Effect of Nucleophile

Some trends are common to both nucleophilicity and basicity. For example, the two run in parallel when the attacking atom is the same. Thus, for nucleophilicity, 

Why are species in which the nucleophilic atom is in the second or third row of the periodic table more nucleophilic than those containing, oxygen, nitrogen, or fluorine This is related to the polarizability of the atom. With second and third row elements, the outer electrons are further away from the nucleus. Thus, when they approach a charge or dipole, the electron cloud is more easily squashed out of shape, in preparation for the formation of the new bond. We describe these nucleophiles as soft. Polarizability means lower basicity and higher nucleophilicity. RS is more polarizable than RO , 

TABLE 9.2 Relative Reactivity of Nucleo with lodomethane 

Steric effects are also important in determining nudeophilicity. The reaction between a base and a proton is sterically completely undemanding. However, an Sn2 reaction is sterically much more challenging—at the transition state (9.1), five groups must be accommodated around the central carbon atom. Thus, as well as softness and hardness, we need to consider size. Bulky species, such as PhjC and tert-BuO , are good bases but very poor nucleophiles. Triethylamine and quinuclidine, 9.2, have similar basicity, but quinuclidine is the better nucleophile, because the alkyl groups are tied back and out of the way. 

Soft RjS, RSH, RS-, - CN- arenes, alkenes, R3P I2, Btj, RSX, RCHjX (X = halogen, softest with 1), BH3, Cu+, Ag+, zero-valent metals 

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With the dicyclohexylcarbodiimide (DCQ reagent racemization is more pronounced in polar solvents such as DMF than in CHjCl2, for example. An efficient method for reduction of racemization in coupling with DCC is to use additives such as N-hydroxysuccinimide or l-hydroxybenzotriazole. A possible explanation for this effect of nucleophilic additives is that they compete with the amino component for the acyl group to form active esters, which in turn reaa without racemization. There are some other condensation agents (e.g. 2-ethyl-7-hydroxybenz[d]isoxazolium and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline) that have been found not to lead to significant racemization. They have, however, not been widely tested in peptide synthesis. 

The Stvfl mechanism is an ionization mechanism The nucleophile does not participate until after the rate determining step has taken place Thus the effects of nucleophile and alkyl halide structure are expected to be different from those observed for reactions pro ceedmg by the 8 2 pathway How the structure of the alkyl halide affects the rate of Stvfl reactions is the topic of the next section... 

The net effect of nucleophilic acyl substitution is the replacement of the leaving group by the entering nucleophile. We ll see in Chapter 21, for instance, that acid chlorides are rapidly converted into esters by treatment with alkoxide ions (Figure 4). 

Effect of nucleophile R reacts with nucleophilic solvents rather than with Nu" (solvolysis), except when R is relatively stable Rate depends on nucleophilicity r >Br >Cr RS. >RO Equilibrium lies towards weaker Bronsted base... 

For a review of the effect of nucleophile association on nucleophilicity. sec Guibc Bram Bull. Soc. Chim. Fr. 1975, 933-948. 

Effect of nucleophile on rate Rate of substitution is independent of both concentration and nature of nucleophile. Nucleophile does not participate until after ratedetermining step. (Section 8.8) Rate depends on both nature of nucleophile and its concentration. (Sections 8.3 and 8.7)... 

The effect of nucleophilic dienes on the copolymerization of ethylene and propylene has been reported by Gladding, Fisher and Collette (88). Table 8 shows that 1.4-hexadiene decreased the tendency for propylene to enter into the ethylene-propylene terpolymer, produced by a triisobutyl aluminum-vanadium oxychloride catalyst. 

Effects of Nucleophile No effect on rate (favored by weaker nucleophiles because SN2 is slower) Stronger nucleophiles cause faster rate... 

Certainly, the reactive species has to be an enolate. The conceivable candidates are the enolate D (malonic acid monoanion, Figure 10.49), the enolate E (malonic acid dianion ), and the enolate F (malonic add trianion ). The nucleophilicity increases greatly in this order, but the concentrations of these species also drastically decrease. The combined effect of nucleophilicity and abundance determines which nucleophile initiates the Knoevenagel condensation. It is therefore important to know the concentrations of the various species. 

Strong Lewis acids and suitable reaction conditions (e.g., high dielectric constant, low temperature) unbalance the electron structure of olefins. The effect of nucleophilicity is demonstrated in the simplest olefinic series ethylene polymerization is practically impossible with aluminum chloride in methyl chloride diluent at —100° C. propene yields a low molecular weight oil under the same reaction conditions and isobutene polymerizes with extreme rapidity to high molecular weight rubbery products. 

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