Nucleophilic constant solvent effects

There is an ongoing controversy about whether there is any stabilization of the transition state for nucleophilic substitution at tertiary aliphatic carbon from interaction with nucleophilic solvent." ° This controversy has developed with the increasing sophistication of experiments to characterize solvent effects on the rate constants for solvolysis reactions. Grunwald and Winstein determined rate constants for solvolysis of tert-butyl chloride in a wide variety of solvents and used these data to define the solvent ionizing parameter T (Eq. 3). They next found that rate constants for solvolysis of primary and secondary aliphatic carbon show a smaller sensitivity (m) to changes in Y than those for the parent solvolysis reaction of tert-butyl chloride (for which m = 1 by definition). A second term was added ( N) to account for the effect of changes in solvent nucleophilicity on obsd that result from transition state stabilization by a nucleophilic interaction between solvent and substrate. It was first assumed that there is no significant stabilization of the transition state for solvolysis of tert-butyl chloride from such a nucleophilic interaction. However, a close examination of extensive rate data revealed, in some cases, a correlation between rate constants for solvolysis of fert-butyl derivatives and solvent nucleophicity. " ... 

Many other solvent parameters have been defined in an attempt to model as thoroughly as possible solvent effects on the rate constants for solvolysis. These include (a) Several scales of solvent ionizing power Tx developed for different substrates R—X that are thought to undergo limiting stepwise solvolysis. (b) Several different scales of solvent nucleophilicity developed for substrates of different charge type that undergo concerted bimolecular substitution by solvent. (c) An... 

There are some difficulties with testing this experimentally. The first is that it is not easy to match the same set of bases to electrophiles of quite different reactivity. A second is that the most readily available equilibrium constants characterizing the nucleophiles are pAias of the conjugate acids, which do not necessarily correlate reactivities toward carbocations. Thirdly, one should avoid reactions influenced by diffusion control. Finally, care has to be taken with steric and solvent effects. 

Rates and product selectivities 5 = ([ester product]/[acid product]) x ([water]/ [alcohol solvent] were reported for solvolyses of chloroacetyl chloride at —10 °C and phenylacetyl chloride at 0 °C in EtOH- and MeOH-water mixtures. Additional kinetic data were reported for solvolyses in acetone-water, 2,2,2-trifluoroethanol (TFE)-water, and TFE-EtOH mixtures. Selectivities and solvent effects for chloroacetyl chloride, including the kinetic solvent isotope effect (KSIE) of 2.18 for MeOH, were similar to those for solvolyses of p-nilrobcnzoyl chloride rate constants in acetone-water were consistent with a third-order mechanism, and rates and products in EtOH-and MeOH-water mixtures could be explained quantitatively by competing third-order mechanisms in which one molecule of solvent (alcohol or water) acts as a nucleophile and another acts as a general base (an addition-elimination reaction channel) (29 R = Et, Me, H).23... 

An analysis of these results in terms of solvent effects leads to the observation of similarities with Ritchie s work on the N+ relation. Thus the constant selectivities obtained in the solvolysis reactions of certain methyl derivatives (Table 9) may indicate the existence of a basic similarity between the rate-determining process in these reaction and in the electrophile-nucleophile combination reactions correlated by the IV+ relation. The failure of the methyl halides to conform to this pattern might suggest that their substitution reactions are fundamentally different, and that the free energy of activation is dependent on factors other than desolvation. 

The generally observed identity of the r value for solvolysis reactivity and gas-phase stability AAG(c+> of the corresponding carbocation leads to an important prediction concerning the solvolysis transition state. In a typical (limiting) two-step SnI mechanism with a single dominant transition state, the r values of transition states for the various nucleophile-cation reactions should be essentially controlled by the intrinsic resonance demand of the intermediate cation the substituent effect should be described by a single scale of substituent constants (a) with an r value characteristic of this cation. In a recent laser flash-photolysis study (Das, 1993) on the recombination of stable trityl and benzhydryl cations with nucleophiles and solvents, McClelland et al. (1986, 1989) have treated the substituent effects on solvent-recombination processes by (2). 

