Nucleophilic addition solvent effects

Before we attempt to apply this approach to specific cases, let s have a look at the guidelines summarized in Figure 27-13. The guidelines are presented in the form of a decision tree, with the first consideration being the base strength of the electron pair donor, B. Additional considerations include steric hindrance, nucleophilicity, and solvent effects. 

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. 

It is not difficult to incorporate this result into the general mechanism for hydrogen halide additions. These products are formed as the result of solvent competing with halide ion as the nucleophilic component in the addition. Solvent addition can occur via a concerted mechanism or by capture of a carbocation intermediate. Addition of a halide salt increases the likelihood of capture of a carbocation intermediate by halide ion. The effect of added halide salt can be detected kinetically. For example, the presence of tetramethylammonium... 

Ejfect ofSolvent. In addition to the solvent effects on certain SeI reactions, mentioned earlier (p. 764), solvents can influence the mechanism that is preferred. As with nucleophilic substitution (p. 448), an increase in solvent polarity increases the possibility of an ionizing mechanism, in this case SeI, in comparison with the second-order mechanisms, which do not involve ions. As previously mentioned (p. 763), the solvent can also exert an influence between the Se2 (front or back) and SeI mechanisms in that the rates of Se2 mechanisms should be increased by an increase in solvent polarity, while Sni mechanisms are much less affected. 

It is often difficult to understand at an intuitive level the explanation for the effect of changing substituents on the rate constant ratio kjkp for partitioning of carbocations between nucleophilic addition of solvent and deprotonation. In these cases, insight into the origins of the changes in this rate constant ratio requires a systematic evaluation of substituent effects on the following ... 

By contrast, the addition of a pair of ortho-methyl groups to the aromatic ring of X-[8+] to give X-[10+] has the following dramatic effects on partitioning of the carbocations between nucleophilic addition of solvent and proton transfer 27-41... 

The net effect of the two orrAo-methyl groups at Me-[10+] is a 4200-fold decrease in the rate constant ratio As/Ap for partitioning of the carbocation between nucleophilic addition of solvent and proton transfer.27... 

Substituent effects on ks. The replacement of an a-methyl group at the 4-methoxycumyl carbocation CH3-[14+] by an a-ester or a-amide group destabilizes the parent carbocation by 7 kcalmol-1 relative to the neutral azide ion adduct (Scheme 11 and Table 3) and results in 5-fold and 80-fold decreases, respectively, in ks for nucleophilic addition of a solvent 50/50 (v/v) methanol/water.33 These results follow the trend that strongly electron-withdrawing substituents, which destabilize a-substituted 4-methoxybenzyl carbocations relative to neutral adducts to nucleophiles, do not lead to the expected large increases in the rate constants for addition of solvent.28,33,92-95... 

In fact, the analogy between the mechanisms of heterolytic nucleophilic substitutions and electrophilic bromine additions, shown by the similarity of kinetic substituent and solvent effects (Ruasse and Motallebi, 1991), tends to support Brown s conclusion. If cationic intermediates are formed reversibly in solvolysis, analogous bromocations obtained from bromine and an ethylenic compound could also be formed reversibly. Nevertheless, return is a priori less favourable in bromination than in solvolysis because of the charge distribution in the bromocations. Return in bromination implies that the counter-ion, a bromide ion in protic solvents, attacks the bromine atom of the bromonium ion rather than a carbon atom (see [27]). Now, it is known (Galland et al, 1990) that the charge on this bromine atom is very small in bridged intermediates and obviously nil in /f-bromocarbocations [28]. 

During water-gas shift in pyridine solution, they isolated [PtH(py)L2]BF4, while from water-gas shift run in acetone solution, they isolated raft -[PtF[(CO)L2]BF4. The results indicated a solvent effect. That is, it was difficult to substitute coordinated pyridine with CO, but it was easier to substitute acetone with CO, via [PtH(Solvent)L2]OH + CO <-> [PtH(CO)L2]OH + Solvent. Following this important solvent-facilitated CO addition, they proposed a nucleophilic attack of OH-on the coordinated CO, via [PtH(CO)L2]OH <-> [PtH(COOH)L2]. The next step is thermal decomposition of the species, liberating C02, via the decomposition [PtH(COOH)L2] <-> [PtH2L2] + C02. CO addition was proposed to assist in decomposing the hydride to liberate H2. A more detailed description of the catalytic cycle is provided in Scheme 19. 

Rappoport and co-workers work has continued in a study of the substitution of ( )-and (Z)-/3-bromo- or chloro-styrenes, (1) and (2), by MeS in DMSO-d 6 (sometimes in admixture with CD3OD) as solvent. Product studies indicated retention stereochemistry rate measurements found only a small Br/Cl element effect, slower reactions of the p-OMe bromo compounds, and retardation by CD3OD. These results are consistent with Tiecco s suggestion in 1983 that even this system, activated by only a single phenyl group, reacts through the nucleophilic addition-elimination multistep route. 

Rate constants and products have been reported for solvolysis of benzhydryl chloride and /7-methoxybenzyl chloride in 2,2,2-trifluoroethanol (TFE)-water and-ethanol, along with additional kinetic data for solvolysis of r-butyl and other alkyl halides in 97% TFE and 97% hexafluoropropan-2-ol. The results are discussed in terms of solvent ionizing power Y and nucleophilicity N, and contributions from other solvation effects are considered. Comparisons with other 3 nI reactions show that the solvolyses of benzhydryl chloride in TFE mixtures are unexpectedly fast an additional solvation effect influences solvolysis leading to delocalized cations. 

To conclude this section on the effect of solvent on a-nucleophilicity, we refer to the current, rather controversial, situation pertaining to gas-phase smdies and the a-effect. As reported in our review on the a-effect and its modulation by solvent the gas-phase reaction of methyl formate with HOO and HO , which proceeds via three competitive pathways proton abstraction, nucleophilic addition to the carbonyl group and Sat2 displacement on the methyl group, showed no enhanced nucleophilic reactivity for HOO relative to This was consistent with gas-phase calculational work... 

In addition to exploiting solvent effects on reactivity, there are two other valuable approaches to enhancing reactivity in nucleophilic substitutions. These are use of crown ethers as catalysts and the use of phase-transfer conditions. The crown ethers are a family of cyclic polyethers, three examples of which are shown below ... 

A more familiar example is Sn2 addition of an anionic nucleophile to an alkyl halide. In the gas phase, this occurs without activation energy, and the known barrier for the process in solution is a solvent effect (see discussion in Chapter 6). Finally, reactions of electron-deficient species, including transition-metal complexes, often occur with little or no energy barrier. Processes as hydroboration and 3-hydride elimination are likely candidates. 

He have found that, In hydrocarbon solvents, the activating effect of the pyridine ring upon the reactivity of the doublebond, allows nucleophilic addition from non-solvated R Mg R derivatives. 

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