Nucleophiles and substrate

This reaction proceeds via the transition state illustrated in Fig. 10.2. An Sn2 reaction (second order nucleophilic substitution) in the rate limiting step involves the attack of the nucleophilic reagent on the rear of the (usually carbon) atom to which the leaving group is attached. The rate is thus proportional to both the concentration of nucleophile and substrate and is therefore second order. On the other hand, in an SnI reaction the rate limiting step ordinarily involves the first order formation of an active intermediate (a carbonium ion or partial carbonium ion, for example,) followed by a much more rapid conversion to product. A sampling of a and 3 2° deuterium isotope effects on some SnI and Sn2 solvolysis reactions (i.e. a reaction between the substrate and the solvent medium) is shown in Table 10.2. The... 

We have assumed that the values of as for formation weak encounter complexes between nucleophile and substrate, and between nucleophile and carbocation are similar. This is supported by the observation of similar values of [see above] for formation of encounter complexes between neutral substrate and anionic nucleophile (0.7 between cationic substrate and anionic nucleophile (0.2 and... 

A reaction described as Sn2, abbreviation for substitution, nucleophilic (bimolecular), is a one-step process, and no intermediate is formed. This reaction involves the so-called backside attack of a nucleophile Y on an electrophilic center RX, such that the reaction center the carbon or other atom attacked by the nucleophile) undergoes inversion of stereochemical configuration. In the transition-state nucleophile and exiphile (leaving group) reside at the reaction center. Aside from stereochemical issues, other evidence can be used to identify Sn2 reactions. First, because both nucleophile and substrate are involved in the rate-determining step, the reaction is second order overall rate = k[RX][Y]. Moreover, one can use kinetic isotope effects to distinguish SnI and Sn2 cases (See Kinetic Isotope Effects). 

However, this level of uniformity is not expected of all nucleophiles and substrates. An extreme example of variation in ApAR is provided by comparison of chloride and dimethyl sulfide as nucleophiles reacting, respectively, with the p-methoxybenzyl cation and the structurally very different electrophile, the di-trifluoromethyl quinone methide 57.220 In the case of the p-methoxybenzyl cation the addition of Me2S is more favorable than addition of chloride ion by a factor of 107-fold for the quinone methide it is 100 times less favorable. Toteva and Richard attribute the difference to the large and unfavorable steric and polar interactions between the positively charged... 

In general, the reactions are second-order, first-order with respect to both nucleophile and substrate (17). The relative activating effects of various substituents have been determined (18) to be in the order ... 

The methodology suffers from competition between syn- and anti-mechanisms in acyclic cases. Indeed, the pathway may depend on the nature of nucleophile and substrate.78139 In addition, there is no clearcut differentiation between hard and soft nucleophiles in the model described. 

Hughes and Ingold classified nucleophilic substitution reactions into four electrostatic types according to the charge state of the nucleophile and substrate. 

An experimental Acan be derived from the temperature dependence of the second-order rate constant, which yielded a value of 25.9 kcal/mol.59 Although it appears that this disagrees with the computed free energy of activation (16.6 kcal/ mol) for the reaction of H3N + CH3SH2 in water, the difference actually originates from the intrinsic reactivity of the two reactions. The additional methyl group substitutions both on the nucleophile and substrate raise the gas-phase barrier by 10 kcal/mol to a value of 10.5 kcal/mol at the HF/6-31G(d) level. Taking the methyl substitution effect into account, the computed solvation effect in fact is in accord with experiment,59 which is about 15 kcal/mol (25.9 — 10.5 kcal/mol). 

We have assumed that the values of Kas for formation weak encounter complexes between nucleophile and substrate, and between nucleophile and carbocation are similar. This is supported by the observation of similar values of Kas [see above] for formation of encounter complexes between neutral substrate and anionic nucleophile (0.7 M-1),2 between cationic substrate and anionic nucleophile (0.2 M 1),27 and between neutral substrate and neutral nucleophile (0.3 M-1).20 We use the value of k-d= 1.6 X 10los-1 that can be calculated from Xas = 0.3 M-1 formation of encounter complexes with 1-phenylethyl derivatives and kA = 5 X 109 M-1 s-1 (equation (2)).20 The uncertainty in this value for fc d is approximately equal to the range of experimental values for Xas (0.2-0.7 m 1) 2-20-27... 

Fia. 14. Schematic representation of the possible modes of interaction in functional micelles. The + and — signs indicate the charge on the head group, n, n m and m represent the number of carbon atoms in the hydrocarbon chain, and Fs and Fg a,re the nucleophilic and substrate functional groups. 

We can generalize this type of substitution for any nucleophile and substrate. To simplify things we have ignored the cation for the time being, as it doesn t participate in the reaction. The general equation for this type of substitution at a saturated carbon atom can be written as follows, ignoring the spectator ions... 

These four types of reactions are by far the most common, although others such as anionic substrate + anionic nucleophile can occur if sufficiently reactive reactants are chosen. The factors that influence the reactivity of nucleophiles and substrates will be among the topics considered in this chapter. 

If the nucleophile and substrate are neutral (eq. 6.2), the product will be positively charged. If the nucleophile is a negative ion and the substrate is neutral (eq. 6.3), the product will be neutral. In either case, an unshared electron pair on the nucleophile supplies the electrons for the new covalent bond. 

How can we recognize when a particular nucleophile and substrate react by the 8 2 mechanism There are several telltale signs. 

Using encapsulation of substrate within the cavity of a coordination capsule, the internal reaction site of a substrate can be shielded, and nucleophilic attack will be directed to a less protected terminal site (Fig. 9.22). In this way, regioselectivity of the reaction can be controlled without changing steric and electronic effects of nucleophiles and substrates, or solvent polarity. 

As will be seen, even with nucleophile and substrate held constant, reaction conditions (e.g., solvent and temperature) can be optimized to favor elimination instead of substitution. 

Although the ring closure reactions to obtain heterocycles have been partially studied, due to the diversity of different nucleophiles and substrates that can be used, this is a field of vast possibilities of new developments. 

It is important to be certain you understand the source of the rate increase for the sulfide compound. Intramolecular reactions often have a large rate advantage over inter-molecular reactions because there is no need for the nucleophile and substrate to find each other in solution. Intramolecular assistance in the rate-determining step of a reaction is called anchimeric assistance. Once again, it is important not to be put off by the elaborate name. The concept is quite simple Intramolecular nucleophiles are often more effective displacing agents than intermolecular nucleophiles. What is somewhat more difHcult to anticipate is that an intramolecular displacement by a very weak, but perfectly situated nucleophile can often compete effectively with intermolecular reactions. 

These reactions appear complicated only because the structures of the nucleophiles and substrates are complex. Yet conceptually they are simple, and they illustrate many of the principles we have encountered thus far in Chapter 6. In them we see how nature makes use of the high nucleophilicity of sulfur atoms. We also see how a weakly basic group (e.g., the triphosphate group of ATP) func-... 

---