine are stereochemically similar but exhibit different pKa values, the difference between their rates in the reactions of the fluoro-substrates in acetonitrile could be also due to a change in mechanism, whereby proton transfer from the intermediate 1 in equation 1 becomes rate-limiting when the reagent is morpholine. The change from an uncatalysed to a base-catalysed reaction with decrease in basicity of the nucleophile is well known in ANS for both primary and secondary amines1 200. 

It appears that all these possibilities can be excluded. If reactions (a) or (gf) were rate-limiting the reaction velocity would be independent of the concentration of the substrate, while reaction (e) (identical with (Z)) would predict no catalysis by acids or bases. If reactions (b), (d) or (h) determined the rate the reaction would show specific catalysis by hydrogen or hydroxide ions, in place of the general acid-base catalysis actually observed. Reactions (c), (f) and (m) are unacceptable as rate-limiting processes, since they involve simple proton transfers to and from oxygen. Reactions (j) and (k) might well be slow, but their rates would depend upon the nucleophilic reactivity of the catalyst towards carbon rather than on its basic strength towards a proton as shown in Section IV,D it is the latter quantity which correlates closely with the observed rates. 

Ah initio calculations to map out the gas-phase activation free energy profiles of the reactions of trimethyl phosphate (TMP) (246) with three nucleophiles, HO, MeO and F have been carried out. The calculations revealed, inter alia, a novel activation free-energy pathway for HO attack on TMP in the gas phase in which initial addition at phosphorus is followed by pseudorotation and subsequent elimination with simultaneous intramolecular proton transfer. Ah initio calculations and continuum dielectric methods have been employed to map out the lowest activation free-energy profiles for the alkaline hydrolysis of a five-membered cyclic phosphate, methyl ethylene phosphate (247), its acyclic analogue, trimethyl phosphate (246), and its six-membered ring counterpart, methyl propylene phosphate (248). The rate-limiting step for the three reactions was found to be hydroxyl ion attack at the phosphorus atom of the triester. ... 

Rate and equilibrium constants have been reported for the reactions of butylamine, pyrrolidine, and piperidine with trinitrobenzene, ethyl 2,4,6-trinitrophenyl ether, and phenyl 2,4,6-trinitrophenyl ether in acetonitrile, hi these reactions, leading to cr-adduct formation and/or nucleophilic substitution, proton transfer may be rate limiting. Comparisons with data obtained in DMSO show that, while equilibrium constants for adduct formation are lower in acetonitrile, rate constants for proton transfer are higher. This probably reflects the stronger hydrogen bonding between DMSO and NH+ protons in ammonium ions and in zwitterions.113 Reaction of 1,3,5-trinitrobenzene with indole-3-carboxylate ions in methanol has been shown to yield the re-complex (26), which is the likely precursor of nitrogen- and carbon-bonded cr-adducts expected from the reaction.114 There is evidence for the intermediacy of adducts similar to (27) from the reaction of methyl 3,5-dinitrobenzoate with l,8-diazabicyclo[5.4.0]undec-8-ene (DBU) cyclization eventually yields 2-aminoindole derivatives.115... 

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