Solvents and nucleophiles

Figure 11.7 Energy diagrams showing the effects of (a) substrate, (b) nucleophile, (c) leaving group, and (d) solvent on Sn2 reaction rates. Substrate and leaving group effects are felt primarily in the transition state. Nucleophile and solvent effects are felt primarily in the reactant ground state.

The effects on S tl reactions of the four variables—substrate, leaving group, nucleophile, and solvent—are summarized in the following statements ... 

In some cases, the use of a large excess of alcohol is an option to drive the reaction to completion. Alcoholysis of glutamic acid dimethyl ester derivatives with acylase I was regio- and enantioselective (Figure 6.15). An excess of butanol was used as nucleophile and solvent [62]. 

Nucleophilic Trapping of Radical Cations. To investigate some of the properties of Mh radical cations these intermediates have been generated in two one-electron oxidant systems. The first contains iodine as oxidant and pyridine as nucleophile and solvent (8-10), while the second contains Mn(0Ac) in acetic acid (10,11). Studies with a number of PAH indicate that the formation of pyridinium-PAH or acetoxy-PAH by one-electron oxidation with Mn(0Ac)3 or iodine, respectively, is related to the ionization potential (IP) of the PAH. For PAH with relatively high IP, such as phenanthrene, chrysene, 5-methyl chrysene and dibenz[a,h]anthracene, no reaction occurs with these two oxidant systems. Another important factor influencing the specific reactivity of PAH radical cations with nucleophiles is localization of the positive charge at one or a few carbon atoms in the radical cation. 

In the present study IPA was used as both nucleophile and solvent. The research was started with a screening for suitable ligands. The first Ugands tested were commercially available (Table 3). 

AG and AG0 are the free energies of activation of the reaction under consideration and of the standard reaction, respectively. The latter is, of course, a constant, and at constant temperature, the quantity RT is also constant. Therefore, if a series of displacements are carried out on the same substrate in protic solvents but with different nucleophiles, Equation 4.22 says that the free energy of activation depends linearly on the power of the nucleophile. Likewise, if the nucleophile and solvent are kept constant but the substrate is varied, the equation says that the free energy of activation depends linearly on the susceptibility of the substrate to changes in nucleophilicity. 

Radical cations that are produced by electrochemical oxidation are not stable in solvents with appreciable base character. This results because such radicals are subject to attack by available nucleophiles, and solvents that contain donor electron pairs are good nucleophiles. Cation radicals are most stable in solvents that are good Lewis acids and show negligible basic properties. Some of the solvent systems that have been employed to stabilize electrochemically produced cation radicals include nitromethane and nitrobenzene,21 dichloro-methane,22 trifluoroacetic acid-dichloromethane (1 9),23 nitromethane-AlCl3,24 and AlCl3-NaCl (1 l).25 Organic chemists should be familiar with the stabilization of carbonium ions by superacid media.26 These media usually contain fluorosulfuric acid, or mixtures of fluorosulfuric acid with antimony pen-tachloride and sulfur dioxide, and are potent solvents for the production and stabilization of organic cations. 

The mechanism (SN1) for this reaction is also shown. Note that the nucleophile is water, not hydroxide ion. The second proton on the oxygen is not lost until after the oxygen has bonded to the carbon. A reaction such as this one, in which the nucleophile is also the solvent, is called a solvolysis reaction. In this specific case, where water is both the nucleophile and solvent, it is a hydrolysis reaction. 

Hydrolysis reaction (Section 10.2) A reaction in which water is both the nucleophile and solvent. Hydrophilic compound (Section 2.6) A compound that has a favorable interaction with water because of its polar nature. 

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). 

For vinylacetylene the static CNDO/2 data given in Figure 6 indicate that the two internal carbons are more electrophilic than the terminal ones but terminal attack is presumably favoured because this leads to transition states which are resonance-stabilized > . The confusing issue in the additions to vinylacetylene is the variability in the point of entry with changes in nucleophile and solvent, e.g. thiols attack primarily at the terminal sp carbon - - while alkoxides, phosphides and amides prefer the terminal sp- carbon . Attack on the internal sp carbon may occur when the vinylacetylene contains special substituents , e.g. equation (36). Perhaps these matters would be clarified if equilibrium and rate studies were performed. 

Nucleophilicities relative to a standard solvent can be quantified by the Swain-Scott equation (12)66, in which k and k0 are the second-order rate constants for reactions of the nucleophile and solvent respectively, and s is a measure of the sensitivity of the substrate to nucleophilicity n. By this definition, the nucleophilicity of the solvent is zero. For all reactions examined, there will be competition between attack by solvent (present in large excess) and reaction with added anionic nucleophiles. Hence, only n values well above zero can be obtained with satisfactory reliability. In the original work66, the solvent was water and all but one of the substrates were neutral s was defined as 1.0 for methyl bromide and was calculated to be 0.66 for ethyl tosylate the lowest reliable n value reported was 1.9 for picrate anion, but a value of < 1 for p-tosylate anion was reported66 in a footnote. 

Mayr and co-workers further extended the method by stud)dng reactions of nucleophiles with the S-methyldibenzothiophenium ion (55, equation 8.45). The investigators plotted values of (log fc)/sw versus N for a series of nucleophiles and solvents reacting with 55 and obtained a linear correlation with slope 0.6. A subset of the experimental data is shown in Table 8.15 and plotted in Figure 8.38. The results indicated that the reaction of 55 with nucleophiles is affected only 60% as much by the nucleophilidty of the nucleophile as is the reaction of 54. 

The cross-aldol reaction can be also performed using an excess of aldehyde (5, 500 mol%) acting both as the source of nucleophile and solvent in the presence of water (300 mol%) with the obtained enantiomeric excess being increased [49]. 

The aldol reaction between acetone (3a) and a-phenoxy and phenylsulfanylm-ethyl ketones 87 was possible by using catalyst 79c (Scheme 4.28) affording tertiary alcohols 88 albeit in moderated yields and enantioselectivities, with acetone acting both as nucleophile and solvent. Also, compounds 87 reacted as source of the nucleophile with different aromatic aldehydes using (S)-profine (20 mol%) as catalyst in DMSO at 25°C. Whereas a-phenoxy ketones gave the legioisomer from the reaction... 

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