Theoretical studies nucleophilic substitution

The stereochemical outcome of nucleophilic addition reactions to cyclic ketones is the subject of numerous experimental and theoretical studies, with substituted cyclohexanones and cy-clopcntanones having been intensively studied. In addition reactions to substituted cyclohexanones 1 the problem of simple diastereoselectivity is manifested in the predominance of cither axial attack of a nucleophile, leading to the equatorial alcohol 2 A. or equatorial attack of the nucleophile which leads to the axial alcohol 2B. 

The halogens of halothiophenes are more labile than those of the corresponding benzenes in accordance with theoretical considera-tions which indicate that thiophenes should also undergo nucleophilic substitutions more rapidly than benzenes. Hurd and Kreuz" found that in qualitative experiments 3,5-dinitro-2-chlorothiophene was more reactive toward piperidine and methanolic potassium hydroxide than 2,4-dinitrochlorobenzene. A quantitative study on the reaction of the six isomeric bromonitrothiophenes with piperidine (Table V) shows that the thiophenes react about one thousand times... 

How deeply one wishes to query the mechanism depends on the detail sought. In one sense, the quest is never done a finer and finer resolution of the mechanism may be obtained with further study. For example, the rates and mechanisms of electron transfer reactions have been studied experimentally and theoretically since the 1950s. but the research continues unabated as issues of ever finer detail and broader import are examined. The same can be said of other reactions—nucleophilic substitution, hydrolysis, etc. 

Additional experimental, theoretical, and computational work is needed to acquire a complete understanding of the microscopic dynamics of gas-phase SN2 nucleophilic substitution reactions. Experimental measurements of the SN2 reaction rate versus excitation of specific vibrational modes of RY (equation 1) are needed, as are experimental studies of the dissociation and isomerization rates of the X--RY complex versus specific excitations of the complex s intermolecular and intramolecular modes. Experimental studies that probe the molecular dynamics of the [X-. r - Y]- central barrier region would also be extremely useful. 

Gas-phase nucleophilic substitution reactions of Y-benzyl chlorides and X-phenoxide or X-thiophenoxide nucleophiles have been investigated by using the PM3 semiempirical MO method. The structure of the transition state was examined. The values of the gas-phase Hammett constants px and py are much greater than for the solution reactions, but a theoretical cross-interaction constant pxy (ca —0.60 for both phenoxides and thiophenoxides) agrees well with an experimental value of —0.62 for the thiophenoxide reactions in MeOH at 20 °C. Other work by the same group has involved theoretical studies of competitive gas-phase 5 n2 and E2 reactions of NCCH2CH2CI with HO and An ab initio method at the 6-31-l-G level was... 

This order of reactivity was observ for add dedeuteration, but for acetylation, formylation, and chlorination it was slightly different thieno[3,2-h]thiophene (2) > thieno[2,3-h]thiophene (1) > thiophene thieno[3,4-6]thiophene (3) was not studied. A substantially greater discrepancy between theoretical and experimental data was observed for nucleophilic substitution from the data on base dedeuteration and competitive metalation reactions/ the order of decreasing reactivity was as follows thieno[2,3-h]thiophene (1) > thieno[3,2-h]thiophene (2) > thiophene. To a certain extent this may be explained by differences in the mechanism of metalation and deuterium exchange with a base. A discrepancy between calculation and experiment was also found for free-radical substitution. ... 

The alkaline hydrolysis of phosphonium salts has been particularly studied from a theoretical point of view as a model for nucleophilic substitution reactions on tetracoor-dinated phosphorus. However, it also has interesting applications, since it corresponds... 

Wu, Y.-D. Tucker, J. A. Houk, K. N. Stereoselectivities of nucleophilic additions to cyclohexanones substituted by polar groups. Experimental investigation of reductions of trans-decalones and theoretical studies of cyclohexanone reductions. The influence of remote electrostatic effects, J. Am. Chem. Soc. 1991,113, 5018-5027. 

The use of solvent isotope effects in studies of reaction mechanism and the theoretical interpretation of the kinetic effect of replacing H2 O by D20 have been thoroughly described [122, 123, 204, 211], Results for reactions involving proton transfer to and from carbon [122, 123, 204] have played a major role in the development of the fractionation factor theory for explaining solvent isotope effects, but other reactions [211(b), 211(c)], for example, nucleophilic substitution at saturated carbon, have also been well studied. In this section it will be shown how detailed information about a proton transfer transition state can be obtained by studying the solvent isotope effect for a reaction with known mechanism. Reactions with the A—SE2 mechanism will be discussed since this probably represents the most widely studied example of the application of solvent isotope effects in proton transfer to and from carbon [42, 47, 122,123, 204, 211(a), 212],... 

Various theoretical studies (2, 3) reveal that nucleophilic substitution on silicon always proceeds through a five-coordinate silicon adduct intermediate. Thus the Sn2 mechanism on Si never resembles that of carbon. 

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