Macroscopic solvent effects can be described by the dielectric constant of a medium, whereas the effects of polarization, induced dipoles, and specific solvation are examples of microscopic solvent effects. Carbenium ions are very strong electrophiles that interact reversibly with several components of the reaction mixture in addition to undergoing initiation, propagation, transfer, and termination. These interactions may be relatively weak as in dispersive interactions, which last less than it takes for a bond vibration (<10 14 sec), and are thus considered to involve "sticky collisions. Stronger interactions lead to long-lived intermediates and/or complex formation, often with a change of hybridization. For example, onium ions are formed with -donors. Even stable trityl ions react very rapidly with amines to form ammonium ions [41], and with water, alcohol, ethers, and esters to form oxonium ions. Onium ion formation is reversible, with the equilibrium constant depending on the nucleophile, cation, solvent, and temperature (cf., Section IV.C.3). 

The most important conclusion from stopped-flow studies is that the rate constants of propagation of several styrene derivatives are approximately kp 105-1 mol, L sec I at 0° C, which is relatively high compared with those of radical and anionic systems (average kp == 102 mol 1L-sec 1 at 0° C). Solvent effects are noticeable, with propagation slower in more nucleophilic 1,2-dichloroethane [17] than in CH2Cl2 [18] under comparable conditions. That is, the carbenium ion reactivity is apparently reduced by interaction with more nucleophilic solvents. However, such interactions do not result in formation of chloronium ions, whose spectra would be very different compared to those of the corresponding carbenium ions. 

The second-order rate constant for the reaction between methoxycarbonyl-acetylene and piperidine increases with increasing solvent polarity. This can be attributed to the increased solvation of the strongly dipolar activated complex, which is formed from neutral molecules [88], Analogous solvent effects have been observed for the nucleophilic addition of aziridine to 3-dimethylaminopropynal [89] and the addition of diethylamine to / -alkoxyvinyl methyl ketones [793],... 

The rate constant kgaiv for solvolysis is assumed to reflect the stability and reactivity of (i.e., faster solvolysis gives a more stable cation, which, therefore, reacts more slowly with nucleophiles). The ratio kt /k , measured by product distribution studies, is a measure of selectivity with respect to the nucleophiles azide ion and water. The plot of log k oiv against log (kn/k ) is messy and rather confusing, containing regions of constant selectivity, RSP behavior, and possibly anti-RSP behavior. The present point is that the measures of reactivity and selectivity may affect the conclusions drawn. The role of solvent effects can be important in modifying RSP behavior. ... 

It is notable that DMSO is a stronger base and probably a stronger H-bond acceptor than methanol (Parker, 1965a). Sn2 reactions of tertiary amines, such aa pyridine and triethylamine, and of dimethyl sulphide, with alkyl halides are much more representative of the class of polar molecule-polar molecule Sif2 reactions than reactions of primary or secondary amines. As shown in Table 11, the former reactions are virtually independent of transfer from dipolar aprotic to protic solvent of the same dielectric constant. It is my belief (Parker, 1961b, 1965a) that only bimolecular reactions of anionic nucleophiles have their rates strongly influenced by protic-dipolar aprotic solvent effects. 

While this result confirmed the feasibility of the general approach, it did not precipitate wider exploration of dielectric medium effects. Recently, however, Wiberg et al. have incorporated the Onsager self-consistent reaction-field model into ab initio MO theory in an implementation which provides analytical gradients and second derivatives. The model considers just the dipole of the solute molecules and a spherical cavity whose radius is chosen for a given solute molecule from the molecular volume estimated at the 0.001 eB electron-density contour (B is the Bohr radius), plus an empirical constant 0.5 A to account for the nearest approach of solvent molecules [164]. Cieplak and Wiberg have used this model to probe solvent effects on the transition states for nucleophilic additions to substituted acetaldehydes [165]. For each... 

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